Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor outcomes. The main causes of HCC-related deaths are recurrence and metastasis. Long noncoding RNAs (lncRNAs) are recently identified as critical regulators in cancers. However, the lncRNAs involved in HCC recurrence and metastasis are poorly understood. In this study, via analyzing The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, we identified a novel lncRNA LINC01134, which is highly expressed in HCC tissues and correlated with microvascular invasion, macrovascular invasion, recurrence, and poor overall survival of HCC patients. Functional experiments revealed that ectopic expression of LINC01134 promotes HCC cell migration and invasion in vitro and HCC liver metastasis and lung metastasis in vivo. Knockdown of LINC01134 represses HCC cell migration and invasion in vitro and HCC liver metastasis and lung metastasis in vivo. Mechanistically, we found that LINC01134 directly binds the promoter of AKT1S1 and activates AKT1S1 expression. Via activating AKT1S1, LINC01134 further activates NF-κB signaling. The expression of LINC01134 is significantly positively correlated with that of AKT1S1 in HCC tissues. In line with LINC01134, AKT1S1 is also highly expressed in HCC tissues and correlated with poor survival of HCC patients. Functional rescue experiments showed that repressing AKT1S1 or NF-κB signaling abrogates the roles of LINC01134 in HCC. Taken together, these findings recognized LINC01134 as a novel oncogenic lncRNA, which indicates vascular invasion, recurrence, and poor overall survival of HCC patients. LINC01134 promotes HCC metastasis via activating AKT1S1 expression and subsequently activating NF-κB signaling. This study suggested LINC01134 as a potential prognostic biomarker and therapeutic target for HCC.
Highlights
Liver cancer is one of the most common malignances worldwide (Bray et al, 2018)
Via analyzing The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) dataset, we identified a novel Long noncoding RNAs (lncRNAs) LINC01134, which is associated with poor survival of Hepatocellular carcinoma (HCC) patients
Reanalyzing TCGA LIHC dataset, we found that LINC01134 is significantly highly expressed in HCC tissues (n = 369) compared with normal liver tissues (n = 50) (Figure 1A)
Summary
Liver cancer is one of the most common malignances worldwide (Bray et al, 2018). It is ranked sixth for incidence and fourth for mortality, with 841,080 estimated new cases and 781,631 estimated deaths in 2018 globally (Bray et al, 2018). The overall cancer mortality has fallen since 1991, the mortality for liver cancer is still increasing until now (Siegel et al, 2020). Hepatocellular carcinoma (HCC) is the major subtype and accounts for 90% of liver cancer. The outcomes of most HCC patients are still very poor with a 5-year survival rate of only about 18% (Siegel et al, 2020). Identification of specific molecular changes underlying HCC progression will facilitate the development of novel therapeutic strategies against HCC (Auger et al, 2015; Nasr et al, 2019)
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