HOXA11-AS promotes the migration and invasion of hepatocellular carcinoma cells by inhibiting miR-124 expression by binding to EZH2
The objective of this study was to examine the function of the long non-coding RNA (lncRNA) HOXA11-AS in hepatocellular carcinoma (HCC). In total, samples from liver tumor and surrounding normal liver tissues were collected from 66 cases of HCC patients. Normal liver cell line HL-7702 and HCC cell lines HepG2, Hep3B, MHCC-97H and BEL7402 were used. Cells were transfected with different small interference RNAs or vectors. Then, transwell assay, qRT-PCR, CHIP, RIP and Western blot experiments were performed. We found that the HOXA11-AS expression level was higher in HCC samples than surrounding normal liver tissues. And the higher expression level of HOXA11-AS in HCC patients indicated a lower 5-year survival rate. Knockdown of HOXA11-AS in HepG2 and Hep3B cells caused impaired cell invasion and migration abilities. Otherwise, upregulation of HOXA11-AS in MHCC-97H and BEL7402 cells displayed higher invasion and migration capabilities. We also demonstrated that HOXA11-AS could inhibit miR-124 expression by binding to EZH2. Furthermore, overexpression of miR-124 or knockdown EZH2 expression could reverse the HOXA11-AS-induced migration and invasion effects in HCC cells. In summary, the high HOXA11-AS expression in HCC patients is associated with the poor outcome. HOXA11-AS could inhibit miR-124 expression by binding to EZH2 and thus promoted the migration and invasion of HCC cells.
KeywordsHCC HOXA11-AS miR-124 EZH2 Invasion Migration
All the authors participated in the design, data analysis and interpretation and review of the manuscript; YNZ, ZZS, GYG and DC conducted the experiments; CW analyzed the data; and WLZ and YSB prepared the manuscript.
This work was supported by grants from the Science and Technology Development Project of JiLin Province (20180101124JC), the Special Project for Health Research of JiLin Province (2018SCZ031), the Health Technology Innovation Project of JiLin Province (3D517ED43430), and the Norman Bethune Program of JiLin University (2012201).
Compliance with ethical standards
Conflict of interest
The authors declare no potential conflicts of interest with respect to the research, authorship and publication of this article.
The participants provided informed consent, and the ethics committee of the hospital issued approval of the study and its protocols.
- 1.Hu J, Song C, Duan B, Zhang X, Li D, Zhu L, Gao H. LncRNA-SVUGP2 suppresses progression of hepatocellular carcinoma. Oncotarget. 2017;8:97835–50.Google Scholar
- 2.Manlio V. Protein intake, chronic liver diseases, and hepatocellular carcinoma. Hepatology. 2015;61:730.Google Scholar
- 5.Haiying C, Tao M, Xuemin L, Manni S, Chunxiao T, Jing L, He W, Juan D. Long non-coding RNA MALAT-1 is downregulated in preeclampsia and regulates proliferation, apoptosis, migration and invasion of JEG-3 trophoblast cells. Int J Clin Exp Pathol. 2015;8:12718–27.Google Scholar
- 7.Li SP, Xu HX, Yu Y, He JD, Wang Z, Xu YJ, Wang CY, Zhang HM, Zhang RX, Zhang JJ. LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway. Oncotarget. 2016;7:42431–46.Google Scholar
- 8.Wang F, Ying HQ, He BS, Pan YQ, Deng QW, Sun HL, Chen J, Liu X, Wang SK. Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway. Oncotarget. 2015;6:7899–917.Google Scholar
- 11.Yu W, Peng W, Jiang H, Sha H, Li J. LncRNA HOXA11-AS promotes proliferation and invasion by targeting miR-124 in human non-small cell lung cancer cells. Tumour Biol. 2017;39:1010428317721440.Google Scholar
- 13.Liu B, Li J, Liu X, Zheng M, Yang Y, Lyu Q, Jin L. Long non-coding RNA HOXA11-AS promotes the proliferation HCC cells by epigenetically silencing DUSP5. Oncotarget. 2017;8:109509–21.Google Scholar
- 14.Richards EJ, Permuth-Wey J, Li Y, Chen YA, Coppola D, Reid BM, Lin HY, Teer JK, Berchuck A, Birrer MJ, Lawrenson K, Monteiro AN, Schildkraut JM, Goode EL, Gayther SA, Sellers TA, Cheng JQ. A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer. Oncotarget. 2015;6:34745–57.CrossRefGoogle Scholar
- 17.Kim HJ, Eoh KJ, Kim LK, Nam EJ, Yoon SO, Kim KH, Lee JK, Kim SW, Kim YT. The long noncoding RNA HOXA11 antisense induces tumor progression and stemness maintenance in cervical cancer. Oncotarget. 2011;7:83001.Google Scholar
- 26.Wang XN, Zhang LH, Cui XD, Wang MX, Zhang GY, Yu PL. lncRNA HOXA11-AS is involved in fracture healing through regulating mir-124-3p. Eur Rev Med Pharmacol Sci. 2017;21:4771–6.Google Scholar
- 27.Colvin H, Nishida N, Konno M, Haraguchi N, Takahashi H, Nishimura J, Hata T, Kawamoto K, Asai A, Tsunekuni K, Koseki J, Mizushima T, Satoh T, Doki Y, Mori M, Ishii H. Oncometabolite D-2-Hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer. Sci Rep. 2016;6:36289.CrossRefGoogle Scholar
- 28.Jiang FZ, He YY, Wang HH, Zhang HL, Zhang J, Yan XF, Wang XJ, Che Q, Ke JQ, Chen Z, Tong H, Zhang YL, Wang FY, Li YR, Wan XP. Mutant p53 induces EZH2 expression and promotes epithelial-mesenchymal transition by disrupting p68-Drosha complex assembly and attenuating miR-26a processing. Oncotarget. 2015;6:44660–74.Google Scholar
- 33.Chen JF, Luo X, Xiang LS, Li HT, Zha L, Li N, He JM, Xie GF, Xie X, Liang HJ. EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/beta-catenin signaling. Oncotarget. 2016;7:41540–58.Google Scholar