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RNA sequencing-based microRNA expression signature in esophageal squamous cell carcinoma: oncogenic targets by antitumor miR-143-5p and miR-143-3p regulation

Journal of Human Genetics volume 65, pages 1019–1034 (2020)Cite this article

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Abstract

Aberrantly expressed microRNAs (miRNAs) disrupt intracellular RNA networks and contribute to malignant transformation of cancer cells. Utilizing the latest RNA sequencing technology, we newly created the miRNA expression signature of esophageal squamous cell carcinoma (ESCC). A total of 47 miRNAs were downregulated in ESCC tissues, and these miRNAs were candidates for antitumor miRNAs in ESCC cells. Analysis of the signature revealed that several passenger strands of miRNAs were significantly downregulated in ESCC, e.g., miR-28-3p, miR-30a-3p, miR-30c-3p, miR-133a-3p, miR-139-3p, miR-143-5p, and miR-145-3p. Recent studies indicate that some passenger strands of miRNAs closely involved in cancer pathogenesis. In this study, we focused on both strands of pre-miR-143, and investigated their antitumor roles and target oncogenes in ESCC. Ectopic expression of miR-143-5p and miR-143-3p significantly attenuated malignant phenotypes (e.g., proliferation, migration, and invasive abilities) in ESCC cell lines. We revealed that six genes (HN1, HMGA2, NETO2, STMN1, TCF3, and MET) were putative targets of miR-143-5p regulation, and one gene (KRT80) was a putative target of miR-143-3p regulation in ESCC cells. Our ESCC miRNA signature and analysis strategy provided important insights into the molecular pathogenesis of ESCC.

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References

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

    Article  PubMed  Google Scholar 

  2. Lin Y, Totsuka Y, He Y, Kikuchi S, Qiao Y, Ueda J, et al. Epidemiology of esophageal cancer in Japan and China. J Epidemiol. 2013;23:233–42.

    Article  PubMed  Google Scholar 

  3. Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400–12.

    Article  PubMed  Google Scholar 

  4. Watanabe M, Otake R, Kozuki R, Toihata T, Takahashi K, Okamura A, et al. Recent progress in multidisciplinary treatment for patients with esophageal cancer. Surg Today. 2020;50:12–20.

    Article  PubMed  Google Scholar 

  5. Tanaka Y, Yoshida K, Suetsugu T, Imai T, Matsuhashi N, Yamaguchi K. Recent advancements in esophageal cancer treatment in Japan. Ann Gastroenterol Surg. 2018;2:253–65.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hirano H, Kato K. Systemic treatment of advanced esophageal squamous cell carcinoma: chemotherapy, molecular-targeting therapy and immunotherapy. Jpn J Clin Oncol. 2019;49:412–20.

    Article  PubMed  Google Scholar 

  7. Anfossi S, Babayan A, Pantel K, Calin GA. Clinical utility of circulating non-coding RNAs—an update. Nat Rev Clin Oncol. 2018;15:541–63.

    Article  PubMed  Google Scholar 

  8. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15:509–24.

    Article  CAS  PubMed  Google Scholar 

  9. Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2019;20:21–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 2015;15:321–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Disco. 2017;16:203–22.

    Article  CAS  Google Scholar 

  12. Koshizuka K, Nohata N, Hanazawa T, Kikkawa N, Arai T, Okato A, et al. Deep sequencing-based microRNA expression signatures in head and neck squamous cell carcinoma: dual strands of pre-miR-150 as antitumor miRNAs. Oncotarget. 2017;8:30288–304.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Goto Y, Kurozumi A, Arai T, Nohata N, Kojima S, Okato A, et al. Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer. Br J Cancer. 2017;117:409–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yonemori K, Seki N, Idichi T, Kurahara H, Osako Y, Koshizuka K, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget. 2017;8:70097–115.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Arai T, Kojima S, Yamada Y, Sugawara S, Kato M, Yamazaki K, et al. Micro-ribonucleic acid expression signature of metastatic castration-resistant prostate cancer: regulation of NCAPH by antitumor miR-199a/b-3p. Int J Urol. 2019;26:506–20.

    Article  CAS  PubMed  Google Scholar 

  16. Toda H, Seki N, Kurozumi S, Shinden Y, Yamada Y, Nohata N, et al. RNA-sequence-based microRNA expression signature in breast cancer: tumor-suppressive miR-101-5p regulates molecular pathogenesis. Mol Oncol. 2020;14:426–46.

