Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence

Gao,Jian‑Zhi; Li,Jia; Du,Jing‑Li; Li,Xiao‑Lei

doi:10.3892/ol.2016.4130

Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence

Authors:
- Jian‑Zhi Gao
- Jia Li
- Jing‑Li Du
- Xiao‑Lei Li
View Affiliations

Affiliations: Department of Basic Medical Sciences, Xinxiang Medical College, Xinxiang, Henan 453003, P.R. China, Department of Pathology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China, Department of Molecular Biology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
Published online on: January 19, 2016 https://doi.org/10.3892/ol.2016.4130
Pages: 1791-1798

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to investigate the expression level of HOX transcript antisense RNA (HOTAIR) in hepatocellular carcinoma (HCC) and its association with various clinicopathological characteristics, and to further explore the molecular mechanisms of HOTAIR function in HCC. Quantitative reverse transcription‑polymerase chain reaction (RT‑PCR) was used to detect the expression level of HOTAIR in 60 paired fresh HCC samples and adjacent normal liver tissue samples. The association between HOTAIR expression and clinicopathological parameters was analyzed. Lentivirus‑mediated HOTAIR‑specific small hairpin RNA vectors were transfected into HepG2 cells. Cell proliferation and invasion in vitro were examined by MTT and Transwell assays, respectively. A xenograft model was used to analyze the tumorigenesis of liver cancer cells in vivo. In addition, semi‑quantitative RT‑PCR was used to detect the expression level of Wnt/β-catenin signaling molecules under the condition of HOTAIR inhibition. The results revealed that the expression level of HOTAIR in HCC tissues was higher than that in adjacent non‑cancerous tissues. HOTAIR expression was significantly associated with poor tumor differentiation (P=0.002), metastasis (P=0.002) and early recurrence (P=0.001). In vitro, the inhibition of HOTAIR in liver cancer cells resulted in the suppression of cell proliferation and invasion. HOTAIR depletion significantly inhibited the rate of growth of liver cancer cells in vivo. Furthermore, the expression levels of Wnt and β‑catenin were downregulated when HOTAIR expression was suppressed. In conclusion, HOTAIR is important in the progression and recurrence of HCC, partly through the regulation of the Wnt/β‑catenin signaling pathway. Targeting HOTAIR may be a novel therapeutic strategy for HCC.

