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The comprehensive landscape of miR-34a in cancer research

  • Non-Thematic Review
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

MicroRNA-34 (miR-34) plays central roles in human diseases, especially cancers. Inactivation of miR-34 is detected in cancer cell lines and tumor tissues versus normal controls, implying its potential tumor-suppressive effect. Clinically, miR-34 has been identified as promising prognostic indicators for various cancers. In fact, members of the miR-34 family, especially miR-34a, have been convincingly proved to affect almost the whole cancer progression process. Here, a total of 512 (miR-34a, 10/21), 85 (miR-34b, 10/16), and 114 (miR-34c, 10/14) putative targets of miR-34a/b/c are predicted by at least ten miRNA databases, respectively. These targets are further analyzed in gene ontology (GO), KEGG pathway, and the Reactome pathway dataset. The results suggest their involvement in the regulation of signal transduction, macromolecule metabolism, and protein modification. Also, the targets are implicated in critical signaling pathways, such as MAPK, Notch, Wnt, PI3K/AKT, p53, and Ras, as well as apoptosis, cell cycle, and EMT-related pathways. Moreover, the upstream regulators of miR-34a, mainly including transcription factors (TFs), lncRNAs, and DNA methylation, will be summarized. Meanwhile, the potential TF upstream of miR-34a/b/c will be predicted by PROMO, JASPAR, Animal TFDB 3.0, and GeneCard databases. Notably, miR-34a is an attractive target for certain cancers. In fact, miR-34a-based systemic delivery combined with chemotherapy or radiotherapy can more effectively control tumor progression. Collectively, this review will provide a panorama for miR-34a in cancer research.

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Abbreviations

TFs:

transcription factors

EMT:

epithelial-mesenchymal transition

NACT:

neoadjuvant chemotherapy

HCC:

hepatocellular carcinoma

NSCLC:

non-small cell lung carcinoma

PCa:

prostate cancer

CRC:

colorectal cancer

DMPM:

diffuse malignant peritoneal mesothelioma

TNBC:

triple-negative breast cancer

PTX:

paclitaxel

CYA:

cyclopamine

ADR:

adriamycin

YY1:

Yin Yang 1

CCNE1:

cyclin E1

LDHA:

lactate dehydrogenase A

DLL1:

delta-like1

EHCC:

extrahepatic cholangiocarcinoma

NPC:

nasopharyngeal carcinoma

ACC:

adrenocortical carcinoma

BLCA:

bladder urothelial carcinoma

BRCA:

breast invasive carcinoma

CESC:

cervical squamous cell carcinoma and endocervical adenocarcinoma

CHOL:

cholangiocarcinoma

COAD:

colon adenocarcinoma

DLBC/DLBCL:

lymphoid neoplasm diffuse large B cell lymphoma

ESCA:

esophageal carcinoma

ESCC:

esophageal squamous cell carcinoma

GBM:

glioblastoma multiforme

HNSC:

head and neck squamous cell carcinoma

KICH:

kidney chromophobe

KIRC:

kidney renal clear cell carcinoma

KIRP:

kidney renal papillary cell carcinoma

LAML/AML:

acute myeloid leukemia

LGG:

brain lower grade glioma

LIHC:

liver hepatocellular carcinoma

LUAD:

lung adenocarcinoma

LUSC:

lung squamous cell carcinoma

MESO:

mesothelioma

OV:

ovarian serous cystadenocarcinoma

PAAD:

pancreatic adenocarcinoma

PCPG:

pheochromocytoma and paraganglioma

PRAD:

prostate adenocarcinoma

READ:

rectum adenocarcinoma

SARC:

sarcoma

SKCM:

skin cutaneous melanoma

STAD:

stomach adenocarcinoma

TGCT:

testicular germ cell tumors

THCA:

thyroid carcinoma

THYM:

thymoma

UCEC:

uterine corpus endometrial carcinoma

UCS:

uterine carcinosarcoma

UVM:

uveal melanoma

References

  1. Jiang, L., & Hermeking, H. (2017). miR-34a and miR-34b/c suppress intestinal tumorigenesis. Cancer Research, 77, 2746–2758.

    Article  CAS  PubMed  Google Scholar 

  2. Kennerdell, J. R., Liu, N., & Bonini, N. M. (2018). MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging. Nature Communications, 9, 4188–4200.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Liu, N., Landreh, M., Cao, K., Abe, M., Hendriks, G. J., Kennerdell, J. R., et al. (2012). The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature, 482, 519–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu, Q., Seeger, F. H., Castillo, J., Iekushi, K., Boon, R. A., Farcas, R., et al. (2012). Micro-RNA-34a contributes to the impaired function of bone marrow-derived mononuclear cells from patients with cardiovascular disease. Journal of the American College of Cardiology, 59, 2107–2117.

    Article  CAS  PubMed  Google Scholar 

  5. Di Martino, M. T., Leone, E., Amodio, N., Foresta, U., Lionetti, M., Pitari, M. R., et al. (2012). Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: In vitro and in vivo evidence. Clinical Cancer Research, 18, 6260–6270.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Zhang, L., Liao, Y., & Tang, L. (2019). MicroRNA-34 family: A potential tumor suppressor and therapeutic candidate in cancer. Journal of Experimental & Clinical Cancer Research, 38, 53–65.

    Article  Google Scholar 

  7. Liu, C., Kelnar, K., Liu, B., Chen, X., Calhoun-Davis, T., Li, H., et al. (2011). The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nature Medicine, 17, 211–215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lou, W., Chen, Q., Ma, L., Liu, J., Yang, Z., Shen, J., et al. (2013). Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model. Journal of Molecular Medicine, 91, 715–725.

    Article  CAS  PubMed  Google Scholar 

  9. Lin, X., Chen, W., Wei, F., Zhou, B. P., Hung, M. C., & Xie, X. (2017). Nanoparticle delivery of miR-34a eradicates long-term-cultured breast cancer stem cells via targeting C22ORF28 directly. Theranostics, 7, 4805–4824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Scognamiglio, I., Di Martino, M. T., Campani, V., Virgilio, A., Galeone, A., Gullà, A., et al. (2014). Transferrin-conjugated SNALPs encapsulating 2′-O-methylated miR-34a for the treatment of multiple myeloma. BioMed Research International, 2014, 217365–217372.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kasinski, A. L., Kelnar, K., Stahlhut, C., Orellana, E., Zhao, J., Shimer, E., et al. (2015). A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer. Oncogene, 34, 3547–3555.

    Article  CAS  PubMed  Google Scholar 

  12. Tivnan, A., Orr, W. S., Gubala, V., Nooney, R., Williams, D. E., McDonagh, C., et al. (2012). Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles. PLoS One, 7, e38129–e38140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pramanik, D., Campbell, N. R., Karikari, C., Chivukula, R., Kent, O. A., Mendell, J. T., et al. (2011). Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Molecular Cancer Therapeutics, 10, 1470–1480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tiram, G., Segal, E., Krivitsky, A., Shreberk-Hassidim, R., Ferber, S., Ofek, P., et al. (2016). Identification of dormancy-associated microRNAs for the design of osteosarcoma-targeted dendritic polyglycerol nanopolyplexes. ACS Nano, 10, 2028–2045.

    Article  CAS  PubMed  Google Scholar 

  15. Ofek, P., Calderón, M., Mehrabadi, F. S., Krivitsky, A., Ferber, S., Tiram, G., et al. (2016). Restoring the oncosuppressor activity of microRNA-34a in glioblastoma using a polyglycerol-based polyplex. Nanomedicine, 12, 2201–2214.

    Article  CAS  PubMed  Google Scholar 

  16. Wang, S., Cao, M., Deng, X., Xiao, X., Yin, Z., Hu, Q., et al. (2015). Degradable hyaluronic acid/protamine sulfate interpolyelectrolyte complexes as miRNA-delivery nanocapsules for triple-negative breast cancer therapy. Advanced Healthcare Materials, 4, 281–290.

    Article  CAS  PubMed  Google Scholar 

  17. Shatsberg, Z., Zhang, X., Ofek, P., Malhotra, S., Krivitsky, A., Scomparin, A., et al. (2016). Functionalized nanogels carrying an anticancer microRNA for glioblastoma therapy. Journal of Controlled Release, 239, 159–168.

    Article  CAS  PubMed  Google Scholar 

  18. Jang, E., Kim, E., Son, H. Y., Lim, E. K., Lee, H., Choi, Y., et al. (2016). Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. Biomaterials, 105, 12–24.

    Article  CAS  PubMed  Google Scholar 

  19. Chen, W., Liu, Y., Liang, X., Huang, Y., & Li, Q. (2017). Chondroitin sulfate-functionalized polyamidoamine as a tumor-targeted carrier for miR-34a delivery. Acta Biomaterialia, 57, 238–250.

    Article  CAS  PubMed  Google Scholar 

  20. Li, Y., Zhang, J., Zhang, L., Si, M., Yin, H., & Li, J. (2013). Diallyl trisulfide inhibits proliferation, invasion and angiogenesis of osteosarcoma cells by switching on suppressor microRNAs and inactivating of Notch-1 signaling. Carcinogenesis, 34, 1601–1610.

