SWELL1 promotes cell growth and metastasis of hepatocellular carcinoma in vitro and in vivo

Abstract

Background: SWELL1 was recently demonstrated to be an indispensable part of the volume-regulated anion channel (VRAC). VRAC is reported to participate in cell proliferation, survival, and migration. However, the correlation between SWELL1 and hepatocellular carcinoma (HCC) remains poorly-understood. In this study, we tried to explore the role of SWELL1 in HCC. Methods: Immunohistochemistry and quantitative real-time-PCR (qRT-PCR) was used to measure SWELL1 expression in HCC samples obtained from patients with HCC. The effects of SWELL1 on HCC cell proliferation, apoptosis, and metastasis were analysed by corresponding cytological experiments including Cell Counting Kit-8 (CCK8), colony-forming, 5-ethynyl-2-deoxyuridine (EdU), cell cycle analysis, TUNEL, Annexin V and PI staining, wound healing, transwell, and so on. BALB/c nude mice were used for the in vivo assays. qRT-PCR and western blotting was performed for molecular mechanisms. Findings: SWELL1 was highly expressed in HCC tissues, and related to the poor prognosis. In vitro, the over-expression of SWELL1 significantly induced cell proliferation and migration, and inhibited apoptosis, whereas suppressing SWELL1 had the opposite effects. Moreover, knockdown of SWELL1 suppressed the growth and metastasis of HCC in vivo. Further experiments revealed that SWELL1 induced cell growth by activating the cyclinD1/CDK2 pathway via the connection with PKCa at the signalling level, and regulated cell migration through the JNK pathway in HCC. Interpretation: SWELL1 acts as a promoter in the growth and metastasis of HCC cells and may be a potential intervention target for HCC.

Profiling Cisplatin Resistance in Head and Neck Cancer: A Critical Role of the VRAC Ion Channel for Chemoresistance

“…While NOTCH signaling is centrally involved in cell proliferation, differentiation, and survival [ 41 , 42 ], SNAI1 is involved in the induction of EMT processes, which are critical for the shedding of circulating tumor cells and metastasis [ 43 , 44 ]. In this context, an involvement of VRAC expression in the promotion of metastatic growth in the absence of cisplatin therapy was suggested [ 38 , 45 ].…”

The Role of Chloride Channels in the Multidrug Resistance

“…Similarly, VRAC is associated with the proliferation of nasopharyngeal cancer cells and human ovarian cancer cells, and VRAC inhibitors inhibited the transition from the G1 to S phase of these cells [36]. In addition, suppression of LRRC8A inhibited the growth of colon and hepatocellular carcinoma cells in vivo in nude mice [38,39]. Cell migration is associated with the differential activity of ion channels and transporters involved in local changes in cell volume, including VRAC.…”

In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling

“…Tumor-derived cell lines are the most widely used cell lines in HCC research [ 256 , 324 ]. Indeed, they are harnessed to assess cancer characteristics, such as cell proliferation, migration, metastasis, evasion of cell death and invasion [ 278 , 281 , 325 , 326 , 327 , 328 , 329 ]. Moreover, liver cancer cell lines are frequently used for elucidating molecular mechanisms of HCC during overexpression or silencing gene studies [ 282 , 326 , 327 , 329 ].…”