Abstract
Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Long non-coding (lnc) RNAs regulate complex cellular functions, such as cell growth, differentiation, metabolism, and metastasis. Although deregulation of lncRNA expression has been detected in HCC, many of the hepato-carcinogenesis-associated lncRNAs remain yet unidentified. Here, we aimed to investigate the involvement of a specific HCC-dysregulated lncRNA, FAM215A, and characterize its molecular regulation mechanism. We show for the first time that FAM215A is overexpressed in HCC, and its expression level correlates with tumor size, vascular invasion, and pathology stage. Overexpression of FAM215A accelerates cell proliferation and metastasis in HCC cells. According to Gene Expression Omnibus Dataset analysis, FAM215A is induced in doxorubicin (DOX)-resistant HCC cells. Overexpression of FAM215A increases DOX resistance in two HCC cell lines, and this is associated with enhanced expression of lysosome-associated membrane protein 2 (LAMP2). FAM215A interacts with LAMP2 to protect it from ubiquitination. Together, our results show that the lncRNA, FAM215A, is highly expressed in HCC, where it interacts with and stabilizes LAMP2 to increase tumor progression while decreasing doxorubicin sensitivity.
Highlights
Hepatocellular carcinoma (HCC) ranks among the most common cancers in many countries and is the second most common cause of cancer death worldwide
We found that lysosome-associated membrane protein 2 (LAMP2) ubiquitination was decreased in FAM215A-overexpressing J7 or Mahlavu cells, whereas it was increased in FAM215A-repressing Hep3B and J7 cells (Figure 5C)
Our findings clearly indicate that FAM215A increases tumor progression and DOX resistance in HCC by interacting with and increasing the stability of LAMP2 (Figure 6G)
Summary
Hepatocellular carcinoma (HCC) ranks among the most common cancers in many countries and is the second most common cause of cancer death worldwide. Most HCC is associated with liver cirrhosis that represents major risk factors (HBV- or HCV-related chronic liver disease, toxins and drugs) for HCC development, being implicated in more than 70% of HCC cases worldwide [1,2]. Cells 2020, 9, 961 to cause non-alcoholic fatty liver disease (NAFLD). NAFLD covers a range of clinical diseases from hepatic steatosis to severe inflammatory steatohepatitis (NASH) [3]. Alpha-fetoprotein (AFP) is the main tumor biomarker available to guide the management of HCC; its low accuracy limits its usefulness as a screening test [4]. We urgently need to identify novel therapeutic targets and biomarkers, with the goal of developing effective strategies to improve the prognosis of HCC [5]
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