Abstract
Hepatocellular carcinoma (HCC) is characterized by a high rate of incidence and recurrence, and resistance to chemotherapy may aggravate the poor prognosis of HCC patients. Sorafenib resistance is a conundrum to the treatment of advanced/recurrent HCC. Therefore, studies on the molecular pathogenesis of HCC and the resistance to sorafenib are of great interest. Here, we report that GINS1 was highly expressed in HCC tumors, associated with tumor grades, and predicted poor patient survival using Gene Expression Omnibus (GEO) databases exploration. Cell cycle, cell proliferation assay and in vivo xenograft mouse model indicated that knocking down GINS1 induced in G1/S phase cell cycle arrest and decreased tumor cells proliferation in vitro and in vivo. Spheroid formation assay results showed that GINS1 promoted the stem cell activity of HCC tumor cells. Furthermore, GEO database (GSE17112) analysis showed that HRAS oncogenic gene set was enriched in GINS1 high-expressed cancer cells, and quantitative real-time PCR, and Western blot results proved that GINS1 enhanced HCC progression through regulating HRAS signaling pathway. Moreover, knocking down endogenous GINS1 with shGINS1 increased the sensitivity of HCC cells to sorafenib, and restoring HRAS or stem associated pathway partly recovered the sorafenib resistance. Overall, the collective findings highlight GINS1 functions in hepatocarcinogenesis and sorafenib resistance, and indicate its potential use of GINS1 in drug-resistant HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancer and the fifth leading causes of cancer-related deaths worldwide (Llovet et al, 2016)
GINS1 showed the most significant up-regulation in the late-phase of HCC accompanied with a promoter hypo-methylation when compared with the adjacent normal liver tissues (Figure 1E; Chandrashekar et al, 2017)
The results indicated that GINS1 may function as a key player in HCC progression
Summary
Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancer and the fifth leading causes of cancer-related deaths worldwide (Llovet et al, 2016). Due to the late diagnosis and the resistance to conventional chemotherapeutic drug, HCC patients at advanced stage usually survived no more than 1 year (Llovet et al, 2016). GINS1 Induced Sorafenib Resistance in HCC therapy, a multi-kinase inhibitor Sorafenib becomes the standard therapy for patients with advanced-stage HCC (Ikeda et al, 2018; Marisi et al, 2018; He et al, 2019). Dysregulation of cell cycle-related proteins, leading to unrestrained proliferation, has been shown to be a hallmark of HCC development and progression (Pascale et al, 2002). High expression of GINS1 was found in breast and lung cancer, and was related to enhanced ability in tumor proliferation and poor patient prognosis (Nakahara et al, 2010; Zhang et al, 2015)
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