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MicroRNA let-7b suppresses human gastric cancer malignancy by targeting ING1

Cancer Gene Therapy volume 22, pages 122–129 (2015)Cite this article

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Abstract

MicroRNAs (miRNAs) are important regulators that play key roles in tumorigenesis and tumor progression. In this study, we investigate whether let-7b acts as a tumor suppressor to inhibit invasion and metastasis in gastric cancers. We analyzed the expression of let-7b in 60 pair-matched gastric neoplastic and adjacent non-neoplastic tissues by quantitative real-time polymerase chain reaction. Functional analysis of let-7b expression was assessed in vitro in gastric cancer cell lines with let-7b precursor and inhibitor. The roles of let-7b in tumorigenesis and tumor metastasis were analyzed using a stable let-7b expression plasmid in nude mice. A luciferase reporter assay was used to assess the effect of let-7b on inhibitor of growth family, member 1 (ING1) expression. Real-time PCR showed decreased levels of let-7b expression in metastatic gastric cancer tissues and cell lines that are potentially highly metastatic. Cell invasion and migration were significantly impaired in GC9811-P and SGC7901-M cell lines after transfection with let-7b mimics. Nude mice with xenograft models of gastric cancer confirmed that let-7b could inhibit gastric cancer metastasis in vivo after transfection by the lentivirus pGCsil-GFP- let-7b. Luciferase reporter assays demonstrated that let-7b directly binds to the 3′-UTR of ING1, and real-time PCR and western blotting further indicated that let-7b downregulated the expression of ING1 at the mRNA and protein levels. Our study demonstrates that overexpression of let-7b in gastric cancer can inhibit invasion and migration of gastric cancer cells through directly targeting the tumor metastasis-associated gene ING1. These findings help clarify the molecular mechanisms involved in gastric cancer metastasis and indicate that let-7b modulation may be a bona fide treatment of gastric cancer.

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References

  1. Chen J, Chen LJ, Zhou HC, Yang RB, Lu Y, Xia YL et al. Prognostic value of matrix metalloproteinase-9 in gastric cancer: a meta-analysis. Hepatogastroenterology 2014; 61: 518–524.

    PubMed  Google Scholar 

  2. Yang Y, Bai ZG, Yin J, Wu GC, Zhang ZT . Role of c-Src activity in the regulation of gastric cancer cell migration. Oncol Rep 2014; 32: 45–49.

    Article  CAS  Google Scholar 

  3. Li Y, Tan BB, Zhao Q, Fan LQ, Wang D, Liu Y . ZNF139 promotes tumor metastasis by increasing migration and invasion in human gastric cancer cells. Neoplasma 2014; 61: 291–298.

    Article  CAS  Google Scholar 

  4. Yu SY, Li Y, Fan LQ, Zhao Q, Tan BB, Liu Y . Impact of Annexin A3 expression in gastric cancer cells. Neoplasma 2014; 61: 257–264.

    Article  CAS  Google Scholar 

  5. Oo HZ, Sentani K, Sakamoto N, Anami K, Naito Y, Uraoka N et al. Overexpression of ZDHHC14 promotes migration and invasion of scirrhous type gastric cancer. Oncol Rep 2014; 32: 403–410.

    Article  CAS  Google Scholar 

  6. Li XS, Xu Q, Fu XY, Luo WS . Heat shock protein 22 overexpression is associated with the progression and prognosis in gastric cancer. J Cancer Res Clin Oncol 2014; 140: 1305–1313.

    Article  CAS  Google Scholar 

  7. Guan SS, Chang J, Cheng CC, Luo TY, Ho AS, Wang CC et al. Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growth in vitro and in vivo. Oncotarget 2014; 5: 4868–4880.

    Article  Google Scholar 

  8. Luo BH, Xiong F, Wang JP, Li JH, Zhong M, Liu QL et al. Epidermal growth factor-like domain-containing protein 7 (EGFL7) enhances EGF receptor-AKT signaling, epithelial-mesenchymal transition, and metastasis of gastric cancer cells. PLoS One 2014; 9: e99922.

