Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0702-z) contains supplementary material, which is available to authorized users.

MicroRNA‐367‐3p overexpression represses the proliferation and invasion of cervical cancer cells through downregulation of SPAG5‐mediated Wnt/β‐catenin signalling

“…Our study confirmed the role for miR‐367‐3p as a tumour suppressive miRNA in cervical cancer. However, there are also studies reporting an oncogenic function of miR‐367‐3p with respect to tumour progression . These findings report a disparate function for miR‐367‐3p in tumour progression and indicate that the precise expression status and function of miR‐367‐3p may be dependent on the type of tumour involved.…”

LINC00968 functions as an oncogene in osteosarcoma by activating the PI3K/AKT/mTOR signaling

“…For example, LINC01567 can acts as a sponge of microRNA‐93 in regulating human colon cancer stem cells (Yu, Mi, Dong, & Zou, ). LncRNA CASC2 can suppress epithelial‐mesenchymal transition of hepatocellular carcinoma cells via targeting miR‐367 (Wang, Liu et al, ). LncRNA‐TCONS_00026907 is involved in cervical cancer progression through inhibiting miR‐143‐5p (Jin et al, ).…”

Low Expression of LncRNA Cancer Susceptibility Candidate 2 and its Clinical Significance in Cancer Tissues

“…These cancers ranged from an early stage to advanced clinical stages (I, II, III, and IV). Of the 8 studies, 3 included a follow-up of greater than or equal to 60 months [23, 27, 28]; the remaining 5 studies covered less than 5 years [21, 22, 24-26]. The expression of lncRNA CASC2 in all eligible studies was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and normalized relative to GAPDH or RNU6B using the 2 –ΔΔCt method.…”

“…In hepatocellular carcinoma, lncRNA CASC2 may regulate cell biological behavior through the MAPK signaling pathway [17]. Additionally, it suppressed the epithelial-mesenchymal transition of hepatocellular carcinoma cells through the CASC2/ miR-367/FBXW7 axis [24]. CASC2 was also reported to act as a tumor suppressor lncRNA by regulating several signaling pathways, such as the Wnt/β-catenin signaling pathway [23] or the MAPK signaling pathway [31] or to be a direct target gene of miR-21, suppressing malignancy [32, 33].…”