View Figures

View References

1	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
2	Bosch FX, Ribes J, Diaz M and Cléries R: Primary liver cancer: Worldwide incidence and trends. Gastroenterology. 127(5 Suppl 1): S5–S16. 2004. View Article : Google Scholar : PubMed/NCBI
3	Turdean S, Gurzu S, Turcu M, Voidazan S and Sin A: Current data in clinicopathological characteristics of primary hepatic tumors. Rom J Morphol Embryol. 53(Suppl 3): 719–724. 2012.PubMed/NCBI
4	Severi T, van Malenstein H, Verslype C and van Pelt JF: Tumor initiation and progression in hepatocellular carcinoma: Risk factors, classification and therapeutic targets. Acta pharmacol Sin. 31:1409–1420. 2010. View Article : Google Scholar : PubMed/NCBI
5	Tang ZY: Hepatocellular carcinoma surgery-review of the past and prospects for the 21st century. J Surg Oncol. 91:95–96. 2005. View Article : Google Scholar : PubMed/NCBI
6	Qi LN, Bai T, Chen ZS, Wu FX, Chen YY, De Xiang B, Peng T, Han ZG and Li LQ: The p53 mutation spectrum in hepatocellular carcinoma from Guangxi, China: Role of chronic hepatitis B virus infection and aflatoxin B1 exposure. Liver Int. 35:999–1009. 2015. View Article : Google Scholar : PubMed/NCBI
7	Ye H, Zhang C, Wang BJ, Tan XH, Zhang WP, Teng Y and Yang X: Synergistic function of Kras mutation and HBx in initiation and progression of hepatocellular carcinoma in mice. Oncogene. 33:5133–5138. 2014. View Article : Google Scholar : PubMed/NCBI
8	Li J, Gao JZ, Du JL and Wei LX: Prognostic and clinicopathological significance of glypican-3 overexpression in hepatocellular carcinoma: A meta-analysis. World J Gastroenterol. 20:6336–6344. 2014. View Article : Google Scholar : PubMed/NCBI
9	Sun Q, Wang R, Wang Y, et al: Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma. Oncol Rep. 31:933–939. 2014.PubMed/NCBI
10	Zhang CH, Xu GL, Jia WD, Ge YS, Li JS, Ma JL and Ren WH: Prognostic significance of osteopontin in hepatocellular carcinoma: A meta-analysis. Int J Cancer. 130:2685–2692. 2012. View Article : Google Scholar : PubMed/NCBI
11	Xie L, Jiang H and Wu F: Role of Wnt/β-catenin signaling pathway in promoting tumorigenesis of hepatocellular carcinoma. Nan Fang Yi Ke Da Xue Xue Bao. 34:913–917. 2014.(In Chinese). PubMed/NCBI
12	Janku F, Kaseb AO, Tsimberidou AM, Wolff RA and Kurzrock R: Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget. 5:3012–3022. 2014. View Article : Google Scholar : PubMed/NCBI
13	Perkel JM: Visiting ‘noncodarnia’. Biotechniques. 54:301, 303–304. 2013.
14	Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermüller J, Hofacker IL, et al: RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. 316:1484–1488. 2007. View Article : Google Scholar : PubMed/NCBI
15	Hung T and Chang HY: Long noncoding RNA in genome regulation: Prospects and mechanisms. RNA Biol. 7:582–585. 2010. View Article : Google Scholar : PubMed/NCBI
16	Koerner MV, Pauler FM, Huang R and Barlow DP: The function of non-coding RNAs in genomic imprinting. Development. 136:1771–1783. 2009. View Article : Google Scholar : PubMed/NCBI
17	Costanzi C and Pehrson JR: Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature. 393:599–601. 1998. View Article : Google Scholar : PubMed/NCBI
18	Fu X, Ravindranath L, Tran N, Petrovics G and Srivastava S: Regulation of apoptosis by a prostate-specific and prostate cancer-associated noncoding gene, PCGEM1. DNA Cell Biol. 25:135–141. 2006. View Article : Google Scholar : PubMed/NCBI
19	Reis EM, Nakaya HI, Louro R, Canavez FC, Flatschart AV, Almeida GT, Egidio CM, Paquola AC, Machado AA, Festa F, et al: Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer. Oncogene. 23:6684–6692. 2004. View Article : Google Scholar : PubMed/NCBI
20	Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E and Chang HY: Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 129:1311–1323. 2007. View Article : Google Scholar : PubMed/NCBI
21	Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 464:1071–1076. 2010. View Article : Google Scholar : PubMed/NCBI
22	Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E and Chang HY: Long noncoding RNA as modular scaffold of histone modification complexes. Science. 329:689–693. 2010. View Article : Google Scholar : PubMed/NCBI
23	Wu ZH, Wang XL, Tang HM, Jiang T, Chen J, Lu S, Qiu GQ, Peng ZH and Yan DW: Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer. Oncol Rep. 32:395–402. 2014.PubMed/NCBI
24	Huang J, Ke P, Guo L, Wang W, Tan H, Liang Y and Yao S: Lentivirus-mediated RNA interference targeting the long noncoding RNA HOTAIR inhibits proliferation and invasion of endometrial carcinoma cells in vitro and in vivo. Int J Gynecol Cancer. 24:635–642. 2014. View Article : Google Scholar : PubMed/NCBI
25	Liu XH, Liu ZL, Sun M, Liu J, Wang ZX and De W: The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer. BMC Cancer. 13:4642013. View Article : Google Scholar : PubMed/NCBI
26	Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S and Safe S: HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 32:1616–1625. 2013. View Article : Google Scholar : PubMed/NCBI
27	Qiu JJ, Lin YY, Ye LC, Ding JX, Feng WW, Jin HY, Zhang Y, Li Q and Hua KQ: Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer. Gynecol Oncol. 134:121–128. 2014. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
29	Shao R, Bao S, Bai X, Blanchette C, Anderson RM, Dang T, Gishizky ML, Marks JR and Wang XF: Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression. Mol Cell Biol. 24:3992–4003. 2004. View Article : Google Scholar : PubMed/NCBI
30	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
31	Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI
32	Hu TH, Wang CC, Huang CC, Chen CL, Hung CH, Chen CH, Wang JH, Lu SN, Lee CM, Changchien CS and Tai MH: Down-regulation of tumor suppressor gene PTEN, overexpression of p53, plus high proliferating cell nuclear antigen index predict poor patient outcome of hepatocellular carcinoma after resection. Oncol Rep. 18:1417–1426. 2007.PubMed/NCBI
33	Niland CN, Merry CR and Khalil AM: Emerging roles for long non-coding RNAs in cancer and neurological disorders. Front Genet. 3:252012. View Article : Google Scholar : PubMed/NCBI
34	Spizzo R, Almeida MI, Colombatti A and Calin GA: Long non-coding RNAs and cancer: A new frontier of translational research? Oncogene. 31:4577–4587. 2012. View Article : Google Scholar : PubMed/NCBI
35	Li X, Wu Z, Mei Q, Li X, Guo M, Fu X and Han W: Long non-coding RNA HOTAIR, a driver of malignancy, predicts negative prognosis and exhibits oncogenic activity in oesophageal squamous cell carcinoma. Br J Cancer. 109:2266–2278. 2013. View Article : Google Scholar : PubMed/NCBI
36	Gupta RA, Shah N, Wang KC, et al: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 464:1071–1076. 2010. View Article : Google Scholar : PubMed/NCBI
37	Geng YJ, Xie SL, Li Q, Ma J and Wang GY: Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res. 39:2119–2128. 2011. View Article : Google Scholar : PubMed/NCBI
38	Xu ZY, Yu QM, Du YA, Yang LT, Dong RZ, Huang L, Yu PF and Cheng XD: Knockdown of long non-coding RNA HOTAIR suppresses tumor invasion and reverses epithelial-mesenchymal transition in gastric cancer. Int J Biol Sci. 9:587–597. 2013. View Article : Google Scholar : PubMed/NCBI
39	Ge XS, Ma HJ, Zheng XH, Ruan HL, Liao XY, Xue WQ, Chen YB, Zhang Y and Jia WH: HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway. Cancer Sci. 104:1675–1682. 2013. View Article : Google Scholar : PubMed/NCBI
40	Qu B, Liu BR, Du YJ, Chen J, Cheng YQ, Xu W and Wang XH: Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncol Lett. 7:1175–1178. 2014.PubMed/NCBI
41	Dahmani R, Just PA and Perret C: The Wnt/β-catenin pathway as a therapeutic target in human hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 35:709–713. 2011. View Article : Google Scholar : PubMed/NCBI