Abstract
BackgroundRecently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular carcinoma (HCC) remain unclear.MethodsThe expression of CASC2 and miR-367 in HCC specimens and cell lines were detected by real-time PCR. Western blotting and immunohistochemistry were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers in HCC. Transwell assays were used to determine migration and invasion of HCC cells. A mouse model for lung metastasis was established to evaluated HCC metastasis in vivo. The correlation among CASC2, miR-367 and F-box and WD repeat domain containing 7 (FBXW7) were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay.ResultsHere, CASC2 expression was significantly downregulated in HCC tissues, especially in aggressive and recurrent cases. In accordance, CASC2 underexpression was observed in HCC cell lines compared to LO2. In vitro and in vivo experiments revealed that CASC2 inhibited migration and invasion of HCC cells. Additionally, CASC2 repressed EMT process of HCC cells. Further studies demonstrated that CASC2 could function as a competing endogenous RNA (ceRNA) by sponging miR-367 in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-367 promoted migration, invasion and EMT progression of HCC cells. Moreover, further investigations disclosed that FBXW7 was a downstream target of miR-367 and CASC2 prohibited EMT progression and subsequently exerted its anti-metastatic effects via CASC2/miR-367/FBXW7 axis in HCC cells. Clinically, CASC2 underexpression and miR-367 overexpression were closely correlated with the metastasis-associated clinicopathologic features. Notably, CASC2 low-expressing and miR-367 high-expressing HCC patients showed the poorest clinical outcome.ConclusionsOverall, we conclude that the CASC2/miR-367/FBXW7 axis may be a ponderable and promising therapeutic target for HCC.
Highlights
It has been reported that long non-coding RNA cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs
The results revealed that CASC2 expression in hepatocellular carcinoma (HCC) tissues was dramatically decreased, compared with adjacent non-tumor tissues (P < 0.001, Fig. 1a)
The data from R2: Genomics Analysis and Visualization Platform including GEO and TCGA database showed that the expression of CASC2 was significantly downregulated in HCC tissues compared to normal liver tissues (P < 0.05, respectively, Additional file 1: Fig. S1), which were consistent with our results
Summary
It has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). The existing researches have showed that the abnormally expressed lncRNAs, miRNAs and proteins regulate the EMT progression of HCC cells via their interactions [5,6,7]. They are recognized as valuable and sanguine therapeutic targets to withstand the metastasis of HCC. LncRNA ATB, a regulator of transforming growth factor-β (TGF-β) signaling, could competitively bind to the miR-200 family and increased the expressions of zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2, and promoted the metastasis, invasion and EMT progression in HCC [7]. LncRNA HULC regulates HCC cell preternatural lipid metabolism via the HULC/miRNA-9/ RXRA axis [8]
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