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Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a

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Summary

The pharmacokinetic (PK) and potential effects of Emodin on liver cancer were systematically evaluated in this study. Both the intragastric administration (i.g.) and hypodermic injection (i.h.) of Emodin exhibited a strong absorption (absorption rate < 1 h) and elimination capacity (t1/2 ≈ 2 h). The tissue distribution of Emodin after i.h. was rapid and wide. The stability of Emodin in three species of liver microsomes wasrat >human> beagle dog. These PK data provided the basis for the subsequent animal experiments. In liver cancer patient tissues, the expression of vascular endothelial growth factor (VEGF)-induced signaling pathways, including phosphorylated VEGF receptor 2 (VEGFR2), AKT, and ERK1/2,were simultaneously elevated, but miR-34a expression was reduced and negatively correlated with SMAD2 and SMAD4. Emodin inhibited the expression of SMAD2/4 in HepG2 cells by inducing the miR-34a level. Subsequently, BALB/c nude mice received a daily subcutaneous injection of HepG2 cells with or without Emodin treatment (1 mg/kg or 10 mg/kg), and Emodin inhibited tumorigenesis and reduced the mortality rate in a dose-dependent manner. In vivo experiments showed that cell proliferation, migration, and invasion were promoted by VEGF or miR-34a signal treatment but were inhibited when combined with Emodin treatment. All these results demonstrated that Emodin inhibited tumorigenesis in liver cancer by simultaneously inhibiting the VEGFR2-AKT-ERK1/2signaling pathway and promoting a miR-34a-mediated signaling pathway.

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References

  1. Adult Primary Liver Cancer Treatment (PDQ(R)) (2002) Patient version. PDQ Cancer Information Summaries. Bethesda (MD), In

    Google Scholar 

  2. McGuire S (2016) World cancer report 2014. Geneva, Switzerland: World Health Organization, international agency for research on cancer, WHO Press, 2015. Adv Nutr 7(2):418–419. https://doi.org/10.3945/an.116.012211

    Article  PubMed  PubMed Central  Google Scholar 

  3. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 (2016). Lancet 388 (10053):1459–1544. https://doi.org/10.1016/S0140-6736(16)31012-1

  4. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 (2015). Lancet 385 (9963):117–171. https://doi.org/10.1016/S0140-6736(14)61682-2

  5. Bruix J, Sherman M (2011) Management of hepatocellular carcinoma: an update. Hepatology 53(3):1020–1022. https://doi.org/10.1002/hep.24199

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang Z, Zhang G, Wu J, Jia M (2013) Adjuvant therapy for hepatocellular carcinoma: current situation and prospect. Drug Discov Ther 7(4):137–143

    CAS  PubMed  Google Scholar 

  7. Keating GM (2017) Sorafenib: A Review in Hepatocellular Carcinoma. Target Oncol 12(2):243–253. https://doi.org/10.1007/s11523-017-0484-7

    Article  PubMed  Google Scholar 

  8. Chang LC, Huang N, Chou YJ, Lee CH, Kao FY, Huang YT (2008) Utilization patterns of Chinese medicine and Western medicine under the National Health Insurance Program in Taiwan, a population-based study from 1997 to 2003. BMC Health Serv Res 8:170. https://doi.org/10.1186/1472-6963-8-170

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lin YH, Chen KK, Chiu JH (2010) Prevalence, patterns, and costs of Chinese medicine use among prostate cancer patients: a population-based study in Taiwan. Integr. Cancer Ther 9(1):16–23. https://doi.org/10.1177/1534735409359073

    Article  PubMed  Google Scholar 

  10. Wang Z, Li J, Ji Y, An P, Zhang S, Li Z (2013) Traditional herbal medicine: a review of potential of inhibitory hepatocellular carcinoma in basic research and clinical trial. Evid-Based Compl Alt 2013:268963. https://doi.org/10.1155/2013/268963

