The long noncoding RNA cancer susceptibility candidate 2 (CASC2) has been shown to play a crucial role in cancer cell chemoresistance. However, its function and underlying molecular mechanism in hepatocellular carcinoma (HCC) chemoresistance remain unknown. In this study, we used cisplatin (DDP)-resistant HCC cells to investigate CASC2 function and its underlying mechanism. The results demonstrated that CASC2 expression was significantly reduced in HCC tissues and cells, especially in DDP-resistant HCC tissues and cells. Lower CASC2 expression was strongly correlated with shorter survival times in patients with HCC. Functionally, CASC2 overexpression sensitized DDP-resistant Huh7/DDP and SMMC-7721/DDP cells to DDP. Mechanically, CASC2 improved the sensitivity of HCC cells to DDP through sponging miR-222. Taken together, these findings suggested that overexpression of CASC2 overcame DDP resistance in HCC by regulating miR-222 expression, thereby providing a potential therapeutic strategy for overcoming HCC cell chemoresistance.
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References
1.
AmbrosV. (2001). microRNAs: tiny regulators with great potential. Cell, 107, 823–826.
2.
BaldinuP., CossuA., MancaA., SattaM.P., SiniM.C., PalombaG., et al. (2007). CASC2a gene is down-regulated in endometrial cancer. Anticancer Res, 27, 235–243.
CarringtonJ.C., and AmbrosV. (2003). Role of microRNAs in plant and animal development. Science (New York, NY), 301, 336–338.
5.
El-SeragH.B., and MasonA.C. (1999). Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med, 340, 745–750.
6.
FengY., ZouW., HuC., LiG., ZhouS., HeY., et al. (2017). Modulation of CASC2/miR-21/PTEN pathway sensitizes cervical cancer to cisplatin. Arch Biochem Biophys, 623–624, 20–30.
7.
GalanskiM. (2006). Recent developments in the field of anticancer platinum complexes. Recent Pat Anticancer Drug Discov, 1, 285–295.
8.
GalardiS., MercatelliN., GiordaE., MassaliniS., FrajeseG.V., CiafreS.A., et al. (2007). miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem, 282, 23716–23724.
9.
GaoW., LinS., ChengC., ZhuA., HuY., ShiZ., et al. (2019). Long non-coding RNA CASC2 regulates Sprouty2 via functioning as a competing endogenous RNA for miR-183 to modulate the sensitivity of prostate cancer cells to docetaxel. Arch Biochem Biophys, 665, 69–78.
GuoL.L., SongC.H., WangP., DaiL.P., ZhangJ.Y., and WangK.J. (2015). Competing endogenous RNA networks and gastric cancer. World J Gastroenterol, 21, 11680–11687.
12.
HuangG., WuX., LiS., XuX., ZhuH., and ChenX. (2016). The long noncoding RNA CASC2 functions as a competing endogenous RNA by sponging miR-18a in colorectal cancer. Sci Rep 6,26524.
13.
JiangC., ShenF., DuJ., FangX., LiX., SuJ., et al. (2018). Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR-193a-5p and regulating mTOR expression. Biomed Pharmacother, 97, 844–850.
14.
JinX., CaiL., WangC., DengX., YiS., LeiZ., et al. (2018). CASC2/miR-24/miR-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3. Cell Death Dis 9,318.
15.
JohnssonP., LipovichL., GranderD., and MorrisK.V. (2014). Evolutionary conservation of long non-coding RNAs; sequence, structure, function. Biochim Biophys Acta, 1840, 1063–1071.
16.
KarakatsanisA., PapaconstantinouI., GazouliM., LyberopoulouA., PolymeneasG., and VorosD. (2013). Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog, 52, 297–303.
17.
KoberleB., TomicicM.T., UsanovaS., and KainaB. (2010). Cisplatin resistance: preclinical findings and clinical implications. Biochim Biophys Acta, 1806, 172–182.
18.
LebwohlD., and CanettaR. (1998). Clinical development of platinum complexes in cancer therapy: an historical perspective and an update. Eur J Cancer (Oxford, Engl 1990), 34, 1522–1534.