    Article  CAS  PubMed  Google Scholar 

  17. Mitra R, Adams CM, Jiang W, Greenawalt E, Eischen CM. Pan-cancer analysis reveals cooperativity of bothstrands of microRNA that regulate tumorigenesis and patient survival. Nat Commun. 2020;11:968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Matsushita R, Yoshino H, Enokida H, Goto Y, Miyamoto K, Yonemori M, et al. Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p): inhibition of bladder cancer cell aggressiveness. Oncotarget. 2016;7:28460–87.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mataki H, Seki N, Mizuno K, Nohata N, Kamikawaji K, Kumamoto T, et al. Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma. Oncotarget. 2016;7:72084–98.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yamada Y, Koshizuka K, Hanazawa T, Kikkawa N, Okato A, Idichi T, et al. Passenger strand of miR-145-3p acts as a tumor-suppressor by targeting MYO1B in head and neck squamous cell carcinoma. Int J Oncol. 2018;52:166–78.

    CAS  PubMed  Google Scholar 

  21. Misono S, Seki N, Mizuno K, Yamada Y, Uchida A, Arai T, et al. Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis. J Hum Genet. 2018;63:1015–28.

    Article  CAS  PubMed  Google Scholar 

  22. Shimonosono M, Idichi T, Seki N, Yamada Y, Arai T, Arigami T, et al. Molecular pathogenesis of esophageal squamous cell carcinoma: identification of the antitumor effects of miR1453p on gene regulation. Int J Oncol. 2019;54:673–88.

    CAS  PubMed  Google Scholar 

  23. Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, et al. miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 2010;127:2804–14.

    Article  CAS  PubMed  Google Scholar 

  24. Osako Y, Seki N, Kita Y, Yonemori K, Koshizuka K, Kurozumi A, et al. Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma. Int J Oncol. 2016;49:2255–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Osako Y, Seki N, Koshizuka K, Okato A, Idichi T, Arai T, et al. Regulation of SPOCK1 by dual strands of pre-miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma. J Hum Genet. 2017;62:935–44.

    Article  CAS  PubMed  Google Scholar 

  26. Ni Y, Meng L, Wang L, Dong W, Shen H, Wang G, et al. MicroRNA-143 functions as a tumor suppressor in human esophageal squamous cell carcinoma. Gene. 2013;517:197–204.

    Article  CAS  PubMed  Google Scholar 

  27. Liu R, Liao J, Yang M, Sheng J, Yang H, Wang Y, et al. The cluster of miR-143 and miR-145 affects the risk for esophageal squamous cell carcinoma through co-regulating fascin homolog 1. PLoS ONE. 2012;7:e33987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zeinali T, Mansoori B, Mohammadi A, Baradaran B. Regulatory mechanisms of miR-145 expression and the importance of its function in cancer metastasis. Biomed Pharmacother. 2019;109:195–207.

    Article  CAS  PubMed  Google Scholar 

  29. Ye D, Shen Z, Zhou S. Function of microRNA-145 and mechanisms underlying its role in malignant tumor diagnosis and treatment. Cancer Manag Res. 2019;11:969–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu WX, Liu Z, Deng F, Wang DD, Li XW, Tian T, et al. MiR-145: a potential biomarker of cancer migration and invasion. Am J Transl Res. 2019;11:6739–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu M, Zhang Q, Tian XH, Wang JL, Niu YX, Li G. lncRNA CCAT1 is a biomarker for the proliferation and drug resistance of esophageal cancer via the miR-143/PLK1/BUBR1 axis. Mol Carcinog. 2019;58:2207–17.

    Article  CAS  PubMed  Google Scholar 

  32. Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, et al. p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci USA. 2009;106:3207–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wu XL, Cheng B, Li PY, Huang HJ, Zhao Q, Dan ZL, et al. MicroRNA-143 suppresses gastric cancer cell growth and induces apoptosis by targeting COX-2. World J Gastroenterol. 2013;19:7758–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. He M, Zhan M, Chen W, Xu S, Long M, Shen H, et al. MiR-143-5p deficiency triggers EMT and metastasis by targeting HIF-1alpha in gallbladder cancer. Cell Physiol Biochem. 2017;42:2078–92.

    Article  CAS  PubMed  Google Scholar 

  35. Sanada H, Seki N, Mizuno K, Misono S, Uchida A, Yamada Y, et al. Involvement of dual strands of miR-143 (miR-143-5p and miR-143-3p) and their target oncogenes in the molecular pathogenesis of lung adenocarcinoma. Int J Mol Sci. 2019;20:4482.