    Article  CAS  PubMed  Google Scholar 

  21. Xiao, X., Chen, B., Liu, X., Liu, P., Zheng, G., Ye, F., et al. (2014). Diallyl disulfide suppresses SRC/Ras/ERK signaling-mediated proliferation and metastasis in human breast cancer by up-regulating miR-34a. PLoS One, 9, e112720–e112726.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Guo, J., Li, W., Shi, H., Xie, X., Li, L., Tang, H., et al. (2013). Synergistic effects of curcumin with emodin against the proliferation and invasion of breast cancer cells through upregulation of miR-34a. Molecular and Cellular Biochemistry, 382, 103–111.

    Article  CAS  PubMed  Google Scholar 

  23. Norouzi, S., Majeed, M., Pirro, M., Generali, D., & Sahebkar, A. (2018). Curcumin as an adjunct therapy and microRNA modulator in breast cancer. Current Pharmaceutical Design, 24, 171–177.

    Article  CAS  PubMed  Google Scholar 

  24. Kang, J., Kim, E., Kim, W., Seong, K. M., Youn, H., Kim, J. W., et al. (2013). Rhamnetin and cirsiliol induce radiosensitization and inhibition of epithelial-mesenchymal transition (EMT) by miR-34a-mediated suppression of Notch-1 expression in non-small cell lung cancer cell lines. The Journal of Biological Chemistry, 288, 27343–27357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jiang, Z. Q., Li, M. H., Qin, Y. M., Jiang, H. Y., Zhang, X., & Wu, M. H. (2018). Luteolin inhibits tumorigenesis and induces apoptosis of non-small cell lung cancer cells via regulation of microRNA-34a-5p. International Journal of Molecular Sciences, 19, 447–464.

    Article  PubMed Central  CAS  Google Scholar 

  26. Zhou, B., Yi, H., Tan, J., Wu, Y., Liu, G., & Qiu, Z. (2015). Anti-proliferative effects of polyphenols from pomegranate rind (Punica granatum L.) on EJ bladder cancer cells via regulation of p53/miR-34a axis. Phytotherapy Research, 29, 415–422.

    Article  CAS  PubMed  Google Scholar 

  27. Nadal, E., Chen, G., Gallegos, M., Lin, L., Ferrer-Torres, D., Truini, A., et al. (2013). Epigenetic inactivation of microRNA-34b/c predicts poor disease-free survival in early-stage lung adenocarcinoma. Clin Cancer Re, 19, 6842–6852.

    Article  CAS  Google Scholar 

  28. Deng, X., Cao, M., Zhang, J., Hu, K., Yin, Z., Zhou, Z., et al. (2014). Hyaluronic acid-chitosan nanoparticles for co-delivery of MiR-34a and doxorubicin in therapy against triple negative breast cancer. Biomaterials, 35, 4333–4344.

    Article  CAS  PubMed  Google Scholar 

  29. Yao, C., Liu, J., Wu, X., Tai, Z., Gao, Y., Zhu, Q., et al. (2016). Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy. Journal of Controlled Release, 232, 203–214.

    Article  CAS  PubMed  Google Scholar 

  30. Wang, Y., Chen, J., Liang, X., Han, H., Wang, H., & Yang, Y. (2017). An ATP-responsive codelivery system of doxorubicin and MiR-34a to synergistically inhibit cell proliferation and migration. Molecular Pharmaceutics, 14, 2323–2332.

    Article  CAS  PubMed  Google Scholar 

  31. Shi, S., Han, L., Deng, L., Zhang, Y., Shen, H., Gong, T., et al. (2014). Dual drugs (microRNA-34a and paclitaxel)-loaded functional solid lipid nanoparticles for synergistic cancer cell suppression. Journal of Controlled Release, 194, 228–237.

    Article  CAS  PubMed  Google Scholar 

  32. Gibori, H., Eliyahu, S., Krivitsky, A., Ben-Shushan, D., Epshtein, Y., Tiram, G., et al. (2018). (2018). Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer. Nature Communications, 9, 16–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Li, L., Yuan, L., Luo, J., Gao, J., Guo, J., & Xie, X. (2013). MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clinical and Experimental Medicine, 13, 109–117.

    Article  PubMed  CAS  Google Scholar 

  34. Yang, S., Li, Y., Gao, J., Zhang, T., Li, S., Luo, A., et al. (2013). MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene, 32, 4294–4303.

    Article  CAS  PubMed  Google Scholar 

  35. Luo, D., Wilson, J. M., Harvel, N., Liu, J., Pei, L., Huang, S., et al. (2013). A systematic evaluation of miRNA:mRNA interactions involved in the migration and invasion of breast cancer cells. Journal of Translational Medicine, 11, 57–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Frères, P., Josse, C., Bovy, N., Boukerroucha, M., Struman, I., Bours, V., et al. (2015). Neoadjuvant chemotherapy in breast cancer patients induces miR-34a and miR-122 expression. Journal of Cellular Physiology, 230, 473–481.

    Article  PubMed  CAS  Google Scholar 

  37. Imani, S., Zhang, X., Hosseinifard, H., Fu, S., & Fu, J. (2017). The diagnostic role of microRNA-34a in breast cancer: A systematic review and meta-analysis. Oncotarget, 8, 23177–23187.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Agarwal, S., Hanna, J., Sherman, M. E., Figureueroa, J., & Rimm, D. L. (2015). Quantitative assessment of miR34a as an independent prognostic marker in breast cancer. British Journal of Cancer, 112, 61–68.

    Article  CAS  PubMed  Google Scholar 

  39. Liu, B., Su, F., Li, Y., Qi, X., Liu, X., Liang, W., et al. (2017). Changes of serum miR34a expression during neoadjuvant chemotherapy predict the treatment response and prognosis in stage II/III breast cancer. Biomedicine & Pharmacotherapy, 88, 911–917.

    Article  CAS  Google Scholar 

  40. Roth, C., Rack, B., Müller, V., Janni, W., Pantel, K., & Schwarzenbach, H. (2010). Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Research, 12, R90–R97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Eichelser, C., Flesch-Janys, D., Chang-Claude, J., Pantel, K., & Schwarzenbach, H. (2013). Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR-34a, miR-155, and miR-373 in human breast cancer development and progression. Clinical Chemistry, 59, 1489–1496.

    Article  CAS  PubMed  Google Scholar 

  42. Chiu, L. Y., Kishnani, P. S., Chuang, T. P., Tang, C. Y., Liu, C. Y., Bali, D., et al. (2014). Identification of differentially expressed microRNAs in human hepatocellular adenoma associated with type I glycogen storage disease: A potential utility as biomarkers. Journal of Gastroenterology, 49, 1274–1284.

    Article  CAS  PubMed  Google Scholar 

  43. Mizuguchi, Y., Mishima, T., Yokomuro, S., Arima, Y., Kawahigashi, Y., Shigehara, K., et al. (2011). Sequencing and bioinformatics-based analyses of the microRNA transcriptome in hepatitis B-related hepatocellular carcinoma. PLoS One, 6, e15304–e15314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Xu, X., Chen, W., Miao, R., Zhou, Y., Wang, Z., Zhang, L., et al. (2015). miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway. Oncotarget, 6, 3988–4004.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Dang, Y., Luo, D., Rong, M., & Chen, G. (2013). Underexpression of miR-34a in hepatocellular carcinoma and its contribution towards enhancement of proliferating inhibitory effects of agents targeting c-MET. PLoS One, 8, e61054–e61064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ren, F. H., Yang, H., He, R. Q., Lu, J. N., Lin, X. G., Liang, H. W., et al. (2018). Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma. BMC Cancer, 18, 12–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Li, N., Fu, H., Tie, Y., Hu, Z., Kong, W., Wu, Y., et al. (2009). miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Letters, 275, 44–53.

    Article  CAS  PubMed  Google Scholar 

  48. Li, X., Lu, P., Li, B., Yang, R., Chu, Y., Zhang, Z., et al. (2016). Sensitization of hepatocellular carcinoma cells to irradiation by miR-34a through targeting lactate dehydrogenase-A. Molecular Medicine Reports, 13, 3661–3667.

    Article  CAS  PubMed  Google Scholar 

  49. Xiang, Z. L., Zhao, X. M., Zhang, L., Yang, P., Fan, J., Tang, Z. Y., et al. (2016). MicroRNA-34a expression levels in serum and intratumoral tissue can predict bone metastasis in patients with hepatocellular carcinoma. Oncotarget, 7, 87246–87256.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Tian, Y. W., Shen, Q., Jiang, Q. F., Wang, Y. X., Li, K., & Xue, H. Z. (2017). Decreased levels of miR-34a and miR-217 act as predictor biomarkers of aggressive progression and poor prognosis in hepatocellular carcinoma. Minerva Medica, 108, 108–113.

    Article  PubMed  Google Scholar 

  51. Pineau, P., Volinia, S., McJunkin, K., Marchio, A., Battiston, C., Terris, B., et al. (2010). miR-221 overexpression contributes to liver tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 107, 264–269.

    Article  CAS  PubMed  Google Scholar 

  52. Gougelet, A., Sartor, C., Bachelot, L., Godard, C., Marchiol, C., Renault, G., et al. (2016). Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations. Gut, 65, 1024–1034.