    Article  Google Scholar 

  11. Fuhong D, Xiang G, Haiying L, Jiangye W, Xueming G, Wenxiao C (2018) Evaluation of efficacy and safety for Brucea javanica oil emulsion in the control of the malignant pleural effusions via thoracic perfusion. BMC Cancer 18(1):411. https://doi.org/10.1186/s12885-018-4328-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zou Y, Guo CG, Yang ZG, Sun JH, Zhang MM, Fu CY (2016) A small interfering RNA targeting vascular endothelial growth factor efficiently inhibits growth of VX2 cells and VX2 tumor model of hepatocellular carcinoma in rabbit by transarterial embolization-mediated siRNA delivery. Drug Des Devel Ther 10:1243–1255. https://doi.org/10.2147/DDDT.S94122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lin CC, Shieh DE (1996) The anti-inflammatory activity of Scutellaria rivularis extracts and its active components, baicalin, baicalein and wogonin. Am J Chin Med 24(1):31–36. https://doi.org/10.1142/S0192415X96000050

    Article  CAS  PubMed  Google Scholar 

  14. Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC (2004) Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clin Exp Pharmacol Physiol 31(1–2):65–69

    Article  CAS  Google Scholar 

  15. Chang WC, Lin YL, Lee MJ, Shiow SJ, Wang CJ (1996) Inhibitory effect of crocetin on benzo(a)pyrene genotoxicity and neoplastic transformation in C3H10T1/2 cells. Anticancer Res 16(6B):3603–3608

    CAS  PubMed  Google Scholar 

  16. Wang JB, Zhao HP, Zhao YL, Jin C, Liu DJ, Kong WJ, Fang F, Zhang L, Wang HJ, Xiao XH (2011) Hepatotoxicity or hepatoprotection? Pattern recognition for the paradoxical effect of the Chinese herb Rheum palmatum L. in treating rat liver injury. PLoS One 6(9):e24498. https://doi.org/10.1371/journal.pone.0024498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang M, Zhao R, Wang W, Mao X, Yu J (2012) Lipid regulation effects of Polygoni Multiflori Radix, its processed products and its major substances on steatosis human liver cell line L02. J Ethnopharmacol 139(1):287–293. https://doi.org/10.1016/j.jep.2011.11.022

    Article  CAS  PubMed  Google Scholar 

  18. Lee MH, Kao L, Lin CC (2011) Comparison of the antioxidant and transmembrane permeative activities of the different Polygonum cuspidatum extracts in phospholipid-based microemulsions. J Agric Food Chem 59(17):9135–9141. https://doi.org/10.1021/jf201577f

    Article  CAS  PubMed  Google Scholar 

  19. Dey D, Ray R, Hazra B (2014) Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates. Phytotherapy Research 28(7):1014–1021. https://doi.org/10.1002/ptr.5090

    Article  CAS  PubMed  Google Scholar 

  20. Liu Z, Wei F, Chen LJ, Xiong HR, Liu YY, Luo F, Hou W, Xiao H, Yang ZQ (2013) In vitro and in vivo studies of the inhibitory effects of emodin isolated from Polygonum cuspidatum on Coxsakievirus B(4). Molecules 18(10):11842–11858. https://doi.org/10.3390/molecules181011842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim J, Lee JS, Jung J, Lim I, Lee JY, Park MJ (2015) Emodin suppresses maintenance of stemness by augmenting proteosomal degradation of epidermal growth factor receptor/epidermal growth factor receptor variant III in glioma stem cells. Stem Cells Dev 24(3):284–295. https://doi.org/10.1089/scd.2014.0210

    Article  CAS  PubMed  Google Scholar 

  22. Zhang X, Zhang R, Lv P, Yang J, Deng Y, Xu J, Zhu R, Zhang D, Yang Y (2015) Emodin up-regulates glucose metabolism, decreases lipolysis, and attenuates inflammation in vitro. J Diabetes 7(3):360–368. https://doi.org/10.1111/1753-0407.12190

    Article  CAS  PubMed  Google Scholar 

  23. Qu K, Shen NY, Xu XS, Su HB, Wei JC, Tai MH, Meng FD, Zhou L, Zhang YL, Liu C (2013) Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction. Acta Pharmacol Sin 34(9):1217–1228. https://doi.org/10.1038/aps.2013.58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun YP, Liu JP (2015) Blockade of emodin on amyloid-beta 25-35-induced neurotoxicity in AbetaPP/PS1 mice and PC12 cells through activation of the class III phosphatidylinositol 3-kinase/Beclin-1/B-cell lymphoma 2 pathway. Planta Med 81(2):108–115. https://doi.org/10.1055/s-0034-1383410