    Article  Google Scholar 

  9. Vaiopoulos AG, Kostakis ID, Gkioka E, Athanasoula KC, Pikoulis E, Papalambros A et al. Detection of circulating tumor cells in colorectal and gastric cancer using a multiplex PCR assay. Anticancer Res 2014; 34: 3083–3092.

    CAS  PubMed  Google Scholar 

  10. Choi MR, An CH, Chung YJ, Choi YJ, Yoo NJ, Lee SH . Mutational and expressional analysis of ERBB3 gene in common solid cancers. APMIS 2014; 122: 1207–1212.

    Article  CAS  Google Scholar 

  11. Musiani D, Konda JD, Pavan S, Torchiaro E, Sassi F, Noghero A et al. Heat-shock protein 27 (HSP27, HSPB1) is up-regulated by MET kinase inhibitors and confers resistance to MET-targeted therapy. FASEB J e-pub ahead of print 5 June 2014.

  12. Xu L, Qu X, Li H, Li C, Liu J, Zheng H et al. Src/caveolin-1-regulated EGFR activation antagonizes TRAIL-induced apoptosis ingastric cancer cells. Oncol Rep 2014; 32: 318–324.

    Article  CAS  Google Scholar 

  13. Aprile G, Giampieri R, Bonotto M, Bittoni A, Ongaro E, Cardellino GG et al. The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey. Expert Opin Investig Drugs 2014; 23: 925–942.

    Article  CAS  Google Scholar 

  14. Kurokawa Y, Matsuura N, Kawabata R, Nishikawa K, Ebisui C, Yokoyama Y et al. Prognostic Impact of Major Receptor Tyrosine Kinase Expression in Gastric Cancer. Ann Surg Oncol 2014; 21: 584–590.

    Article  Google Scholar 

  15. Nielsen TO, Friis-Hansen L, Poulsen SS, Federspiel B, Sorensen BS . Expression of the EGF family in gastric cancer: downregulation of HER4 and its activating ligand NRG4. PLoS One 2014; 9: e94606.

    Article  Google Scholar 

  16. Pertino MW, Lopez C, Theoduloz C, Schmeda-Hirschmann G . 1,2,3-triazole-substituted oleanolic Acid derivatives: synthesis and antiproliferative activity. Molecules 2013; 18: 7661–7667.

    Article  CAS  Google Scholar 

  17. Rasul A, Khan M, Yu B, Ali M, Bo YJ, Yang H et al. a sesquiterpene lactone, induces apoptosis in SGC-7901 cells via mitochondrial and phosphatidylinositol 3-kinase/Akt signaling pathways. Arch Pharm Res 2013; 36: 1262–1269.

    Article  CAS  Google Scholar 

  18. Hong KJ, Wu DC, Cheng KH, Chen LT, Hung WC . RECK inhibits stemness gene expression and tumorigenicity of gastric cancer cells by suppressing ADAM-mediated Notch1 activation. J Cell Physiol 2014; 229: 191–201.

    Article  CAS  Google Scholar 

  19. Liu QS, Zhang J, Liu M, Dong WG . Lentiviral-mediated miRNA against liver-intestine cadherin suppresses tumor growth and invasiveness of human gastric cancer. Cancer Sci 2010; 101: 1807–1812.

    Article  Google Scholar 

  20. Yang B, Jing C, Wang J, Guo X, Chen Y, Xu R et al. Identification of microRNAs associated with lymphangiogenesis in human gastric cancer. Clin Transl Oncol 2014; 16: 374–379.

    Article  CAS  Google Scholar 

  21. Guo LH, Li H, Wang F, Yu J, He JS . The tumor suppressor roles of miR-433 and miR-127 in gastric cancer. Int J Mol Sci 2013; 14: 14171–14184.