    Article  CAS  PubMed  Google Scholar 

  53. Hu, Y., Pu, Q., Cui, B., & Lin, J. (2015). MicroRNA-34a inhibits tumor invasion and metastasis in gastric cancer by targeting Tgif2. International Journal of Clinical and Experimental Pathology, 8, 8921–8928.

    PubMed  PubMed Central  Google Scholar 

  54. Cao, W., Yang, W., Fan, R., Li, H., Jiang, J., Geng, M., et al. (2014). miR-34a regulates cisplatin-induce gastric cancer cell death by modulating PI3K/AKT/survivin pathway. Tumour Biology, 35, 1287–1295.

    Article  CAS  PubMed  Google Scholar 

  55. Peng, Y., Guo, J. J., Liu, Y. M., & Wu, X. L. (2014). MicroRNA-34A inhibits the growth, invasion and metastasis of gastric cancer by targeting PDGFR and MET expression. Bioscience Reports, 34, e00112–e00122.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Wang, A. M., Huang, T. T., Hsu, K. W., Huang, K. H., Fang, W. L., Yang, M. H., et al. (2014). Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis. Oncotarget, 5, 5002–5016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang, Z., Kong, Y., Yang, W., Ma, F., Zhang, Y., Ji, S., et al. (2016). Upregulation of microRNA-34a enhances the DDP sensitivity of gastric cancer cells by modulating proliferation and apoptosis via targeting MET. Oncology Reports, 36, 2391–2397.

    Article  CAS  PubMed  Google Scholar 

  58. Deng, X., Zheng, H., Li, D., Xue, Y., Wang, Q., Yan, S., et al. (2018). MicroRNA-34a regulates proliferation and apoptosis of gastric cancer cells by targeting silent information regulator 1. Experimental and Therapeutic Medicine, 15, 3705–3714.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhou, Y., Ding, B. Z., Lin, Y. P., & Wang, H. B. (2018). MiR-34a, as a suppressor, enhance the susceptibility of gastric cancer cell to luteolin by directly targeting HK1. Gene, 644, 56–65.

    Article  CAS  PubMed  Google Scholar 

  60. Zhou, Y., Huang, T., Siu, H. L., Wong, C. C., Dong, Y., Wu, F., et al. (2017). IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis. Molecular Cancer, 16, 77–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Li, Y. L., Liu, X. M., Zhang, C. Y., Zhou, J. B., Shao, Y., Liang, C., et al. (2017). MicroRNA-34a/EGFR axis plays pivotal roles in lung tumorigenesis. Oncogenesis, 6, e372–e382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mudduluru, G., Ceppi, P., Kumarswamy, R., Scagliotti, G. V., Papotti, M., & Allgayer, H. (2011). Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene, 30, 2888–2899.

    Article  CAS  PubMed  Google Scholar 

  63. Song, C., Lu, P., Sun, G., Yang, L., Wang, Z., & Wang, Z. (2017). miR-34a sensitizes lung cancer cells to cisplatin via p53/miR-34a/MYCN axis. Biochemical and Biophysical Research Communications, 482, 22–27.

    Article  CAS  PubMed  Google Scholar 

  64. Lin, X., Lin, B. W., Chen, X. L., Zhang, B. L., Xiao, X. J., Shi, J. S., et al. (2017). PAI-1/PIAS3/Stat3/miR-34a forms a positive feedback loop to promote EMT-mediated metastasis through Stat3 signaling in non-small cell lung cancer. Biochemical and Biophysical Research Communications, 493, 1464–1470.

    Article  CAS  PubMed  Google Scholar 

  65. Gallardo, E., Navarro, A., Viñolas, N., Marrades, R. M., Diaz, T., Gel, B., et al. (2009). miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer. Carcinogenesis, 30, 1903–1909.

    Article  CAS  PubMed  Google Scholar 

  66. Zhao, K., Cheng, J., Chen, B., Liu, Q., Xu, D., & Zhang, Y. (2017). Circulating microRNA-34 family low expression correlates with poor prognosis in patients with non-small cell lung cancer. Journal of Thoracic Disease, 9, 3735–3746.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kashat, M., Azzouz, L., Sarkar, S. H., Kong, D., Li, Y., & Sarkar, F. H. (2012). Inactivation of AR and Notch-1 signaling by miR-34a attenuates prostate cancer aggressiveness. American Journal of Translational Research, 4, 432–442.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Song, C. J., Chen, H., Chen, L. Z., Ru, G. M., Guo, J. J., & Ding, Q. N. (2018). The potential of microRNAs as human prostate cancer biomarkers: A meta-analysis of related studies. Journal of Cellular Biochemistry, 119, 2763–2786.

    Article  CAS  PubMed  Google Scholar 

  69. Kumar, B., Yadav, A., Lang, J., Teknos, T. N., & Kumar, P. (2012). Dysregulation of microRNA-34a expression in head and neck squamous cell carcinoma promotes tumor growth and tumor angiogenesis. PLoS One, 7, e37601–e37613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nugent, M., Miller, N., & Kerin, M. J. (2012). Circulating miR-34a levels are reduced in colorectal cancer. Journal of Surgical Oncology, 106, 947–952.

    Article  CAS  PubMed  Google Scholar 

  71. Zhang, D., Zhou, J., & Dong, M. (2014). Dysregulation of microRNA-34a expression in colorectal cancer inhibits the phosphorylation of FAK via VEGF. Digestive Diseases and Sciences, 59, 958–967.

    Article  CAS  PubMed  Google Scholar 

  72. Yu, G., Yao, W., Xiao, W., Li, H., Xu, H., & Lang, B. (2014). MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44. Journal of Experimental & Clinical Cancer Research, 33, 779–791.

    Article  Google Scholar 

  73. Yang, L., Song, X., Zhu, J., Li, M., Ji, Y., Wu, F., et al. (2017). Tumor suppressor microRNA-34a inhibits cell migration and invasion by targeting MMP-2/MMP-9/FNDC3B in esophageal squamous cell carcinoma. International Journal of Oncology, 51, 378–388.

    Article  CAS  PubMed  Google Scholar 

  74. Li, Y., Guessous, F., Zhang, Y., Dipierro, C., Kefas, B., Johnson, E., et al. (2009). MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Research, 69, 7569–7576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Dong, P., Xiong, Y., Watari, H., Hanley, S. J., Konno, Y., Ihira, K., et al. (2016). MiR-137 and miR-34a directly target Snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells. Journal of Experimental & Clinical Cancer Research, 35, 132–140.

    Article  CAS  Google Scholar 

  76. Corney, D. C., Hwang, C. I., Matoso, A., Vogt, M., Flesken-Nikitin, A., Godwin, A. K., et al. (2010). Frequent downregulation of miR-34 family in human ovarian cancers. Clinical Cancer Research, 16, 1119–1128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Liu, J., Ma, L., Li, C., Zhang, Z., Yang, G., & Zhang, W. (2013). Tumor-targeting TRAIL expression mediated by miRNA response elements suppressed growth of uveal melanoma cells. Molecular Oncology, 7, 1043–1055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Marino, M. T., Grilli, A., Baricordi, C., Manara, M. C., Ventura, S., Pinca, R. S., et al. (2014). Prognostic significance of miR-34a in Ewing sarcoma is associated with cyclin D1 and ki-67 expression. Annals of Oncology, 25, 2080–2086.

    Article  CAS  PubMed  Google Scholar 

  79. Chen, L., Yang, C., Feng, J., Liu, X., Tian, Y., Zhao, L., et al. (2017). Clinical significance of miR-34a expression in thyroid diseases - An (18)F-FDG PET-CT study. Cancer Management and Research, 9, 903–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Toraih, E. A., & Ibrahiem, A. T. (2017). MicroRNA-34a: A key regulator in the hallmarks of renal cell carcinoma. Oxidative Medicine and Cellular Longevity, 2017, 3269379–3269390.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Vychytilova-Faltejskova, P., Kiss, I., Klusova, S., Hlavsa, J., Prochazka, V., Kala, Z., et al. (2015). MiR-21, miR-34a,miR-198 and miR-217 as diagnostic and prognostic biomarkers for chronic pancreatitis and pancreatic ductal adenocarcinoma. Diagnostic Pathology, 10, 38–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Wang, X., Li, J., Dong, K., Lin, F., Long, M., Ouyang, Y., et al. (2015). Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cellular Signalling, 27, 443–452.

    Article  CAS  PubMed  Google Scholar 

  83. Hashemi, M., Bahari, G., Naderi, M., Sadeghi-Bojd, S., & Taheri, M. (2016). Pri-miR-34b/c rs4938723 polymorphism is associated with the risk of childhood acute lymphoblastic leukemia. Cancer Genetics, 209, 493–496.

    Article  CAS  PubMed  Google Scholar 

  84. Tong, N., Chu, H., Wang, M., Xue, Y., Du, M., Lu, L., et al. (2016). Pri-miR-34b/c rs4938723 polymorphism contributes to acute lymphoblastic leukemia susceptibility in Chinese children. Leukemia & Lymphoma, 57, 1436–1441.

