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Long non-coding RNA HOXA-AS3 facilitates the malignancy in colorectal cancer by miR-4319/SPNS2 axis

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Abstract

Growing evidence has shown the oncogenic role of long non-coding RNA HOXA-AS3 in the progression of several types of cancers, while the effect of HOXA-AS3 on colorectal cancer (CRC) remains unclear. In this study, HOXA-AS3 was significantly over-expressed in CRC clinical samples and human CRC cell lines (SW480, SW620, HCT116, COLO205, and LOVO). HOXA-AS3 knockdown was further achieved by specific siRNAs in COLO205 and LOVO cell lines. The depletion of HOXA-AS3 remarkably inhibited cell proliferation, induced cell cycle arrest, and promoted cell apoptosis in CRC cell lines. Additionally, HOXA-AS3 knockdown was determined to facilitate miR-4319 expression and reduce expression level of sphingolipid transporter 2 (SPNS2) in CRC cell lines. The dual luciferase reporter assay suggested that HOXA-AS3 acted as a sponge of miR-4319, and miR-4319 further directly targeted SPNS2 for expression regulation. Besides, HOXA-AS3 was determined to mediate CRC cell proliferation and apoptosis via miR-4319/SPNS2 axis. Moreover, tumorigenesis experiment validated that HOXA-AS3 promoted CRC progression in vivo by regulating miR-4319, SPNS2, and protein kinase B (AKT) signaling. In summary, this study reveals the novel role of HOXA-AS3 in pathogenesis of CRC and provides a candidate for CRC therapeutic target.

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References

  1. Baena R, Salinas P (2015) Diet and colorectal cancer. Maturitas 80:258–264

    Article  CAS  Google Scholar 

  2. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86

    Article  CAS  Google Scholar 

  3. Bian S (2020) miR-4319 inhibited the development of thyroid cancer by modulating FUS-stabilized SMURF1. J Cell Biochem 121:174–182. https://doi.org/10.1002/jcb.29026

    Article  CAS  PubMed  Google Scholar 

  4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  5. Bujko K, Glimelius B, Valentini V, Michalski W, Spalek M (2015) Postoperative chemotherapy in patients with rectal cancer receiving preoperative radio(chemo)therapy: a meta-analysis of randomized trials comparing surgery +/- a fluoropyrimidine and surgery + a fluoropyrimidine +/- oxaliplatin. Eur J Surg Oncol 41:713–723. https://doi.org/10.1016/j.ejso.2015.03.233

    Article  CAS  PubMed  Google Scholar 

  6. Cao HL, Liu ZJ, Huang PL, Yue YL, Xi JN (2019) lncRNA-RMRP promotes proliferation, migration and invasion of bladder cancer via miR-206. Eur Rev Med Pharmacol Sci 23:1012–1021

    PubMed  Google Scholar 

  7. Chan JJ, Tay Y (2018) Noncoding RNA:RNA regulatory networks in cancer. Int J Mol Sci 19:1310. https://doi.org/10.3390/ijms19051310

    Article  CAS  PubMed Central  Google Scholar 

  8. Chen W, Li Q, Zhang G, Wang H, Zhu Z, Chen L (2020) LncRNA HOXA-AS3 promotes the malignancy of glioblastoma through regulating miR-455-5p/USP3 axis. J Cell Mol Med 24:11755–11767. https://doi.org/10.1111/jcmm.15788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dekker E, Rex DK (2018) Advances in CRC prevention: screening and surveillance. Gastroenterology 154:1970–1984

    Article  Google Scholar 

  10. Donoviel MS, Hait NC, Ramachandran S, Maceyka M, Takabe K, Milstien S, Oravecz T, Spiegel S (2015) Spinster 2, a sphingosine-1-phosphate transporter, plays a critical role in inflammatory and autoimmune diseases. FASEB J 29:5018–5028. https://doi.org/10.1096/fj.15-274936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fang Y, Fullwood MJ (2016) Roles, functions, and mechanisms of long non-coding RNAs in cancer. Genomics Proteomics Bioinformatics 14:42–54. https://doi.org/10.1016/j.gpb.2015.09.006

    Article  PubMed  PubMed Central  Google Scholar 

  12. Farinetti A, Zurlo V, Manenti A, Coppi F, Mattioli AV (2017) Mediterranean diet and colorectal cancer: a systematic review. Nutrition 43:83–88