    Article  CAS  PubMed  Google Scholar 

  25. Liu Y, Chen X, Qiu M, Chen W, Zeng Z, Chen Y (2014) Emodin ameliorates ethanol-induced fatty liver injury in mice. Pharmacology 94(1–2):71–77. https://doi.org/10.1159/000363413

    Article  CAS  PubMed  Google Scholar 

  26. Li WY, Chan RY, Yu PH, Chan SW (2013) Emodin induces cytotoxic effect in human breast carcinoma MCF-7 cell through modulating the expression of apoptosis-related genes. Pharm Biol 51(9):1175–1181. https://doi.org/10.3109/13880209.2013.782322

    Article  CAS  PubMed  Google Scholar 

  27. Li WY, Ng YF, Zhang H, Guo ZD, Guo DJ, Kwan YW, Leung GP, Lee SM, Yu PH, Chan SW (2014) Emodin elicits cytotoxicity in human lung adenocarcinoma A549 cells through inducing apoptosis. Inflammopharmacology 22(2):127–134. https://doi.org/10.1007/s10787-013-0186-4

    Article  CAS  PubMed  Google Scholar 

  28. Yaoxian W, Hui Y, Yunyan Z, Yanqin L, Xin G, Xiaoke W (2013) Emodin induces apoptosis of human cervical cancer hela cells via intrinsic mitochondrial and extrinsic death receptor pathway. Cancer Cell Int 13(1):71. https://doi.org/10.1186/1475-2867-13-71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang PH, Huang CY, Chen MC, Lee YT, Yue CH, Wang HY, Lin H (2013) Emodin and aloe-Emodin suppress breast Cancer cell proliferation through ER alpha inhibition. Evid-Based Compl Alt 2013:376123. https://doi.org/10.1155/2013/376123

    Article  Google Scholar 

  30. Xie MJ, Ma YH, Miao L, Wang Y, Wang HZ, Xing YY, Xi T, Lu YY (2014) Emodin-provoked oxidative stress induces apoptosis in human colon cancer HCT116 cells through a p53-mitochondrial apoptotic pathway. Asian Pac J Cancer P 15(13):5201–5205

    Article  Google Scholar 

  31. Kirsch M, Schackert G, Black PM (2004) Metastasis and angiogenesis. Cancer Treat Res 117:285–304

    Article  CAS  Google Scholar 

  32. Geiger TR, Peeper DS (2009) Metastasis mechanisms. Biochim Biophys Acta 1796(2):293–308. https://doi.org/10.1016/j.bbcan.2009.07.006

    Article  CAS  PubMed  Google Scholar 

  33. Kudo M (2006) Early detection and characterization of hepatocellular carcinoma: value of imaging multistep human hepatocarcinogenesis. Intervirology 49(1–2):64–69. https://doi.org/10.1159/000087265

    Article  PubMed  Google Scholar 

  34. Torimura T, Sata M, Ueno T, Kin M, Tsuji R, Suzaku K, Hashimoto O, Sugawara H, Tanikawa K (1998) Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol 29(9):986–991

    Article  CAS  Google Scholar 

  35. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol Off J Am Soc Clin Oncol 28(6):1061–1068. https://doi.org/10.1200/JCO.2009.23.9764

    Article  CAS  Google Scholar 

  36. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312. https://doi.org/10.1016/S0140-6736(12)61900-X

    Article  CAS  PubMed  Google Scholar 

  37. Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355. https://doi.org/10.1038/nature02871

    Article  CAS  PubMed  Google Scholar 

  38. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  Google Scholar 

  39. Bartel DP (2018) Metazoan MicroRNAs. Cell 173(1):20–51. https://doi.org/10.1016/j.cell.2018.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mraz M, Pospisilova S (2012) MicroRNAs in chronic lymphocytic leukemia: from causality to associations and back. Expert Rev Hematol 5(6):579–581. https://doi.org/10.1586/ehm.12.54

    Article  CAS  PubMed  Google Scholar 

  41. Lim LP, Glasner ME, Yekta S, Burge CB, Bartel DP (2003) Vertebrate microRNA genes. Science 299(5612):1540. https://doi.org/10.1126/science.1080372

    Article  CAS  PubMed  Google Scholar 

  42. Mraz M, Malinova K, Kotaskova J, Pavlova S, Tichy B, Malcikova J, Stano Kozubik K, Smardova J, Brychtova Y, Doubek M, Trbusek M, Mayer J, Pospisilova S (2009) miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 23(6):1159–1163. https://doi.org/10.1038/leu.2008.377