    Article  CAS  Google Scholar 

  85. He, J., Zou, Y., Liu, X., Zhu, J., Zhang, J., Zhang, R., et al. (2018). Association of common genetic variants in pre-microRNAs and neuroblastoma susceptibility: A two-center study in Chinese children. Molecular Therapy--Nucleic Acids, 11, 1–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Li, L., Zhu, J., Lu, T., Liu, W., Tang, J., Zhang, J., et al. (2019). Association of miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms with neuroblastoma susceptibility: Evidence from seven centers. Translational Oncology, 12, 1282–1288.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Li, Y., Zhuo, Z. J., Zhou, H., Liu, J., Xiao, Z., Xiao, Y., et al. (2019). miR-34b/c rs4938723 T>C decreases neuroblastoma risk: A replication study in the Hunan children. Disease Markers, 2019, 6514608–6514615.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Liu, P., Zhuo, Z. J., Zhu, J., Yang, Z., Xin, Y., Li, S., et al. (2020). Association of TP53 rs1042522 C>G and miR-34b/c rs4938723 T>C polymorphisms with hepatoblastoma susceptibility: A seven-center case-control study. The Journal of Gene Medicine, 22, e3182–e3189.

    Article  CAS  PubMed  Google Scholar 

  89. Jiao, C., Zhu, A., Jiao, X., Ge, J., & Xu, X. (2016). Combined low miR-34s are associated with unfavorable prognosis in children with hepatoblastoma: A Chinese population-based study. Journal of Pediatric Surgery, 51, 1355–1361.

    Article  PubMed  Google Scholar 

  90. Karami, A., Sadeghian, M., Azizi, M., & Asaadi, T. G. (2019). Aberrant promoter hypermethylation of Mir34a and Mir200b Genes in pediatric acute lymphoblastic leukemia. Iranian Journal of Pediatrics, 29, e89226–e89232.

    Article  Google Scholar 

  91. Cao, L., Wang, N., Pan, J., Hu, S., Zhao, W., He, H., et al. (2016). Clinical significance of microRNA-34b expression in pediatric acute leukemia. Molecular Medicine Reports, 13, 2777–2784.

    Article  CAS  PubMed  Google Scholar 

  92. Thor, T., Künkele, A., Pajtler, K. W., Wefers, A. K., Stephan, H., Mestdagh, P., et al. (2015). MiR-34a deficiency accelerates medulloblastoma formation in vivo. International Journal of Cancer, 136, 2293–2303.

    Article  CAS  PubMed  Google Scholar 

  93. Weeraratne, S. D., Amani, V., Neiss, A., Teider, N., Scott, D. K., Pomeroy, S. L., et al. (2011). miR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma. Neuro-oncology, 13, 165–175.

    Article  CAS  PubMed  Google Scholar 

  94. Bettinsoli, P., Ferrari-Toninelli, G., Bonini, S. A., Prandelli, C., & Memo, M. (2017). Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma. BMC Cancer, 17, 352–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Darrigo Júnior, L. G., Lira, R. C. P., Fedatto, P. F., Marco Antonio, D. S., Valera, E. T., Aguiar, S., et al. (2019). MicroRNA profile of pediatric pilocytic astrocytomas identifies two tumor-specific signatures when compared to non-neoplastic white matter. Journal of Neuro-Oncology, 141, 373–382.

    Article  PubMed  Google Scholar 

  96. Birks, D. K., Barton, V. N., Donson, A. M., Handler, M. H., Vibhakar, R., & Foreman, N. K. (2011). Survey of MicroRNA expression in pediatric brain tumors. Pediatric Blood & Cancer, 56, 211–216.

    Article  Google Scholar 

  97. Costa, F. F., Bischof, J. M., Vanin, E. F., Lulla, R. R., Wang, M., Sredni, S. T., et al. (2011). Identification of microRNAs as potential prognostic markers in ependymoma. PLoS One, 6, e25114–e25124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bayraktar, R., Ivan, C., Bayraktar, E., Kanlikilicer, P., Kabil, N. N., Kahraman, N., et al. (2018). Dual suppressive effect of miR-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion. Clinical Cancer Research, 24, 4225–4241.

    Article  CAS  PubMed  Google Scholar 

  99. Liu, K., Huang, J., Xie, M., Yu, Y., Zhu, S., Kang, R., et al. (2014). MIR34A regulates autophagy and apoptosis by targeting HMGB1 in the retinoblastoma cell. Autophagy, 10, 442–452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Xiao, X., Huang, X., Ye, F., Chen, B., Song, C., Wen, J., et al. (2016). The miR-34a-LDHA axis regulates glucose metabolism and tumor growth in breast cancer. Scientific Reports, 6, 21735–21742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhao, G., Guo, J., Li, D., Jia, C., Yin, W., Sun, R., et al. (2013). MicroRNA-34a suppresses cell proliferation by targeting LMTK3 in human breast cancer mcf-7 cell line. DNA and Cell Biology, 32, 699–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang, Y., Zhang, X., Chao, Z., Kung, H. F., Lin, M. C., Dress, A., et al. (2017). MiR-34a modulates ErbB2 in breast cancer. Cell Biology International, 41, 93–101.

    Article  CAS  PubMed  Google Scholar 

  103. Xu, M., Li, D., Yang, C., & Ji, J. S. (2018). MicroRNA-34a inhibition of the TLR signaling pathway via CXCL10 suppresses breast cancer cell invasion and migration. Cellular Physiology and Biochemistry, 46, 1286–1304.

    Article  CAS  PubMed  Google Scholar 

  104. Park, E. Y., Chang, E., Lee, E. J., Lee, H. W., Kang, H. G., Chun, K. H., et al. (2014). Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Research, 74, 7573–7582.

    Article  CAS  PubMed  Google Scholar 

  105. Si, W., Li, Y., Shao, H., Hu, R., Wang, W., Zhang, K., et al. (2016). MiR-34a inhibits breast cancer proliferation and progression by targeting Wnt1 in Wnt/β-catenin signaling pathway. The American Journal of the Medical Sciences, 352, 191–199.

    Article  PubMed  Google Scholar 

  106. Garofalo, M., Jeon, Y. J., Nuovo, G. J., Middleton, J., Secchiero, P., Joshi, P., et al. (2013). MiR-34a/c-dependent PDGFR-α/β downregulation inhibits tumorigenesis and enhances TRAIL-induced apoptosis in lung cancer. PLoS One, 8, e67581–e67592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Han, Z., Zhang, Y., Yang, Q., Liu, B., Wu, J., Zhang, Y., et al. (2015). miR-497 and miR-34a retard lung cancer growth by co-inhibiting cyclin E1 (CCNE1). Oncotarget, 6, 13149–13163.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Zhang, H. F., Wang, Y. C., & Han, Y. D. (2018). MicroRNA-34a inhibits liver cancer cell growth by reprogramming glucose metabolism. Molecular Medicine Reports, 17, 4483–4489.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Cheng, L., Gao, S., Song, X., Dong, W., Zhou, H., Zhao, L., et al. (2016). Comprehensive N-glycan profiles of hepatocellular carcinoma reveal association of fucosylation with tumor progression and regulation of FUT8 by microRNAs. Oncotarget, 7, 61199–61214.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Yamamura, S., Saini, S., Majid, S., Hirata, H., Ueno, K., Deng, G., et al. (2012). MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells. PLoS One, 7, e29722–e29733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chakravarthi, B., Chandrashekar, D. S., Agarwal, S., Balasubramanya, S. A. H., Pathi, S. S., Goswami, M. T., et al. (2018). miR-34a regulates expression of the Stathmin-1 oncoprotein and prostate cancer progression. Molecular Cancer Research, 16, 1125–1137.

    Article  CAS  PubMed  Google Scholar 

  112. Wu, X., Zhong, D., Gao, Q., Zhai, W., Ding, Z., & Wu, J. (2013). MicroRNA-34a inhibits human osteosarcoma proliferation by downregulating ether à go-go 1 expression. International Journal of Medical Sciences, 10, 676–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Vetter, N. S., Kolb, E. A., Mills, C. C., & Sampson, V. B. (2017). The microtubule network and cell death are regulated by an miR-34a/Stathmin 1/βIII-tubulin axis. Molecular Cancer Research, 15, 953–964.

    Article  CAS  PubMed  Google Scholar 

  114. de Antonellis, P., Medaglia, C., Cusanelli, E., Andolfo, I., Liguori, L., De Vita, G., et al. (2011). MiR-34a targeting of Notch ligand delta-like 1 impairs CD15+/CD133+ tumor-propagating cells and supports neural differentiation in medulloblastoma. PLoS One, 6, e24584–e24600.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. El Bezawy, R., De Cesare, M., Pennati, M., Deraco, M., Gandellini, P., Zuco, V., et al. (2017). Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism. Journal of Hematology & Oncology, 10, 19–32.

    Article  CAS  Google Scholar 

  116. Sun, H., Tian, J., Xian, W., Xie, T., & Yang, X. (2015). miR-34a inhibits proliferation and invasion of bladder cancer cells by targeting orphan nuclear receptor HNF4G. Disease Markers, 2015, 879254–879262.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Liu, R., Xie, H., Luo, C., Chen, Z., Zhou, X., Xia, K., et al. (2015). Identification of FLOT2 as a novel target for microRNA-34a in melanoma. Journal of Cancer Research and Clinical Oncology, 141, 993–1006.

