miR‑494 inhibits cancer‑initiating cell phenotypes and reverses resistance to lapatinib by downregulating FGFR2 in HER2‑positive gastric cancer

  • Authors:
    • Yanxia Yu
    • Xuejuan Yu
    • Hong Liu
    • Qingxun Song
    • Yongmei Yang
  • View Affiliations

  • Published online on: May 16, 2018     https://doi.org/10.3892/ijmm.2018.3680
  • Pages: 998-1007
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Abstract

In gastric cancer, >15% of cases are associated with the amplification of human epidermal growth factor receptor 2 (HER2), which leads to poor clinical outcomes. Lapatinib, a potent ATP‑competitive inhibitor, is a small, orally active molecule, which inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1. The activation of receptor tyrosine kinases can contribute to lapatinib resistance in HER2‑positive gastric cancer. The aim of the present study was to explore the effects of miR‑494 and FGFR2 in regulation of cancer‑initiating cell phenotypes and therapeutic efficiency of lapatinib in HER2‑positive gastric cancer. Western blot analysis was used to identify that the expression of fibroblast growth factor receptor 2 (FGFR2), a receptor tyrosine kinase, was upregulated in gastric cancer tissues. Formation of cancer initiating cells (CICs) and resistance to lapatinib were determined using sphere growth assay and MTT assay, respectively. The overexpression of FGFR2 promoted the generation of cancer‑initiating cells (CICs) and resistance to lapatinib in HER2‑positive gastric cancer YCC1 cells. In addition, it was observed that overexpression of microRNA (miR)‑494 downregulated the protein expression of FGFR2, inhibited the formation of CICs and reversed lapatinib resistance in YCC1‑F cells (HER2‑positive, FGFR2 overexpressing and lapatinib‑resistant gastric cancer cells). Therefore, it was concluded that miR‑494 inhibited the CIC phenotype and reversed resistance to lapatinib by inhibiting FGFR2 in HER2‑positive gastric cancer.

References

1 

Yuan E: Taiwan area: Death rate of ten leading sites of malignant neoplasms. Taiwan: Department of Health, Executive Yuan; pp. 160–173. 2006

2 

Terry MB, Gaudet MM and Gammon MD: The epidemiology of gastric cancer. Semin Radiat Oncol. 12:111–127. 2002. View Article : Google Scholar : PubMed/NCBI

3 

Ushijima T and Sasako M: Focus on gastric cancer. Cancer Cell. 5:121–125. 2004. View Article : Google Scholar : PubMed/NCBI

4 

González CA, Sala N and Capellá G: Genetic susceptibility and gastric cancer risk. Int J Cancer. 100:249–260. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Zheng L, Wang L, Ajani J and Xie K: Molecular basis of gastric cancer development and progression. Gastric Cancer. 7:61–77. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Smith MG, Hold GL, Tahara E and El-Omar EM: Cellular and molecular aspects of gastric cancer. 12:2979–2990. 2006.

7 

El-Rifai W and Powell SM: Molecular biology of gastric cancer. Semin Radiat Oncology. 12:128–140. 2002. View Article : Google Scholar

8 

Watson SA, Grabowska AM, El-Zaatari M and Takhar A: Gastrin-active participant or bystander in gastric carcinogenesis? Nat Rev Cancer. 6:936–946. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Resende C, Ristimäki A and Machado JC: Genetic and epigenetic alteration in gastric carcinogenesis. Helicobacter. 15(Suppl 1): S34–S39. 2010. View Article : Google Scholar

10 

Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, Yamashita J, Matsuda M, Sakaguchi T, Hirao T and Nakano H: The prognostic significance of amplification and overexpression of c-MET and c-erb B-2 in human gastric carcinomas. Cancer. 85:1894–1902. 1999. View Article : Google Scholar : PubMed/NCBI

11 

Chen CT, Kim H, Liska D, Gao S, Christensen JG and Weiser MR: MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther. 11:660–669. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Yoo CH, et al: HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 51:1371–1379. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Zhang XL, Yang YS, Xu DP, Qu JH, Guo MZ, Gong Y and Huang J: Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg. 33:2112–2118. 2009. View Article : Google Scholar : PubMed/NCBI

14 

De Vita F, Giuliani F, Silvestris N, Catalano G, Ciardiello F and Orditura M: Human epidermal growth factor receptor 2 (HER2) in gastric cancer: A new therapeutic target. Cancer Treat Rev. 36(Suppl 3): S11–S15. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 355:2733–2743. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Hierro C, Rodon J and Tabernero J: Fibroblast growth factor (FGF) receptor/FGF inhibitors: Novel targets and strategies for optimization of response of solid tumors. Semin Oncol. 42:801–819. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, Zhang S, Lee M, Wu J, Lim KH, et al: A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 61:673–684. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Huang T, Wang L, Liu D, Li P, Xiong H, Zhuang L, Sun L, Yuan X and Qiu H: FGF7/FGFR2 signal promotes invasion and migration in human gastric cancer through upregulation of thrombospondin-1. Int J Oncol. 50:1501–1512. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Kim HP, Han SW, Song SH, Jeong EG, Lee MY, Hwang D, Im SA, Bang YJ and Kim TY: Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer. Oncogene. 33:3334–3341. 2014. View Article : Google Scholar