19.
LiY., LvS., NingH., LiK., ZhouX., XvH., et al. (2018). Down-regulation of CASC2 contributes to cisplatin resistance in gastric cancer by sponging miR-19a. Biomed Pharmacother, 108, 1775–1782.
20.
LiaoY., ShenL., ZhaoH., LiuQ., FuJ., GuoY., et al. (2017). LncRNA CASC2 Interacts with miR-181a to modulate glioma growth and resistance to TMZ through PTEN pathway. J Cell Biochem, 118, 1889–1899.
21.
LinC., and YangL. (2018). Long noncoding RNA in cancer: wiring signaling circuitry. Trends Cell Biol, 28, 287–301.
22.
Martens-UzunovaE.S., BottcherR., CroceC.M., JensterG., VisakorpiT., and CalinG.A. (2014). Long noncoding RNA in prostate, bladder, and kidney cancer. Eur Urol, 65, 1140–1151.
23.
PalmieriG., PaliogiannisP., SiniM.C., MancaA., PalombaG., DonedduV., et al. (2017). Long non-coding RNA CASC2 in human cancer. Crit Rev Oncol Hematol, 111, 31–38.
24.
ShenS., LinY., YuanX., ShenL., ChenJ., ChenL., et al. (2016). Biomarker microRNAs for diagnosis, prognosis and treatment of hepatocellular carcinoma: a functional survey and comparison. Sci Rep 6,38311.
25.
SunX., DuP., YuanW., DuZ., YuM., YuX., et al. (2015). Long non-coding RNA HOTAIR regulates cyclin J via inhibition of microRNA-205 expression in bladder cancer. Cell Death Dis 6,e1907.
26.
WangH., TanG., DongL., ChengL., LiK., WangZ., et al. (2012). Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS One 7,e34210.
27.
WangK., LongB., ZhouL.Y., LiuF., ZhouQ.Y., LiuC.Y., et al. (2014). CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nat Commun 5,3596.
28.
WangL., ShangX., and FengQ. (2019). LncRNA TATDN1 contributes to the cisplatin resistance of non-small cell lung cancer through TATDN1/miR-451/TRIM66 axis. Cancer Biol Ther, 20, 261–271.
29.
WangP., ChenD., MaH., and LiY. (2017b). LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR-21-5p/SOX7 axis. OncoTargets Ther, 10, 5137–5149.
30.
WangP., LiuY.H., YaoY.L., LiZ., LiZ.Q., MaJ., et al. (2015). Long non-coding RNA CASC2 suppresses malignancy in human gliomas by miR-21. Cell Signal, 27, 275–282.
31.
WangY., LiuZ., YaoB., LiQ., WangL., WangC., et al. (2017a). Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis. Mol Cancer 16,123.
32.
WongQ.W., ChingA.K., ChanA.W., ChoyK.W., ToK.F., LaiP.B., et al. (2010). MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling. Clin Cancer Res, 16, 867–875.
33.
YuY., LiangS., ZhouY., LiS., LiY., and LiaoW. (2019). HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling. J Cell Biochem, 120, 2816–2827.
34.
ZengL.P., HuZ.M., LiK., and XiaK. (2016). miR-222 attenuates cisplatin-induced cell death by targeting the PPP2R2A/Akt/mTOR Axis in bladder cancer cells. J Cell Mol Med, 20, 559–567.
35.
ZhangH.L., SiL.B., ZengA., LongF., QiZ., ZhaoR., et al. (2018). MicroRNA-21 antisense oligonucleotide improves the sensitivity of A375 human melanoma cell to cisplatin: an in vitro study. J Cell Biochem, 119, 3129–3141.
36.
ZhangY., DangY.W., WangX., YangX., ZhangR., LvZ.L., et al. (2017). Comprehensive analysis of long non-coding RNA PVT1 gene interaction regulatory network in hepatocellular carcinoma using gene microarray and bioinformatics. Am J Transl Res, 9, 3904–3917.
37.
ZhaoJ.J., LinJ., YangH., KongW., HeL., MaX., et al. (2016). MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem, 291, 22859.
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