    Article  CAS  PubMed  Google Scholar 

  118. Li, S., Luo, C., Zhou, J., & Zhang, Y. (2017). MicroRNA-34a directly targets high-mobility group box 1 and inhibits the cancer cell proliferation, migration and invasion in cutaneous squamous cell carcinoma. Experimental and Therapeutic Medicine, 14, 5611–5618.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Lv, T., Song, K., Zhang, L., Li, W., Chen, Y., Diao, Y., et al. (2018). miRNA-34a decreases ovarian cancer cell proliferation and chemoresistance by targeting HDAC1. Biochemistry and Cell Biology, 96, 663–671.

    Article  CAS  PubMed  Google Scholar 

  120. Zhang, R., Su, J., Xue, S. L., Yang, H., Ju, L. L., Ji, Y., et al. (2016). HPV E6/p53 mediated down-regulation of miR-34a inhibits Warburg effect through targeting LDHA in cervical cancer. American Journal of Cancer Research, 6, 312–320.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Li, C., Wang, Y., Lu, S., Zhang, Z., Meng, H., Liang, L., et al. (2015). MiR-34a inhibits colon cancer proliferation and metastasis by inhibiting platelet-derived growth factor receptor α. Molecular Medicine Reports, 12, 7072–7078.

    Article  CAS  PubMed  Google Scholar 

  122. Wang, Z., Wang, W., Huang, K., Wang, Y., Li, J., & Yang, X. (2017). MicroRNA-34a inhibits cells proliferation and invasion by downregulating Notch1 in endometrial cancer. Oncotarget, 8, 111258–111270.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Pang, R. T., Leung, C. O., Lee, C. L., Lam, K. K., Ye, T. M., Chiu, P. C., et al. (2013). MicroRNA-34a is a tumor suppressor in choriocarcinoma via regulation of Delta-like1. BMC Cancer, 13, 25–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yang, Y., Ding, L., Guo, Z. K., Zheng, X. L., Wang, L. S., Sun, H. Y., et al. (2017). The epigenetically-regulated miR-34a targeting c-SRC suppresses RAF/MEK/ERK signaling pathway in K-562 cells. Leukemia Research, 55, 91–96.

    Article  CAS  PubMed  Google Scholar 

  125. Craig, V. J., Cogliatti, S. B., Imig, J., Renner, C., Neuenschwander, S., Rehrauer, H., et al. (2011). Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1. Blood, 117, 6227–6236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lu, G., Sun, Y., An, S., Xin, S., Ren, X., Zhang, D., et al. (2015). MicroRNA-34a targets FMNL2 and E2F5 and suppresses the progression of colorectal cancer. Experimental and Molecular Pathology, 99, 173–179.

    Article  CAS  PubMed  Google Scholar 

  127. Öner, M. G., Rokavec, M., Kaller, M., Bouznad, N., Horst, D., Kirchner, T., et al. (2018). Combined inactivation of TP53 and MIR34A promotes colorectal cancer development and progression in mice via increasing levels of IL6R and PAI1. Gastroenterology, 155, 1868–1882.

    Article  PubMed  CAS  Google Scholar 

  128. Li, H., Rokavec, M., Jiang, L., Horst, D., & Hermeking, H. (2017). Antagonistic effects of p53 and HIF1A on microRNA-34a regulation of PPP1R11 and STAT3 and hypoxia-induced epithelial to mesenchymal transition in colorectal cancer cells. Gastroenterology, 153, 505–520.

    Article  CAS  PubMed  Google Scholar 

  129. Hahn, S., Jackstadt, R., Siemens, H., Hünten, S., & Hermeking, H. (2013). SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition. The EMBO Journal, 32, 3079–3095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Siemens, H., Jackstadt, R., Kaller, M., & Hermeking, H. (2013). Repression of c-Kit by p53 is mediated by miR-34 and is associated with reduced chemoresistance, migration and stemness. Oncotarget, 4, 1399–1415.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Li, Y., Zeng, C., Hu, J., Pan, Y., Shan, Y., Liu, B., et al. (2018). Long non-coding RNA-SNHG7 acts as a target of miR-34a to increase GALNT7 level and regulate PI3K/Akt/mTOR pathway in colorectal cancer progression. Journal of Hematology & Oncology, 11, 89–105.

    Article  CAS  Google Scholar 

  132. Fujita, Y., Kojima, K., Hamada, N., Ohhashi, R., Akao, Y., Nozawa, Y., et al. (2008). Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. Biochemical and Biophysical Research Communications, 377, 114–119.

    Article  CAS  PubMed  Google Scholar 

  133. Wen, D., Peng, Y., Lin, F., Singh, R. K., & Mahato, R. I. (2017). Micellar delivery of miR-34a modulator rubone and paclitaxel in resistant prostate cancer. Cancer Research, 77, 3244–3254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Li, X. J., Ji, M. H., Zhong, S. L., Zha, Q. B., Xu, J. J., Zhao, J. H., et al. (2012). MicroRNA-34a modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1. Archives of Medical Research, 43, 514–521.

    Article  CAS  PubMed  Google Scholar 

  135. Adams, B. D., Wali, V. B., Cheng, C. J., Inukai, S., Booth, C. J., Agarwal, S., et al. (2016). miR-34a silences c-SRC to attenuate tumor growth in triple-negative breast cancer. Cancer Research, 76, 927–939.

    Article  CAS  PubMed  Google Scholar 

  136. Kang, L., Mao, J., Tao, Y., Song, B., Ma, W., Lu, Y., et al. (2015). MicroRNA-34a suppresses the breast cancer stem cell-like characteristics by downregulating Notch1 pathway. Cancer Science, 106, 700–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hao, Q., Lu, X., Liu, N., Xue, X., Li, M., Zhang, C., et al. (2013). Posttranscriptional deregulation of Src due to aberrant miR34a and miR203 contributes to gastric cancer development. BMB Reports, 46, 316–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Liu, Y. W., Sun, M., Xia, R., Zhang, E. B., Liu, X. H., Zhang, Z. H., et al. (2015). LincHOTAIR epigenetically silences miR34a by binding to PRC2 to promote the epithelial-to-mesenchymal transition in human gastric cancer. Cell Death & Disease, 6, e1802–e1810.

    Article  CAS  Google Scholar 

  139. Ahn, Y. H., Gibbons, D. L., Chakravarti, D., Creighton, C. J., Rizvi, Z. H., Adams, H. P., et al. (2012). ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. The Journal of Clinical Investigation, 122, 3170–3183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Chen, W. Y., Liu, S. Y., Chang, Y. S., Yin, J. J., Yeh, H. L., Mouhieddine, T. H., et al. (2015). MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. Oncotarget, 6, 441–457.

    Article  PubMed  Google Scholar 

  141. Liang, J., Li, Y., Daniels, G., Sfanos, K., De Marzo, A., Wei, J., et al. (2015). LEF1 targeting EMT in prostate cancer invasion is regulated by miR-34a. Molecular Cancer Research, 13, 681–688.

    Article  CAS  PubMed  Google Scholar 

  142. Nie, J., Ge, X., Geng, Y., Cao, H., Zhu, W., Jiao, Y., et al. (2015). miR-34a inhibits the migration and invasion of esophageal squamous cell carcinoma by targeting Yin Yang-1. Oncology Reports, 34, 311–317.

    Article  CAS  PubMed  Google Scholar 

  143. Bernardi, C., Soffientini, U., Piacente, F., & Tonetti, M. G. (2013). Effects of microRNAs on fucosyltransferase 8 (FUT8) expression in hepatocarcinoma cells. PLoS One, 8, e76540–e76546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Yu, G., Li, H., Wang, J., Gumireddy, K., Li, A., Yao, W., et al. (2014). miRNA-34a suppresses cell proliferation and metastasis by targeting CD44 in human renal carcinoma cells. The Journal of Urology, 192, 1229–1237.

    Article  CAS  PubMed  Google Scholar 

  145. Yan, K., Gao, J., Yang, T., Ma, Q., Qiu, X., Fan, Q., et al. (2012). MicroRNA-34a inhibits the proliferation and metastasis of osteosarcoma cells both in vitro and in vivo. PLoS One, 7, e33778–e33788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Schirmer, U., Doberstein, K., Rupp, A. K., Bretz, N. P., Wuttig, D., Kiefel, H., et al. (2014). Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma. Oncotarget, 5, 462–472.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Qiao, P., Li, G., Bi, W., Yang, L., Yao, L., & Wu, D. (2015). microRNA-34a inhibits epithelial mesenchymal transition in human cholangiocarcinoma by targeting Smad4 through transforming growth factor-beta/Smad pathway. BMC Cancer, 15, 469–481.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Huang, G., Du, M. Y., Zhu, H., Zhang, N., Lu, Z. W., Qian, L. X., et al. (2018). MiRNA-34a reversed TGF-β-induced epithelial-mesenchymal transition via suppression of SMAD4 in NPC cells. Biomedicine & Pharmacotherapy, 106, 217–224.

    Article  CAS  Google Scholar 

  149. Li, T., Li, L., Li, D., Wang, S., & Sun, J. (2015). MiR-34a inhibits oral cancer progression partially by repression of interleukin-6-receptor. International Journal of Clinical and Experimental Pathology, 8, 1364–1373.

