Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a long non-coding RNA (lncRNA), is up-regulated in many solid tumors and associated with cancer metastasis and recurrence. However, its role in hepatocellular carcinoma (HCC) remains poorly understood. In the present study, we evaluated the expression of MALAT1 by quantitative real-time PCR in 9 liver cancer cell lines and 112 HCC cases including 60 cases who received liver transplantation (LT) with complete follow-up data. Moreover, small interfering RNA (siRNA) was used to inhibit MALAT1 expression to investigate its biological role in tumor progression. We found that MALAT1 was up-regulated in both cell lines and clinical tissue samples. Patients with high expression level of MALAT1 had a significantly increased risk of tumor recurrence after LT, particularly in patients who exceeded the Milan criteria. On multivariate analysis, MALAT1 was an independent prognostic factor for predicting HCC recurrence (hazard ratio, 3.280, P = 0.003).In addition, inhibition of MALAT1 in HepG2 cells could effectively reduce cell viability, motility, invasiveness, and increase the sensitivity to apoptosis. Our data suggest that lncRNA MALAT1 play an important role in tumor progression and could be a novel biomarker for predicting tumor recurrence after LT and serve as a promising therapeutic target.
This is a preview of subscription content, log in to check access.
This study was supported by the Major State Basic Research Development Program (NO.2009CB522407), the Major National S&T Program (NO. 2008ZX10002-026), and the Program for Innovative Research Team of Zhejiang Province of China (NO. 2009R50038) The authors would like to thank the surgeons and nurses for their valuable technical assistance and facilitating the collection of patient information.
Conflict of interest
The authors declare that they have no conflict of interest.
Tano K, Mizuno R, Okada T, Rakwal R, Shibato J, Masuo Y, Ijiri K, Akimitsu N. MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett. 2010;584:4575–80.PubMedCrossRefGoogle Scholar
Belghiti J, Kianmanesh R. Surgical treatment of hepatocellular carcinoma. HPB (Oxford). 2005;7:42–9.CrossRefGoogle Scholar
Bai DS, Dai Z, Zhou J, et al. Capn4 overexpression underlies tumor invasion and metastasis after liver transplantation for hepatocellular carcinoma. Hepatology. 2009;49:460–70.PubMedCrossRefGoogle Scholar
Sieghart W, Wang X, Schmid K, et al. Osteopontin expression predicts overall survival after liver transplantation for hepatocellular carcinoma in patients beyond the Milan criteria. J Hepatol. 2011;54:89–97.PubMedCrossRefGoogle Scholar
Yang Y, Nagano H, Ota H, et al. Patterns and clinicopathologic features of extrahepatic recurrence of hepatocellular carcinoma after curative resection. Surgery. 2007;141:196–202.PubMedCrossRefGoogle Scholar
Zheng SS, Xu X, Wu J, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation. 2008;85:1726–32.PubMedCrossRefGoogle Scholar
Ørom UA, Derrien T, Beringer M, et al. Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010;143:46–58.PubMedCrossRefGoogle Scholar
Chen LL, Gordon G. Long noncoding RNAs in mammalian cells: what, where, and why. WIREs RNA. 2010;1:2–21.PubMedGoogle Scholar
Guo F, Li Y, Liu Y, Wang J, Li Y, Li G. Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochim Biophys Sin (Shanghai). 2010;42:224–9.CrossRefGoogle Scholar
Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.PubMedCrossRefGoogle Scholar
Ji P, Diederichs S, Wang W, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031–41.PubMedCrossRefGoogle Scholar
Lin R, Maeda S, Liu C, Karin M, Edgington TS. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene. 2007;26:851–8.PubMedCrossRefGoogle Scholar
Luo JH, Ren B, Keryanov S, et al. Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology. 2006;44:1012–24.PubMedCrossRefGoogle Scholar
Yamada K, Kano J, Tsunoda H, Yoshikawa H, Okubo C, Ishiyama T, Noguchi M. Phenotypic characterization of endometrial stromal sarcoma of the uterus. Cancer Sci. 2006;97:106–12.PubMedCrossRefGoogle Scholar
Bioulac-Sage P, Rebouissou S, Sa Cunha A, et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology. 2005;128:1211–8.PubMedCrossRefGoogle Scholar
Feng YX, Zhao JS, Li JJ, et al. Liver cancer EphrinA2 promotes tumorigenicity through Rac1 Akt NF-kappaB signaling pathway 120. Hepatology. 2010;51:535–44.PubMedCrossRefGoogle Scholar
Huang G, Hu Z, Li M, Cui Y, Li Y, Guo L, Jiang W, Lu SH. ECRG2 inhibits cancer cell migration, invasion and metastasis through the downregulation of uPA/plasmin activity. Carcinogenesis. 2007;28:2274–81.PubMedCrossRefGoogle Scholar
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–9.PubMedCrossRefGoogle Scholar
Song HY, Liu YK, Feng JT, et al. Proteomic analysis on metastasis-associated proteins of human hepatocellular carcinoma tissues. J Cancer Res Clin Oncol. 2006;132:92–8.PubMedCrossRefGoogle Scholar
Grasso A, Stigliano R, Morisco F, et al. Liver transplantation and recurrent hepatocellular carcinoma: predictive value of nodule size in a retrospective and explant study. Transplantation. 2006;81:1532–41.PubMedCrossRefGoogle Scholar
1.Department of Hepatobiliary and Pancreatic Surgery, Key Lab of Combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated HospitalZhejiang University School of MedicineHangzhouPeople’s Republic of China