    Article  Google Scholar 

  22. Fang Y, Shen H, Li H, Cao Y, Qin R, Long L et al. miR-106a confers cisplatin resistance by regulating PTEN/Akt pathway in gastric cancer cells. Acta Biochim Biophys Sin (Shanghai) 2013; 45: 963–972.

    Article  CAS  Google Scholar 

  23. Wu XJ, Mi YY, Yang H, Hu AK, Li C, Li XD et al. Association of the hsa-mir-499 (rs3746444) polymorphisms with gastric cancer risk in the Chinese population. Onkologie 2013; 36: 573–576.

    Article  CAS  Google Scholar 

  24. Shiotani A, Murao T, Kimura Y, Matsumoto H, Kamada T, Kusunoki H et al. Identification of serum miRNAs as novel non-invasive biomarkers for detection of high risk for early gastric cancer. Br J Cancer 2013; 109: 2323–2330.

    Article  CAS  Google Scholar 

  25. Yoon JH, Choi YJ, Choi WS, Nam SW, Lee JY, Park WS . Functional analysis of the NH2-terminal hydrophobic region and BRICHOS domain of GKN1. Biochem Biophys Res Commun 2013; 440: 689–695.

    Article  CAS  Google Scholar 

  26. Iwaya T, Fukagawa T, Suzuki Y, Takahashi Y, Sawada G, Ishibashi M et al. Contrasting expression patterns of histone mRNA and microRNA 760 in patients with gastric cancer. Clin Cancer Res 2013; 19: 6438–6449.

    Article  CAS  Google Scholar 

  27. Won KJ, Im JY, Yun CO, Chung KS, Kim YJ, Lee JS et al. Human Noxin is an anti-apoptotic protein in response to DNA damage of A549 non-small cell lung carcinoma. Int J Cancer 2014; 134: 2595–2604.

    Article  CAS  Google Scholar 

  28. Nakadate Y, Kodera Y, Kitamura Y, Tachibana T, Tamura T, Koizumi F . Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint. Biochem Biophys Res Commun 2013; 441: 793–798.

    Article  CAS  Google Scholar 

  29. Shen J, Niu W, Zhou M, Zhang H, Ma J, Wang L et al. MicroRNA-410 suppresses migration and invasion by targeting MDM2 in gastric cancer. PLoS One 2014; 9: e104510.

    Article  Google Scholar 

  30. McLean MH, El-Omar EM . Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol 2014; 11: 664–674.

    Article  CAS  Google Scholar 

  31. Shin VY, Chu KM . MiRNA as potential biomarkers and therapeutic targets for gastric cancer. World J Gastroenterol 2014; 20: 10432–10439. Review.

    Article  CAS  Google Scholar 

  32. Zhao H, Wang Y, Yang L, Jiang R, Li W . MiR-25 promotes gastric cancer cells growth and motility by targeting RECK. Mol Cell Biochem 2014; 385: 207–213.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Kim YM, Kim IH, Nam TJ . Inhibition of AGS human gastric cancer cell invasion and proliferation by Capsosiphon fulvescens glycoprotein. Mol Med Rep 2013; 8: 11–16.

    Article  CAS  Google Scholar 

  35. Tong F, Cao P, Yin Y, Xia S, Lai R, Liu S . MicroRNAs in gastric cancer: from benchtop to bedside. Dig Dis Sci 2014; 59: 24–30.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Internal Medicine-Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China

    X Han & Z Wang

  2. Surgical oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China

    Y Chen

  3. Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China

    N Yao

  4. Department of Pharmacology, Bengbu Medical College, Bengbu, Anhui, China

    H Liu

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  1. X Han
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  2. Y Chen
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  5. Z Wang
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Correspondence to Z Wang.

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Han, X., Chen, Y., Yao, N. et al. MicroRNA let-7b suppresses human gastric cancer malignancy by targeting ING1. Cancer Gene Ther 22, 122–129 (2015). https://doi.org/10.1038/cgt.2014.75

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