    Article  CAS  PubMed  Google Scholar 

  43. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ (2007) A microRNA component of the p53 tumour suppressor network. Nature 447(7148):1130–1134. https://doi.org/10.1038/nature05939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bader AG (2012) miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet 3:120. https://doi.org/10.3389/fgene.2012.00120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Daige CL, Wiggins JF, Priddy L, Nelligan-Davis T, Zhao J, Brown D (2014) Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 13(10):2352–2360. https://doi.org/10.1158/1535-7163.MCT-14-0209

    Article  CAS  PubMed  Google Scholar 

  46. Kelnar K, Peltier HJ, Leatherbury N, Stoudemire J, Bader AG (2014) Quantification of therapeutic miRNA mimics in whole blood from nonhuman primates. Anal Chem 86(3):1534–1542. https://doi.org/10.1021/ac403044t

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kwak HJ, Park MJ, Park CM, Moon SI, Yoo DH, Lee HC, Lee SH, Kim MS, Lee HW, Shin WS, Park IC, Rhee CH, Hong SI (2006) Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation. Int J Cancer 118(11):2711–2720. https://doi.org/10.1002/ijc.21641

    Article  CAS  PubMed  Google Scholar 

  48. Lu Y, Zhang J, Qian J (2008) The effect of emodin on VEGF receptors in human colon cancer cells. Cancer Biother Radiopharm 23(2):222–228. https://doi.org/10.1089/cbr.2007.0425

    Article  CAS  PubMed  Google Scholar 

  49. Wang Z, Wang N, Han S, Wang D, Mo S, Yu L, Huang H, Tsui K, Shen J, Chen J (2013) Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PLoS One 8(7):e68566. https://doi.org/10.1371/journal.pone.0068566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cha TL, Chuang MJ, Tang SH, Wu ST, Sun KH, Chen TT, Sun GH, Chang SY, Yu CP, Ho JY, Liu SY, Huang SM, Yu DS (2015) Emodin modulates epigenetic modifications and suppresses bladder carcinoma cell growth. Mol Carcinog 54(3):167–177. https://doi.org/10.1002/mc.22084

    Article  CAS  PubMed  Google Scholar 

  51. Jia X, Yu F, Wang J, Iwanowycz S, Saaoud F, Wang Y, Hu J, Wang Q, Fan D (2014) Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs. Breast Cancer Res Treat 148(2):291–302. https://doi.org/10.1007/s10549-014-3164-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jelassi B, Anchelin M, Chamouton J, Cayuela ML, Clarysse L, Li J, Gore J, Jiang LH, Roger S (2013) Anthraquinone emodin inhibits human cancer cell invasiveness by antagonizing P2X7 receptors. Carcinogenesis 34(7):1487–1496. https://doi.org/10.1093/carcin/bgt099

    Article  CAS  PubMed  Google Scholar 

  53. Zhang X, Chen Y, Zhang T, Zhang Y (2015) Inhibitory effect of emodin on human hepatoma cell line SMMC-7721 and its mechanism. Afr Health Sci 15(1):97–100. https://doi.org/10.4314/ahs.v15i1.13

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ma J, Yang J, Wang C, Zhang N, Dong Y, Wang Y, Lin X (2014) Emodin augments cisplatin cytotoxicity in platinum-resistant ovarian cancer cells via ROS-dependent MRP1 downregulation. Biomed Res Int 2014:107671. https://doi.org/10.1155/2014/107671

    Article  PubMed  PubMed Central  Google Scholar 

  55. Li XX, Dong Y, Wang W, Wang HL, Chen YY, Shi GY, Yi J, Wang J (2013) Emodin as an effective agent in targeting cancer stem-like side population cells of gallbladder carcinoma. Stem Cells Dev 22(4):554–566. https://doi.org/10.1089/scd.2011.0709

    Article  CAS  PubMed  Google Scholar 

  56. Subramaniam A, Loo SY, Rajendran P, Manu KA, Perumal E, Li F, Shanmugam MK, Siveen KS, Park JI, Ahn KS, Hui KM, Kumar AP, Sethi G (2013) An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins. Apoptosis 18(10):1175–1187. https://doi.org/10.1007/s10495-013-0851-5