    PubMed  PubMed Central  Google Scholar 

  150. Zhang, J., Wang, Y., Chen, X., Zhou, Y., Jiang, F., Chen, J., et al. (2015). MiR-34a suppresses amphiregulin and tumor metastatic potential of head and neck squamous cell carcinoma (HNSCC). Oncotarget, 6, 7454–7469.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Li, X., Zhao, H., Zhou, X., & Song, L. (2015). Inhibition of lactate dehydrogenase A by microRNA-34a resensitizes colon cancer cells to 5-fluorouracil. Molecular Medicine Reports, 11, 577–582.

    Article  CAS  PubMed  Google Scholar 

  152. Wu, M. Y., Fu, J., Xiao, X., Wu, J., & Wu, R. C. (2014). MiR-34a regulates therapy resistance by targeting HDAC1 and HDAC7 in breast cancer. Cancer Letters, 354, 311–319.

    Article  CAS  PubMed  Google Scholar 

  153. Kim do, Y., Park, E. Y., Chang, E., Kang, H. G., Koo, Y., Lee, E. J., et al. (2016). A novel miR-34a target, protein kinase D1, stimulates cancer stemness and drug resistance through GSK3/β-catenin signaling in breast cancer. Oncotarget, 7, 14791–14802.

    Article  PubMed  Google Scholar 

  154. Sun, C., Wang, F. J., Zhang, H. G., Xu, X. Z., Jia, R. C., Yao, L., et al. (2017). miR-34a mediates oxaliplatin resistance of colorectal cancer cells by inhibiting macroautophagy via transforming growth factor-β/Smad4 pathway. World Journal of Gastroenterology, 23, 1816–1827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Liu, X., Luo, X., Wu, Y., Xia, D., Chen, W., Fang, Z., et al. (2018). MicroRNA-34a attenuates paclitaxel resistance in prostate cancer cells via direct suppression of JAG1/Notch1 axis. Cellular Physiology and Biochemistry, 50, 261–276.

    Article  CAS  PubMed  Google Scholar 

  156. Liao, H., Xiao, Y., Hu, Y., Xiao, Y., Yin, Z., Liu, L., et al. (2016). Methylation-induced silencing of miR-34a enhances chemoresistance by directly upregulating ATG4B-induced autophagy through AMPK/mTOR pathway in prostate cancer. Oncology Reports, 35, 64–72.

    Article  CAS  PubMed  Google Scholar 

  157. Yang, F., Li, Q. J., Gong, Z. B., Zhou, L., You, N., Wang, S., et al. (2014). MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment. Technology in Cancer Research & Treatment, 13, 77–86.

    Article  CAS  Google Scholar 

  158. Wang, Y., & Wang, L. (2017). miR-34a attenuates glioma cells progression and chemoresistance via targeting PD-L1. Biotechnology Letters, 39, 1485–1492.

    Article  CAS  PubMed  Google Scholar 

  159. Li, Q. C., Xu, H., Wang, X., Wang, T., & Wu, J. (2017). miR-34a increases cisplatin sensitivity of osteosarcoma cells in vitro through up-regulation of c-Myc and Bim signal. Cancer Biomarkers, 21, 135–144.

    Article  CAS  PubMed  Google Scholar 

  160. Zhang, Q., Zhuang, J., Deng, Y., Yang, L., Cao, W., Chen, W., et al. (2017). miR34a/GOLPH3 axis abrogates urothelial bladder cancer chemoresistance via reduced cancer stemness. Theranostics, 7, 4777–4790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Liu, X., Liu, X., Wu, Y., Fang, Z., Wu, Q., Wu, C., et al. (2018). MicroRNA-34a attenuates metastasis and chemoresistance of bladder cancer cells by targeting the TCF1/LEF1 axis. Cellular Physiology and Biochemistry, 48, 87–98.

    Article  CAS  PubMed  Google Scholar 

  162. Pu, Y., Zhao, F., Li, Y., Cui, M., Wang, H., Meng, X., et al. (2017). The miR-34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene. BMC Cancer, 17, 45–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Pu, Y., Zhao, F., Wang, H., Cai, W., Gao, J., Li, Y., et al. (2016). MiR-34a-5p promotes the multi-drug resistance of osteosarcoma by targeting the CD117 gene. Oncotarget, 7, 28420–28434.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Cho, C. Y., Huang, J. S., Shiah, S. G., Chung, S. Y., Lay, J. D., Yang, Y. Y., et al. (2016). Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells. RNA, 22, 303–315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Duan, J., Zhou, K., Tang, X., Duan, J., & Zhao, L. (2016). MicroRNA-34a inhibits cell proliferation and induces cell apoptosis of glioma cells via targeting of Bcl-2. Molecular Medicine Reports, 14, 432–438.

    Article  CAS  PubMed  Google Scholar 

  166. Dong, X., Jin, Z., Chen, Y., Xu, H., Ma, C., Hong, X., et al. (2018). Knockdown of long non-coding RNA ANRIL inhibits proliferation, migration, and invasion but promotes apoptosis of human glioma cells by upregulation of miR-34a. Journal of Cellular Biochemistry, 119, 2708–2718.

    Article  CAS  PubMed  Google Scholar 

  167. Yamakuchi, M., Ferlito, M., & Lowenstein, C. J. (2008). miR-34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 105, 13421–13426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Liu, L., Ren, W., & Chen, K. (2017). MiR-34a promotes apoptosis and inhibits autophagy by targeting HMGB1 in acute myeloid leukemia cells. Cellular Physiology and Biochemistry, 41, 1981–1992.

    Article  CAS  PubMed  Google Scholar 

  169. Sun, T. Y., Xie, H. J., Li, Z., Kong, L. F., Gou, X. N., Li, D. J., et al. (2017). miR-34a regulates HDAC1 expression to affect the proliferation and apoptosis of hepatocellular carcinoma. American Journal of Translational Research, 9, 103–114.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Welch, C., Chen, Y., & Stallings, R. L. (2007). MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene, 26, 5017–5022.

    Article  CAS  PubMed  Google Scholar 

  171. Shen, Z., Zhan, G., Ye, D., Ren, Y., Cheng, L., Wu, Z., et al. (2012). MicroRNA-34a affects the occurrence of laryngeal squamous cell carcinoma by targeting the antiapoptotic gene survivin. Medical Oncology, 29, 2473–2480.

    Article  CAS  PubMed  Google Scholar 

  172. Xia, J., Duan, Q., Ahmad, A., Bao, B., Banerjee, S., Shi, Y., et al. (2012). Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells. Current Drug Targets, 13, 1750–1756.

    Article  CAS  PubMed  Google Scholar 

  173. Wang, B., Li, D., Kovalchuk, I., Apel, I. J., Chinnaiyan, A. M., Wóycicki, R. K., et al. (2018). miR-34a directly targets tRNA(i)(Met) precursors and affects cellular proliferation, cell cycle, and apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 115, 7392–7397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Zauli, G., Voltan, R., di Iasio, M. G., Bosco, R., Melloni, E., Sana, M. E., et al. (2011). miR-34a induces the downregulation of both E2F1 and B-Myb oncogenes in leukemic cells. Clinical Cancer Research, 17, 2712–2724.

    Article  CAS  PubMed  Google Scholar 

  175. Ren, J., Ding, L., Xu, Q., Shi, G., Li, X., & Li, X. (2017). LF-MF inhibits iron metabolism and suppresses lung cancer through activation of P53-miR-34a-E2F1/E2F3 pathway. Scientific Reports, 7, 749–760.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Sun, F., Fu, H., Liu, Q., Tie, Y., Zhu, J., Xing, R., et al. (2008). Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Letters, 582, 1564–1568.

    Article  CAS  PubMed  Google Scholar 

  177. Cortez, M. A., Valdecanas, D., Niknam, S., Peltier, H. J., Diao, L., Giri, U., et al. (2015). In vivo delivery of miR-34a Sensitizes lung tumors to radiation through RAD51 regulation. Molecular Therapy--Nucleic Acids, 4, e270–e278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Pieraccioli, M., Nicolai, S., Pitolli, C., Agostini, M., Antonov, A., & Malewicz, M. (2018). ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma. Proceedings of the National Academy of Sciences of the United States of America, 115, 7356–7361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Lefort, K., Brooks, Y., Ostano, P., Cario-André, M., Calpini, V., Guinea-Viniegra, J., et al. (2013). A miR-34a-SIRT6 axis in the squamous cell differentiation network. The EMBO Journal, 32, 2248–2263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Deng, J., Yang, M., Jiang, R., An, N., Wang, X., & Liu, B. (2017). Long non-coding RNA HOTAIR regulates the proliferation, self-renewal capacity, tumor formation and migration of the cancer stem-like cell (CSC) subpopulation enriched from breast cancer cells. PLoS One, 12, e0170860–e0170874.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Ma, W., Xiao, G. G., Mao, J., Lu, Y., Song, B., Wang, L., et al. (2015). Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness. Oncotarget, 6, 10432–10444.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Raver-Shapira, N., Marciano, E., Meiri, E., Spector, Y., Rosenfeld, N., Moskovits, N., et al. (2007). Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Molecular Cell, 26, 731–743.