20 

Edge SB and Compton CC: The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Liao XH, Lu DL, Wang N, Liu LY, Wang Y, Li YQ, Yan TB, Sun XG, Hu P and Zhang TC: Estrogen receptor α mediates proliferation of breast cancer MCF-7 cells via a p21/PCNA/E2F1-dependent pathway. FEBS J. 281:927–942. 2014. View Article : Google Scholar

22 

Ghosh RD, Ghuwalewala S, Das P, Mandloi S, Alam SK, Chakraborty J, Sarkar S, Chakrabarti S, Panda CK and Roychoudhury S: MicroRNA profiling of cisplatin-resistant oral squamous cell carcinoma cell lines enriched with cancer-stem-cell-like and epithelial-mesenchymal transition-type features. Sci Rep. 6:239322016. View Article : Google Scholar : PubMed/NCBI

23 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar

24 

Lu DL, Sookthai D, Le Cornet C, Katzke VA, Johnson TS, Kaaks R and Fortner RT: Reproducibility of serum oxysterols and lanosterol among postmenopausal women: Results from EPIC-Heidelberg. Clin Biochem. 52:117–122. 2017. View Article : Google Scholar : PubMed/NCBI

25 

Zöller M: CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 11:254–267. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Yoshikawa K, Noguchi K, Nakano Y, Yamamura M, Takaoka K, Hashimoto-Tamaoki T and Kishimoto H: The Hippo pathway transcriptional co-activator, YAP, confers resistance to cisplatin in human oral squamous cell carcinoma. Int J Oncol. 46:2364–2370. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Lee RC, Feinbaum RL and Ambros V: The C. elegans heter-ochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 75:843–854. 1993. View Article : Google Scholar : PubMed/NCBI

28 

Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Müller P, et al: Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 408:86–89. 2000. View Article : Google Scholar : PubMed/NCBI

29 

Luqmani YA, Graham M and Coombes RC: Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues. Br J Cancer. 66:2731992. View Article : Google Scholar : PubMed/NCBI

30 

Nagatsuma AK, Aizawa M, Kuwata T, Doi T, Ohtsu A, Fujii H and Ochiai A: Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer. 18:227–238. 2015. View Article : Google Scholar

31 

Wesche J, Haglund K and Haugsten EM: Fibroblast growth factors and their receptors in cancer. Biochem J. 437:199–213. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Park J, Kim SY, Kim HJ, Kim KM, Choi EY and Kang MS: A reciprocal regulatory circuit between CD44 and FGFR2 via c-myc controls gastric cancer cell growth. Oncotarget. 7:28670–28683. 2016.PubMed/NCBI

33 

Moriyama T, Ohuchida K, Mizumoto K, Cui L, Ikenaga N, Sato N and Tanaka M: Enhanced cell migration and invasion of CD133+ pancreatic cancer cells cocultured with pancreatic stromal cells. Cancer. 116:3357–3368. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Fang XJ, Jiang H, Zhu YQ, Zhang LY, Fan QH and Tian Y: Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells. Oncol Rep. 31:2735–2742. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Kinugasa Y, Matsui T and Takakura N: CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment. Stem Cells. 32:145–156. 2014. View Article : Google Scholar : PubMed/NCBI

36 

He W, Li Y, Chen X, Lu L, Tang B, Wang Z, Pan Y, Cai S, He Y and Ke Z: miR-494 acts as an anti-oncogene in gastric carcinoma by targeting c-myc. J Gastroenterol Hepatol. 29:1427–1434. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Zhao XQ, Liang TJ and Fu JW: miR-494 inhibits invasion and proliferation of gastric cancer by targeting IGF-1R. Eur Rev Med Pharmacol Sci. 20:3818–3824. 2016.PubMed/NCBI

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August 2018
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Copy and paste a formatted citation
APA
Yu, Y., Yu, X., Liu, H., Song, Q., & Yang, Y. (2018). miR‑494 inhibits cancer‑initiating cell phenotypes and reverses resistance to lapatinib by downregulating FGFR2 in HER2‑positive gastric cancer. International Journal of Molecular Medicine, 42, 998-1007. https://doi.org/10.3892/ijmm.2018.3680
MLA
Yu, Y., Yu, X., Liu, H., Song, Q., Yang, Y."miR‑494 inhibits cancer‑initiating cell phenotypes and reverses resistance to lapatinib by downregulating FGFR2 in HER2‑positive gastric cancer". International Journal of Molecular Medicine 42.2 (2018): 998-1007.
Chicago
Yu, Y., Yu, X., Liu, H., Song, Q., Yang, Y."miR‑494 inhibits cancer‑initiating cell phenotypes and reverses resistance to lapatinib by downregulating FGFR2 in HER2‑positive gastric cancer". International Journal of Molecular Medicine 42, no. 2 (2018): 998-1007. https://doi.org/10.3892/ijmm.2018.3680