    Article  CAS  PubMed  Google Scholar 

  57. Meijerink MR, Puijk RS, van Tilborg A, Henningsen KH, Fernandez LG, Neyt M, Heymans J, Frankema JS, de Jong KP, Richel DJ, Prevoo W, Vlayen J (2018) Radiofrequency and microwave ablation compared to systemic chemotherapy and to partial hepatectomy in the treatment of colorectal liver metastases: a systematic review and meta-analysis. Cardiovasc Intervent Radiol 41(8):1189–1204. https://doi.org/10.1007/s00270-018-1959-3

    Article  PubMed  PubMed Central  Google Scholar 

  58. de Lope CR, Tremosini S, Forner A, Reig M, Bruix J (2012) Management of HCC. J Hepatol 56(Suppl 1):S75–S87. https://doi.org/10.1016/S0168-8278(12)60009-9

    Article  CAS  PubMed  Google Scholar 

  59. Shiina S, Sato K, Tateishi R, Shimizu M, Ohama H, Hatanaka T, Takawa M, Nagamatsu H, Imai Y (2018) Percutaneous ablation for hepatocellular carcinoma: comparison of various ablation techniques and surgery. Can J Gastroenterol 2018:4756147. https://doi.org/10.1155/2018/4756147

    Article  Google Scholar 

  60. Xia H, Hui KM (2017) Emergence of aspirin as a promising chemopreventive and chemotherapeutic agent for liver cancer. Cell Death Dis 8(10):e3112. https://doi.org/10.1038/cddis.2017.513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Miura H, Miyazaki T, Kuroda M, Oka T, Machinami R, Kodama T, Shibuya M, Makuuchi M, Yazaki Y, Ohnishi S (1997) Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma. J Hepatol 27(5):854–861

    Article  CAS  Google Scholar 

  62. Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M (1998) Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28(1):68–77. https://doi.org/10.1002/hep.510280111

    Article  CAS  PubMed  Google Scholar 

  63. Wang J, Dan G, Zhao J, Ding Y, Ye F, Sun H, Jiang F, Cheng J, Yuan F, Zou Z (2015) The predictive effect of overexpressed miR-34a on good survival of cancer patients: a systematic review and meta-analysis. Oncotargets Ther 8:2709–2719. https://doi.org/10.2147/OTT.S84043

    Article  CAS  Google Scholar 

  64. Hiyoshi Y, Schetter AJ, Okayama H, Inamura K, Anami K, Nguyen GH, Horikawa I, Hawkes JE, Bowman ED, Leung SY, Harris CC (2015) Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer. PLoS One 10(4):e0124899. https://doi.org/10.1371/journal.pone.0124899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jamieson NB, Morran DC, Morton JP, Ali A, Dickson EJ, Carter CR, Sansom OJ, Evans TR, McKay CJ, Oien KA (2012) MicroRNA molecular profiles associated with diagnosis, clinicopathologic criteria, and overall survival in patients with resectable pancreatic ductal adenocarcinoma. Clinical cancer research : an official journal of the American association for. Cancer Res 18(2):534–545. https://doi.org/10.1158/1078-0432.CCR-11-0679

    Article  CAS  Google Scholar 

  66. Shin J, Xie D, Zhong XP (2013) MicroRNA-34a enhances T cell activation by targeting diacylglycerol kinase zeta. PLoS One 8(10):e77983. https://doi.org/10.1371/journal.pone.0077983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang X, Li J, Dong K, Lin F, Long M, Ouyang Y, Wei J, Chen X, Weng Y, He T, Zhang H (2015) Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal 27(3):443–452. https://doi.org/10.1016/j.cellsig.2014.12.003

    Article  CAS  PubMed  Google Scholar 

  68. Cortez MA, Valdecanas D, Niknam S, Peltier HJ, Diao L, Giri U, Komaki R, Calin GA, Gomez DR, Chang JY, Heymach JV, Bader AG, Welsh JW (2015) In vivo delivery of miR-34a sensitizes lung tumors to radiation through RAD51 regulation. Mol Ther-Nucl Acids 4:e270. https://doi.org/10.1038/mtna.2015.47

    Article  CAS  Google Scholar 

  69. Bruna A, Darken RS, Rojo F, Ocana A, Penuelas S, Arias A, Paris R, Tortosa A, Mora J, Baselga J, Seoane J (2007) High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11(2):147–160. https://doi.org/10.1016/j.ccr.2006.11.023