    Article  CAS  PubMed  Google Scholar 

  183. Kim, N. H., Kim, H. S., Li, X. Y., Lee, I., Choi, H. S., Kang, S. E., et al. (2011). A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. The Journal of Cell Biology, 195, 417–433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Hwang, C. I., Matoso, A., Corney, D. C., Flesken-Nikitin, A., Körner, S., Wang, W., et al. (2011). Wild-type p53 controls cell motility and invasion by dual regulation of MET expression. Proceedings of the National Academy of Sciences of the United States of America, 108, 14240–14245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Luan, S., Sun, L., & Huang, F. (2010). MicroRNA-34a: a novel tumor suppressor in p53-mutant glioma cell line U251. Archives of Medical Research, 41, 67–74.

    Article  CAS  PubMed  Google Scholar 

  186. Xiao, Z., Li, C. H., Chan, S. L., Xu, F., Feng, L., Wang, Y., et al. (2014). A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma. Cancer Research, 74, 6236–6247.

    Article  CAS  PubMed  Google Scholar 

  187. Dijkstra, M. K., van Lom, K., Tielemans, D., Elstrodt, F., Langerak, A. W., van’t Veer, M. B., et al. (2009). 17p13/TP53 deletion in B-CLL patients is associated with microRNA-34a downregulation. Leukemia, 23, 625–627.

    Article  CAS  PubMed  Google Scholar 

  188. Choi, Y. J., Lin, C. P., Ho, J. J., He, X., Okada, N., Bu, P., et al. (2011). miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nature Cell Biology, 13, 1353–1360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Christoffersen, N. R., Shalgi, R., Frankel, L. B., Leucci, E., Lees, M., Klausen, M., et al. (2010). p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death and Differentiation, 17, 236–245.

    Article  CAS  PubMed  Google Scholar 

  190. Galtsidis, S., Logotheti, S., Pavlopoulou, A., Zampetidis, C. P., Papachristopoulou, G., Scorilas, A., et al. (2017). Unravelling a p73-regulated network: The role of a novel p73-dependent target, MIR3158, in cancer cell migration and invasiveness. Cancer Letters, 388, 96–106.

    Article  CAS  PubMed  Google Scholar 

  191. Su, X., Chakravarti, D., Cho, M. S., Liu, L., Gi, Y. J., Lin, Y. L., et al. (2010). TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature, 467, 986–990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Li, J., Wang, K., Chen, X., Meng, H., Song, M., Wang, Y., et al. (2012). Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells. BMC Molecular Biology, 13, 4–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Wang, X., Wang, C., Zhang, X., Hua, R., Gan, L., Huang, M., et al. (2016). Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. Journal of Hematology & Oncology, 9, 90–107.

    Article  CAS  Google Scholar 

  194. Pulikkan, J. A., Peramangalam, P. S., Dengler, V., Ho, P. A., Preudhomme, C., Meshinchi, S., et al. (2010). C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations. Blood, 116, 5638–5649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Peurala, H., Greco, D., Heikkinen, T., Kaur, S., Bartkova, J., Jamshidi, M., et al. (2011). MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer. PLoS One, 6, e26122–e26131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Iqbal, N., Mei, J., Liu, J., & Skapek, S. X. (2014). miR-34a is essential for p19(Arf)-driven cell cycle arrest. Cell Cycle, 13, 792–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Chen, C., Bai, L., & Cao, F. (2019). Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis. Oncogene, 38, 4527–4539.

    Article  CAS  PubMed  Google Scholar 

  198. Xu, T. P., Ma, P., Wang, W. Y., Shuai, Y., Wang, Y. F., Yu, T., et al. (2019). KLF5 and MYC modulated LINC00346 contributes to gastric cancer progression through acting as a competing endogenous RNA and indicates poor outcome. Cell Death and Differentiation, 26, 2179–2193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Siemens, H., Jackstadt, R., Hünten, S., Kaller, M., Menssen, A., Götz, U., et al. (2011). miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle, 10, 4256–4271.

    Article  CAS  PubMed  Google Scholar 

  200. Anastasiadou, E., Stroopinsky, D., Alimperti, S., Jiao, A. L., Pyzer, A. R., Cippitelli, C., et al. (2019). Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia, 33, 132–147.

    Article  CAS  PubMed  Google Scholar 

  201. Song, P. P., Ye, L. F., Zhang, C., Peng, T., & Zhou, X. H. (2016). Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p. Gene, 592, 8–14.

    Article  CAS  PubMed  Google Scholar 

  202. Liu, H., Deng, H., Zhao, Y., Li, C., & Liang, Y. (2018). LncRNA XIST/miR-34a axis modulates the cell proliferation and tumor growth of thyroid cancer through MET-PI3K-AKT signaling. Journal of Experimental & Clinical Cancer Research, 37, 279–290.

    Article  CAS  Google Scholar 

  203. Sun, N., Zhang, G., & Liu, Y. (2018). Long non-coding RNA XIST sponges miR-34a to promotes colon cancer progression via Wnt/β-catenin signaling pathway. Gene, 665, 141–148.

    Article  CAS  PubMed  Google Scholar 

  204. Sun, Z., Zhang, B., & Cui, T. (2018). Long non-coding RNA XIST exerts oncogenic functions in pancreatic cancer via miR-34a-5p. Oncology Reports, 39, 1591–1600.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Liu, F., Chen, N., Gong, Y., Xiao, R., Wang, W., & Pan, Z. (2017). The long non-coding RNA NEAT1 enhances epithelial-to-mesenchymal transition and chemoresistance via the miR-34a/c-Met axis in renal cell carcinoma. Oncotarget, 8, 62927–62938.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Luo, Y., Chen, J. J., Lv, Q., Qin, J., Huang, Y. Z., Yu, M. H., et al. (2019). Long non-coding RNA NEAT1 promotes colorectal cancer progression by competitively binding miR-34a with SIRT1 and enhancing the Wnt/β-catenin signaling pathway. Cancer Letters, 440, 11–22.

    Article  PubMed  CAS  Google Scholar 

  207. Jia, D., Niu, Y., Li, D., & Liu, Z. (2018). lncRNA C2dat1 promotes cell proliferation, migration, and invasion by targeting miR-34a-5p in osteosarcoma cells. Oncology Research, 26, 753–764.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Deng, Y., Zhao, F., Zhang, Z., Sun, F., & Wang, M. (2018). Long noncoding RNA SNHG7 promotes the tumor growth and epithelial-to-mesenchymal transition via regulation of miR-34a signals in osteosarcoma. Cancer Biotherapy & Radiopharmaceuticals, 33, 365–372.

    Article  CAS  Google Scholar 

  209. Yan, X., Zhang, D., Wu, W., Wu, S., Qian, J., Hao, Y., et al. (2017). Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a. Cancer Research, 77, 6704–6716.

    Article  CAS  PubMed  Google Scholar 

  210. Tao, F., Tian, X., Lu, M., & Zhang, Z. (2018). A novel lncRNA, Lnc-OC1, promotes ovarian cancer cell proliferation and migration by sponging miR-34a and miR-34c. Journal of Genetics and Genomics, 45, 137–145.

    Article  PubMed  Google Scholar 

  211. Xi, J., Feng, J., Zeng, S., & Huang, P. (2018). Long noncoding RNA UFC1 is activated by E2F1 and exerts oncogenic properties by functioning as a ceRNA of FOXP3. Cancer Medicine, 7, 3301–3310.

    Article  CAS  PubMed Central  Google Scholar 

  212. He, R., Liu, P., Xie, X., Zhou, Y., Liao, Q., Xiong, W., et al. (2017). circGFRA1 and GFRA1 act as ceRNAs in triple negative breast cancer by regulating miR-34a. Journal of Experimental & Clinical Cancer Research, 36, 145–156.

    Article  CAS  Google Scholar 

  213. Huang, X., Xie, X., Liu, P., Yang, L., Chen, B., Song, C., et al. (2018). Adam12 and lnc015192 act as ceRNAs in breast cancer by regulating miR-34a. Oncogene, 37, 6316–6326.

    Article  CAS  PubMed  Google Scholar 

  214. Liu, Y., Gao, S., Du, Q., & Zhao, Q. (2019). Knockdown of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 inhibits the proliferation and migration of bladder cancer cells by modulating the microRNA-34a/cyclin D1 axis. International Journal of Molecular Medicine, 43, 547–556.

    CAS  PubMed  Google Scholar 

  215. Wang, L., Bu, P., Ai, Y., Srinivasan, T., Chen, H. J., Xiang, K., et al. (2016). A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division. Elife, 5, e14620–e14635.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Fang, C., Qiu, S., Sun, F., Li, W., Wang, Z., Yue, B., et al. (2017). Long non-coding RNA HNF1A-AS1 mediated repression of miR-34a/SIRT1/p53 feedback loop promotes the metastatic progression of colon cancer by functioning as a competing endogenous RNA. Cancer Letters, 410, 50–62.

    Article  CAS  PubMed  Google Scholar 

  217. Li, C. H., Xiao, Z., Tong, J. H., To KF, Fang, X., Cheng, A. S., et al. (2017). EZH2 coupled with HOTAIR to silence MicroRNA-34a by the induction of heterochromatin formation in human pancreatic ductal adenocarcinoma. International Journal of Cancer, 140, 120–129.

