Abstract
Hepatocellular carcinoma (HCC) is characterised by a hypoxic microenvironment and a high rate of heterogeneity and recurrence, and the presence of cancer stem cells (CSCs) in HCC may well explain both of these pathological properties. There is mounting evidence that long non-coding RNAs (lncRNAs) participate in carcinogenesis and maintain cancer stemness of HCC cells. However, the expression modes, regulatory mechanisms and potential roles of stemness-related lncRNAs in HCC are still obscure. LncRNA RUNX1-IT1 is the intronic transcript 1 of the RUNX1, which is also known as chromosome 21 open-reading frame 96 (C21orF96). Although the functions of the RUNX1 have been identified in different diseases, the function and its potential mechanisms of the lncRNA RUNX1-IT1 in HCC still remains to be largely unknown. In this study, we verified that the expression of LncRNA RUNX1-IT1 was decreased in GEO data set, HCC samples and correlated with unfavourable clinicopathologic characteristics and poor prognosis. RUNX1-IT1 repressed HCC cell proliferation, cell cycle progression, invasion and cancer stemness and induced apoptosis in vitro. Overexpression of RUNX1-IT1 impaired the growth, metastasis and stem-like features of HCC cells in vivo. Mechanistically, RUNX1-IT1 directly bound to miR-632 and acted as competing endogenous RNA to facilitate the expression of the miR-632 target gene GSK-3β and subsequently modulate the WNT/β-catenin pathway in HCC cells. Furthermore, hypoxia-driven histone deacetylase 3 (HDAC3), as an upstream regulatory mechanism, was critical for the downregulation of RUNX1-IT1 in HCC. Thus, lncRNA RUNX1-IT1, as a regulator of hypoxia, may function as a potential therapeutic target for conquering HCC.
Highlights
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and accounts for the third leading cause of cancer-associated deaths worldwide[1].Epidemiological data revealed 841,000 new cases of liver cancer and 782,000 mortalities worldwide, among which China represents ~50% of the total number of new cases and deaths[2,3,4]
The novel long non-coding RNAs (lncRNAs) DANCR, which can competitively bind to CTNNB1 (β-catenin) to relieve the inhibitory effects of miR-199a, miR-320a and miR-214 on CTNNB1, markedly enhances the cancer stemness properties of HCC cells to confer tumorigenesis and intrahepatic colonisation or lung metastasis in HCC16
The results revealed that the expression level of RUNX1-IT1 in HCC specimens was greatly decreased in comparison with that of adjacent non-tumour tissues (P < 0.001, Fig. 1a)
Summary
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and accounts for the third leading cause of cancer-associated deaths worldwide[1].Epidemiological data revealed 841,000 new cases of liver cancer and 782,000 mortalities worldwide, among which China represents ~50% of the total number of new cases and deaths[2,3,4]. Hepatocellular carcinoma (HCC) remains one of the most common malignancies and accounts for the third leading cause of cancer-associated deaths worldwide[1]. It is urgent to explore the detailed molecular mechanisms involved in HCC tumorigenicity and heterogeneity and discover more efficient treatment targets for HCC. HCC is characterised by a high rate of heterogeneity and recurrence, and cancer stem cells (CSCs) present in HCC may well explain both of these pathological properties. The molecular definition of CSCs in HCC is still emerging such as CD24, CD44, CD90 and EPCAM7,8, three transcription factors, Oct[4], Nanog and Sox[2], have been strongly identified as master regulators of cancer stemness[9,10]. There exists a tight link between acquiring cancer stem-like traits and EMT induction[11]. The underlying mechanisms that contribute to the self-renewal and maintenance of CSCs are poorly understood
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