    Article  CAS  PubMed  Google Scholar 

  70. Oft M, Akhurst RJ, Balmain A (2002) Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 4(7):487–494. https://doi.org/10.1038/ncb807

    Article  CAS  PubMed  Google Scholar 

  71. Shinto O, Yashiro M, Toyokawa T, Nishii T, Kaizaki R, Matsuzaki T, Noda S, Kubo N, Tanaka H, Doi Y, Ohira M, Muguruma K, Sawada T, Hirakawa K (2010) Phosphorylated smad2 in advanced stage gastric carcinoma. BMC Cancer 10:652. https://doi.org/10.1186/1471-2407-10-652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cortez MA, Ivan C, Valdecanas D, Wang X, Peltier HJ, Ye Y, Araujo L, Carbone DP, Shilo K, Giri DK, Kelnar K, Martin D, Komaki R, Gomez DR, Krishnan S, Calin GA, Bader AG, Welsh JW (2016) PDL1 regulation by p53 via miR-34. J Natl Cancer Inst 108(1). https://doi.org/10.1093/jnci/djv303

  73. Craig VJ, Tzankov A, Flori M, Schmid CA, Bader AG, Muller A (2012) Systemic microRNA-34a delivery induces apoptosis and abrogates growth of diffuse large B-cell lymphoma in vivo. Leukemia 26(11):2421–2424. https://doi.org/10.1038/leu.2012.110

    Article  CAS  PubMed  Google Scholar 

  74. Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D, Bader AG (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res 70(14):5923–5930. https://doi.org/10.1158/0008-5472.CAN-10-0655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhao J, Kelnar K, Bader AG (2014) In-depth analysis shows synergy between erlotinib and miR-34a. PLoS One 9(2):e89105. https://doi.org/10.1371/journal.pone.0089105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y, Zheng X (2009) miR-34a inhibits migration and invasion by down-regulation of c-met expression in human hepatocellular carcinoma cells. Cancer Lett 275(1):44–53. https://doi.org/10.1016/j.canlet.2008.09.035

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by funding from the Fourth Hospital of Hebei Medical University.

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, NO.12, Jiankang Road, Shijiazhuang, 050011, Hebei Province, People’s Republic of China

    Jianguo Bai, Ruifeng Tang, Chao Sun, Guangjun Ma & Wei Yang

  2. Department of Hepatobiliary Surgery, the Affiliated Hospital of Hebei University, Baoding, 071000, Hebei Province, People’s Republic of China

    Jianfei Wu

  3. Department of Emergency, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei Province, People’s Republic of China

    Junwei Ji

  4. Department of ultrasound, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei Province, People’s Republic of China

    Zhaolin Yin

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  7. Guangjun Ma
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Contributions

R.T. and J. B. designed the experiments; C.S. performed the animal experiments; J. J. performed the cell experiments in vitro; Z. Y. and W. Y. performed the western blot analysis and the luciferase assay; G. M. and J. W. performed the immunohistochemistry assay; and J. B. analyzed the data and drafted the manuscript.

Corresponding author

Correspondence to Ruifeng Tang.

Ethics declarations

Conflict of interest

All authors have declared that they have no conflicts of interest to disclose. Jianguo Bai declares that he has no conflict of interest. Jianfei Wu declares that he has no conflict of interest. Ruifeng Tang declares that he has no conflict of interest. Chao Sun declares that he has no conflict of interest. Junwei Ji declares that he has no conflict of interest. Zhaolin Yin declares that he has no conflict of interest. Guangjun Ma declares that he has no conflict of interest. Wei Yang declares that he has no conflict of interest.

Ethical approval

The Guide for the Care and Use of Laboratory Animals [National Research Council (US) Committee for the update of the Guide for the Care and Use of Laboratory Animals, 2011] was followed. All procedures in studies involving animals were performed in accordance with the ethical standards of the Animal Ethics Committee of the Fourth Hospital of Hebei Medical University (Shijiazhuang, Hebei Province, China).

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For this type of study, formal consent is not required.

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Jianguo Bai and Jianfei Wu equally to this study and share first authorship.

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Bai, J., Wu, J., Tang, R. et al. Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a. Invest New Drugs 38, 229–245 (2020). https://doi.org/10.1007/s10637-019-00777-5

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