    Article  CAS  PubMed  Google Scholar 

  218. Li, Q., Song, W., & Wang, J. (2019). TUG1 confers adriamycin resistance in acute myeloid leukemia by epigenetically suppressing miR-34a expression via EZH2. Biomedicine & Pharmacotherapy, 109, 1793–1801.

    Article  CAS  Google Scholar 

  219. Fu, Y., Li, C., Luo, Y., Li, L., Liu, J., & Gui, R. (2018). Silencing of long non-coding RNA MIAT sensitizes lung cancer cells to gefitinib by epigenetically regulating miR-34a. Frontiers in Pharmacology, 9, 82–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Lodygin, D., Tarasov, V., Epanchintsev, A., Berking, C., Knyazeva, T., Körner, H., et al. (2008). Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle, 7, 2591–2600.

    Article  CAS  PubMed  Google Scholar 

  221. Chen, X., Hu, H., Guan, X., Xiong, G., Wang, Y., Wang, K., et al. (2012). CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. International Journal of Cancer, 130, 1607–1613.

    Article  CAS  PubMed  Google Scholar 

  222. Chim, C. S., Wan, T. S., Wong, K. Y., Fung, T. K., Drexler, H. G., & Wong, K. F. (2011). Methylation of miR-34a, miR-34b/c, miR-124-1 and miR-203 in Ph-negative myeloproliferative neoplasms. Journal of Translational Medicine, 9, 197–206.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Chim, C. S., Wong, K. Y., Qi, Y., Loong, F., Lam, W. L., Wong, L. G., et al. (2010). Epigenetic inactivation of the miR-34a in hematological malignancies. Carcinogenesis, 31, 745–750.

    Article  CAS  PubMed  Google Scholar 

  224. Cui, X., Zhao, Z., Liu, D., Guo, T., Li, S., Hu, J., et al. (2014). Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma. Journal of Experimental & Clinical Cancer Research, 33, 20–30.

    Article  CAS  Google Scholar 

  225. Siemens, H., Neumann, J., Jackstadt, R., Mansmann, U., Horst, D., Kirchner, T., et al. (2013). Detection of miR-34a promoter methylation in combination with elevated expression of c-Met and β-catenin predicts distant metastasis of colon cancer. Clinical Cancer Research, 19, 710–720.

    Article  CAS  PubMed  Google Scholar 

  226. Kwon, H., Song, K., Han, C., Zhang, J., Lu, L., Chen, W., et al. (2017). Epigenetic silencing of miRNA-34a in human cholangiocarcinoma via EZH2 and DNA methylation: Impact on regulation of notch pathway. The American Journal of Pathology, 187, 2288–2299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Tanaka, N., Toyooka, S., Soh, J., Kubo, T., Yamamoto, H., Maki, Y., et al. (2012). Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer. Lung Cancer, 76, 32–38.

    Article  PubMed  Google Scholar 

  228. Kubo, T., Toyooka, S., Tsukuda, K., Sakaguchi, M., Fukazawa, T., Soh, J., et al. (2011). Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma. Clinical Cancer Research, 17, 4965–4974.

    Article  CAS  PubMed  Google Scholar 

  229. Lin, L., Jiang, H., Huang, M., Hou, X., Sun, X., Jiang, X., et al. (2015). Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway. Oncology Reports, 34, 663–672.

    Article  CAS  PubMed  Google Scholar 

  230. Zhang, S., Chen, P., Huang, Z., Hu, X., Chen, M., Hu, S., et al. (2015). Sirt7 promotes gastric cancer growth and inhibits apoptosis by epigenetically inhibiting miR-34a. Scientific Reports, 5, 9787–9796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Hu, C. E., Liu, Y. C., Zhang, H. D., & Huang, G. J. (2014). JMJD2A predicts prognosis and regulates cell growth in human gastric cancer. Biochemical and Biophysical Research Communications, 449, 1–7.

    Article  CAS  PubMed  Google Scholar 

  232. Hu, C. E., Liu, Y. C., Zhang, H. D., & Huang, G. J. (2014). The RNA-binding protein PCBP2 facilitates gastric carcinoma growth by targeting miR-34a. Biochemical and Biophysical Research Communications, 448, 437–442.

    Article  CAS  PubMed  Google Scholar 

  233. Yoon, J. H., Choi, W. S., Kim, O., Choi, B. J., Nam, S. W., Lee, J. Y., et al. (2017). Gastrokine 1 inhibits gastric cancer cell migration and invasion by downregulating RhoA expression. Gastric Cancer, 20, 274–285.

    Article  CAS  PubMed  Google Scholar 

  234. Kawai, S., & Amano, A. (2012). BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex. The Journal of Cell Biology, 197, 201–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Jacob, J., Favicchio, R., Karimian, N., Mehrabi, M., Harding, V., Castellano, L., et al. (2016). LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5. Cancer Letters, 372, 137–146.

    Article  CAS  PubMed  Google Scholar 

  236. Pyzer, A. R., Stroopinsky, D., Rosenblatt, J., Anastasiadou, E., Rajabi, H., Washington, A., et al. (2017). MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs. Leukemia, 31, 2780–2790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Rokavec, M., Öner, M. G., Li, H., Jackstadt, R., Jiang, L., Lodygin, D., et al. (2014). IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. The Journal of Clinical Investigation, 124, 1853–1867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Davis, A. P., Grondin, C. J., Johnson, R. J., Sciaky, D., Wiegers, J., Wiegers, T. C., et al. (2021). (2021). Comparative Toxicogenomics Database (CTD): Update 2021. Nucleic Acids Research, 49, D1138–d1143.

    Article  CAS  PubMed  Google Scholar 

  239. Liu, X., Feng, J., Tang, L., Liao, L., Xu, Q., & Zhu, S. (2015). The regulation and function of miR-21-FOXO3a-miR-34b/c signaling in breast cancer. International Journal of Molecular Sciences, 16, 3148–3162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Fang, L. L., Sun, B. F., Huang, L. R., Yuan, H. B., Zhang, S., Chen, J., et al. (2017). Potent inhibition of miR-34b on migration and invasion in metastatic prostate cancer cells by regulating the TGF-β pathway. International Journal of Molecular Sciences, 18, 2762–2778.

    Article  PubMed Central  CAS  Google Scholar 

  241. Li, J., Liu, X., Qiao, Y., Qi, R., Liu, S., Guo, J., et al. (2018). Association between genetic variant in the promoter of Pri-miR-34b/c and risk of glioma. Frontiers in Oncology, 8, 413–417.

    Article  PubMed  PubMed Central  Google Scholar 

  242. Yu, K. (2017). The Rs4938723 polymorphism reduces expression of microRNA-34b and increases the risk of recurrence after endoscopic dissection in early gastric cancer. Cellular Physiology and Biochemistry, 43, 1235–1246.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81872892, 81773766, and 82003811), the Natural Science Foundation of Anhui Province (No. 2008085QH403), and funds from Anhui Medical University (2019xkj002 and XJ201917).

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Authors and Affiliations

  1. New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China

    Sijing Li, Jinyong He, Danyu Du, Xiaoman Zhan, Yuqi Zeng & Li Sun

  2. School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China

    Xiaohui Wei

  3. China Cell-Gene Therapy Translational Medicine Research Center, Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Jinyong He

  4. School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China

    Jinyong He

  5. MARBEC, Université Montpellier, UM-CNRS-IRD-IFREMER, cc 092, Place E. Bataillon, 34095, Montpellier Cedex 05, France

    Quanquan Cao

  6. Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China

    Shengtao Yuan

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  1. Sijing Li
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Additional File 1:

Figure S1. miR-34s-related genes reported in different cancer types; Figure S2. Bioinformatic analysis of potential association/interactions between the predicted targets of miR-34s in human (PDF 643 kb)

Additional File 2:

Table S1. Reported miR-34a expression in cancers; Table S2. Reported miR-34b expression in cancers; Table S3. Reported miR-34c expression in cancers; Table S4. List of the 512 predicted miR-34a targets by at least 10 out of 21 miRNA databases; Table S5. List of the 85 predicted miR-34b targets by at least 10 out of 16 miRNA databases; Table S6. List of the 85 predicted miR-34c targets by at least 10 out of 14 miRNA databases. (PDF 655 kb)

Additional File 3:

Sheet 1: Predicted targets of miR-34a by 21 miRNA databases; Sheet 2: Predicted targets of miR-34b by 16 miRNA databases; Sheet 3: Predicted targets of miR-34c by 14 miRNA databases; Sheet 4: Predicted targets of miR-34a/c/c by at least 10 miRNA databases. (XLSX 2517 kb)

Additional File 4:

Sheet 1: Predicted transcription factors of miR-34a; Sheet 2: Predicted transcription factors of miR-34b; Sheet 3: Predicted transcription factors of miR-34c; Sheet 4: Common predicted transcription factors of miR-34s. (XLSX 21 kb)

Additional File 5:

Chemicals increase the expression of miR-34a/b/c mRNA in certain organisms. (XLSX 17 kb)

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Li, S., Wei, X., He, J. et al. The comprehensive landscape of miR-34a in cancer research. Cancer Metastasis Rev 40, 925–948 (2021). https://doi.org/10.1007/s10555-021-09973-3

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