Abstract
Our study aimed to investigate the expression, functional significance, and related mechanism of long noncoding RNA CRNDE (colorectal neoplasia differentially expressed) in hepatocellular carcinoma (HCC) pathogenesis. The resulted revealed that CRNDE was significantly overexpressed in HCC tissues and cell lines, and was statistically correlated with poor clinical outcome. CRNDE knockdown markedly decreased HCC cell proliferation, migration, and chemoresistance. In addition, in vivo experiments confirmed the suppressive effect of CRNDE knockdown on HCC progression. Mechanically, CRNDE directly bound to EZH2 (enhancer of zeste homolog), SUZ12 (suppressor of zeste 12), SUV39H1, and mediated their inhibition of tumor suppressor genes, including CUGBP Elav-like family member 2 (CELF2) and large tumor suppressor 2 (LATS2). CELF2 exerted tumor suppressive effect in HCC and was involved in CRNDE-mediated oncogenic effect. In addition, the oncogenic effects of CRNDE on HCC proliferation, migration and tumorigenesis, as well as its inhibition of Hippo pathway were abolished by LATS2 overexpression. Together, our work demonstrated the importance of CRNDE in HCC progression and elucidated the underlying molecular mechanisms. These findings provided new insights into HCC pathogenesis and chemoresistance mediated by CRNDE.
Highlights
Hepatocellular carcinoma (HCC), which is a type of hepatoma, is the most common primary cancer in liver and the third leading cause of cancer mortality worldwide[1]
We discovered that the inhibition effect of CRNDE knockdown on HCC proliferation and migration was compromised by the silencing of CUGBP Elav-like family member 2 (CELF2), whereas overexpression of human large tumor suppressor 2 (LATS2), the Hippo signal pathway kinase, could efficiently inhibit the oncogenic properties of CRNDE in HCC
Cell invasion and migration abilities that were inhibited by shCRNDE were recovered upon cotransfection with siCELF2 (Fig. 5l). All these data suggested a pivotal role of CELF2 in HCC tumorigenesis, migration, and chemoresistance, and we provided evidence that CELF2 silencing in HCC cell line 1 reversed the inhibiting effect of shCRNDE on cell viability, invasion, and migration
Summary
Hepatocellular carcinoma (HCC), which is a type of hepatoma, is the most common primary cancer in liver and the third leading cause of cancer mortality worldwide[1]. HCC can be caused by chronic hepatitis B virus and hepatitis C virus infections, cirrhosis, heavy alcohol drinking, or diabetes[2]. Numerous clinical approaches for HCC treatment exist, including surgical resection, liver transplantation, and medical treatment, such as radiation therapy, transarterial chemoembolization, and molecular HCC treatment. Long noncoding RNAs (lncRNAs) are a type of RNA that usually contain >200 nucleotides. In recent years, growing evidence indicates that lncRNAs are implicated in diverse human diseases, including autoimmune disease[8], cardiovascular disease[9], neurodegenerative disease[10], and different cancer types[11,12,13,14]. Several lncRNAs were reported to promote HCC progression by antagonizing let-7, interacting with CTNNB1, or targeting miR-
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