    Article  CAS  PubMed Central  Google Scholar 

  36. Talebi A, Masoodi M, Mirzaei A, Mehrad-Majd H, Azizpour M, Akbari A. Biological and clinical relevance of metastasis-associated long noncoding RNAs in esophageal squamous cell carcinoma: a systematic review. J Cell Physiol. 2020;235:848–68.

    Article  CAS  PubMed  Google Scholar 

  37. Sugihara H, Ishimoto T, Miyake K, Izumi D, Baba Y, Yoshida N, et al. Noncoding RNA expression aberration is associated with cancer progression and is a potential biomarker in esophageal squamous cell carcinoma. Int J Mol Sci. 2015;16:27824–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wu F, Gao H, Liu K, Gao B, Ren H, Li Z, et al. The lncRNA ZEB2-AS1 is upregulated in gastric cancer and affects cell proliferation and invasion via miR-143-5p/HIF-1alpha axis. Onco Targets Ther. 2019;12:657–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu C, Wang JO, Zhou WY, Chang XY, Zhang MM, Zhang Y, et al. Long non-coding RNA LINC01207 silencing suppresses AGR2 expression to facilitate autophagy and apoptosis of pancreatic cancer cells by sponging miR-143-5p. Mol Cell Endocrinol. 2019;493:110424.

    Article  CAS  PubMed  Google Scholar 

  40. Jin X, Chen X, Hu Y, Ying F, Zou R, Lin F, et al. LncRNA-TCONS_00026907 is involved in the progression and prognosis of cervical cancer through inhibiting miR-143-5p. Cancer Med. 2017;6:1409–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang C, Shen S, Zheng X, Ye K, Sun Y, Lu Y, et al. Long noncoding RNA HAGLR acts as a microRNA-143-5p sponge to regulate epithelial-mesenchymal transition and metastatic potential in esophageal cancer by regulating LAMP3. FASEB J. 2019;33:10490–504.

    Article  CAS  PubMed  Google Scholar 

  42. Young AR, Narita M. Oncogenic HMGA2: short or small? Genes Dev. 2007;21:1005–9.

    Article  CAS  PubMed  Google Scholar 

  43. Hammond SM, Sharpless NE. HMGA2, microRNAs, and stem cell aging. Cell. 2008;135:1013–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pfannkuche K, Summer H, Li O, Hescheler J, Droge P. The high mobility group protein HMGA2: a co-regulator of chromatin structure and pluripotency in stem cells? Stem Cell Rev Rep. 2009;5:224–30.

    Article  CAS  PubMed  Google Scholar 

  45. Fedele M, Palmieri D, Fusco A. HMGA2: a pituitary tumour subtype-specific oncogene? Mol Cell Endocrinol. 2010;326:19–24.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang S, Mo Q, Wang X. Oncological role of HMGA2 (Review). Int J Oncol. 2019;55:775–88.

    CAS  PubMed  Google Scholar 

  47. Palumbo A Jr, Da Costa NM, Esposito F, De Martino M, D'Angelo D, de Sousa VP, et al. HMGA2 overexpression plays a critical role in the progression of esophageal squamous carcinoma. Oncotarget. 2016;7:25872–84.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Palumbo Junior A, Da Costa NM, Esposito F, Fusco A, Pinto LF. High mobility group A proteins in esophageal carcinomas. Cell Cycle. 2016;15:2410–3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Wei R, Shang Z, Leng J, Cui L. Increased expression of high-mobility group A2: a novel independent indicator of poor prognosis in patients with esophageal squamous cell carcinoma. J Cancer Res Ther. 2016;12:1291–97.

    Article  CAS  PubMed  Google Scholar 

  50. Li C, Liu X, Liu Y, Liu X, Wang R, Liao J, et al. Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway. Cell Death Dis. 2018;9:1009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This study was supported by KAKENHI grants (grant nos. 17H04285, 18K08626, 18K09338, 18K16322, and 19K09077).

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Authors and Affiliations

  1. Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan

    Masumi Wada, Takako Tanaka, Tetsuya Idichi, Masahiro Noda, Ken Sasaki, Yoshiaki Kita, Hiroshi Kurahara, Kosei Maemura & Shoji Natsugoe

  2. Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba, Japan

    Yusuke Goto, Reona Okada & Naohiko Seki

  3. Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan

    Shogo Moriya

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Wada, M., Goto, Y., Tanaka, T. et al. RNA sequencing-based microRNA expression signature in esophageal squamous cell carcinoma: oncogenic targets by antitumor miR-143-5p and miR-143-3p regulation. J Hum Genet 65, 1019–1034 (2020). https://doi.org/10.1038/s10038-020-0795-x

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