    Article  Google Scholar 

  13. Gu X, Jiang Y, Xue W, Song C, Wang Y, Liu Y, Cui B (2019) SPNS2 promotes the malignancy of colorectal cancer cells via regulating Akt and ERK pathway. Clin Exp Pharmacol Physiol 46:861–871. https://doi.org/10.1111/1440-1681.13124

    Article  CAS  PubMed  Google Scholar 

  14. Han S, Shi Y, Sun L, Liu Z, Song T, Liu Q (2019) MiR-4319 induced an inhibition of epithelial-mesenchymal transition and prevented cancer stemness of HCC through targeting FOXQ1. Int J Biol Sci 15:2936–2947. https://doi.org/10.7150/ijbs.38000

    Article  PubMed  PubMed Central  Google Scholar 

  15. Huang L, Zhang Y, Li Z, Zhao X, Xi Z, Chen H, Shi H, Xin T, Shen R, Wang T (2019) MiR-4319 suppresses colorectal cancer progression by targeting ABTB1. United European Gastroenterol J 7:517–528. https://doi.org/10.1177/2050640619837440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang Y (2018) The novel regulatory role of lncRNA-miRNA-mRNA axis in cardiovascular diseases. J Cell Mol Med 22:5768–5775. https://doi.org/10.1111/jcmm.13866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS (2014) Prediction of cancer incidence and mortality in Korea, 2014. Cancer Res Treat 46:124–130

    Article  CAS  Google Scholar 

  18. Kim JH (2015) Chemotherapy for colorectal cancer in the elderly. World J Gastroenterol 21:5158–5166

    Article  CAS  Google Scholar 

  19. Kong X, Duan Y, Sang Y, Li YA-OX, Zhang H, Liang Y, Liu Y, Zhang N, Yang Q (2019) LncRNA-CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA-215. J Cell Physiol 234:9105–9117

    Article  CAS  Google Scholar 

  20. Lin XA-O, Wang Y (2018) Re-expression of microRNA-4319 inhibits growth of prostate cancer via Her-2 suppression. Clin Transl Oncol 20:1400–1407

    Article  CAS  Google Scholar 

  21. Lin S, Zhang R, An X, Li Z, Fang C, Pan B, Chen W, Xu G, Han W (2019) LncRNA HOXA-AS3 confers cisplatin resistance by interacting with HOXA3 in non-small-cell lung carcinoma cells. Oncogenesis 8:60–60. https://doi.org/10.1038/s41389-019-0170-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ma L-H, Grove CL, Baker R (2014) Development of oculomotor circuitry independent of hox3 genes. Nat Commun 5:4221–4221. https://doi.org/10.1038/ncomms5221

    Article  CAS  PubMed  Google Scholar 

  23. Onyoh EF, Hsu WF, Chang LC, Lee YC, Wu MS, Chiu HM (2019) The rise of colorectal cancer in Asia: epidemiology, screening, and management. Curr Gastroenterol Rep 21:36

    Article  Google Scholar 

  24. Paraskevopoulou MD, Hatzigeorgiou AG (2016) Analyzing MiRNA-LncRNA interactions. Methods Mol Biol 1402:271–286. https://doi.org/10.1007/978-1-4939-3378-5_21

    Article  CAS  PubMed  Google Scholar 

  25. Peng WX, Koirala P, Mo YY (2017) LncRNA-mediated regulation of cell signaling in cancer. Oncogene 36:5661–5667. https://doi.org/10.1038/onc.2017.184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shan Z-Z, Chen P-N, Wang F, Wang J, Fan Q-X (2017) Expression of P-EGFR and P-Akt protein in esophageal squamous cell carcinoma and its prognosis. Oncol Lett 14:2859–2863. https://doi.org/10.3892/ol.2017.6526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shen Z, Li Y, Fang Y, Lin M, Feng X, Li Z, Zhan Y, Liu Y, Mou T, Lan X, Wang Y, Li G, Wang J, Deng H (2020) SNX16 activates c-Myc signaling by inhibiting ubiquitin-mediated proteasomal degradation of eEF1A2 in colorectal cancer development. Mol Oncol 14:387–406. https://doi.org/10.1002/1878-0261.12626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Song M, Bode AM, Dong Z, Lee M-H (2019) AKT as a therapeutic target for cancer. Can Res 79:1019. https://doi.org/10.1158/0008-5472.CAN-18-2738

    Article  CAS  Google Scholar 

  29. Tong Y, Wang M, Dai Y, Bao D, Zhang J, Pan H (2019) LncRNA HOXA-AS3 sponges miR-29c to facilitate cell proliferation, metastasis, and EMT process and activate the MEK/ERK signaling pathway in hepatocellular carcinoma. Hum Gene Ther Clin Dev 30:129–141. https://doi.org/10.1089/humc.2018.266

    Article  CAS  PubMed  Google Scholar 

  30. Wu F, Zhang C, Cai J, Yang F, Liang T, Yan X, Wang H, Wang W, Chen J, Jiang T (2017) Upregulation of long noncoding RNA HOXA-AS3 promotes tumor progression and predicts poor prognosis in glioma. Oncotarget 8:53110–53123. https://doi.org/10.18632/oncotarget.18162

    Article  PubMed  PubMed Central  Google Scholar 

  31. Xu M, Chen X, Lin K, Zeng K, Liu X, Xu X, Pan B, Xu T, Sun L, He B, Pan Y, Sun H, Wang S (2019) lncRNA SNHG6 regulates EZH2 expression by sponging miR-26a/b and miR-214 in colorectal cancer. J Hematol Oncol 12:3–3. https://doi.org/10.1186/s13045-018-0690-5

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yang Y, Li H, Liu Y, Chi C, Ni J, Lin X (2019) MiR-4319 hinders YAP expression to restrain non-small cell lung cancer growth through regulation of LIN28-mediated RFX5 stability. Biomed Pharmacother 115:108956. https://doi.org/10.1016/j.biopha.2019.108956

    Article  CAS  PubMed  Google Scholar 

  33. Zhong L, Jiang X, Zhu Z, Qin H, Dinkins MB, Kong J-N, Leanhart S, Wang R, Elsherbini A, Bieberich E, Zhao Y, Wang G (2019) Lipid transporter Spns2 promotes microglia pro-inflammatory activation in response to amyloid-beta peptide. Glia 67:498–511. https://doi.org/10.1002/glia.23558

    Article  PubMed  Google Scholar 

  34. Zhu X-X, Yan Y-W, Chen D, Ai C-Z, Lu X, Xu S-S, Jiang S, Zhong G-S, Chen D-B, Jiang Y-Z (2016) Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells. Oncotarget 7:63561–63570. https://doi.org/10.18632/oncotarget.11538

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by grants from the Natural Science Foundation of Heilongjiang Province (No. LH2020H121), the Haiyan Foundation of Harbin Medical University Cancer Hospital (No. JJQN2020-16), and the Graduate Research and Practice Innovation Project of Harbin Medical University (No.YJSKYCX2019-53HYD).

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Authors and Affiliations

  1. Department of Pathology, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Harbin, 150081, Heilongjiang, China

    Yang Jiang, Xiao-yu Yu & Jing-shu Geng

  2. Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, 150081, Heilongjiang, China

    Hui-xin Sun

  3. Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Harbin, 150081, Heilongjiang, China

    Xin-yue Gu

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  1. Yang Jiang
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  2. Xiao-yu Yu
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Contributions

YJ and JSG designed the experiments. YJ and XYY performed the majority of experiments. HXS and XYG analyzed the data. YJ and JSG drafted and revised the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Xin-yue Gu or Jing-shu Geng.

Ethics declarations

Research involving human participants and/or animals

This study involves human participants and animals. The collection of clinical specimen was approved by the Committee of Harbin Medical University Cancer Hospital. Moreover, all animal experiments were also approved by Committee of Harbin Medical University Cancer Hospital, and experimental procedures were conducted under the guideline to the care and use of experimental animals.

Informed consent

The written informed consent was obtained from each participant before sample collection. All protocols were followed by the Declaration of Helsinki.

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The authors declare no competing interests.

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Key Points

1. HOXA-AS3 was over-expressed in CRC clinical samples and human CRC cell lines.

2. HOXA-AS3 knockdown inhibits CRC progression in vivo and in vitro.

3. HOXA-AS3 acts as a sponge of miR-4319, which further regulates expression of SPNS2 in CRC cells.

4. HOXA-AS3 knockdown inhibits cell proliferation and induces apoptosis in CRC cells via miR-4319/SPNS2 axis.

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Jiang, Y., Yu, Xy., Sun, Hx. et al. Long non-coding RNA HOXA-AS3 facilitates the malignancy in colorectal cancer by miR-4319/SPNS2 axis. J Physiol Biochem 77, 653–666 (2021). https://doi.org/10.1007/s13105-021-00832-x

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  • DOI: https://doi.org/10.1007/s13105-021-00832-x

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