This study focused on the expression level and role of SCAMP1 in HCC. Using quantitative reverse transcription PCR, we first showed that SCAMP1 was highly expressed in HCC tissues and cell lines, and SCAMP1 expression was correlated with tumor size, TNM stage and poor prognosis in HCC patients. Consistent with the upregulation of SCAMP1 in HCC, several studies have reported that the expression of SCAMP1 was increased in ovarian cancer [24], glioma [22] and pediatric renal cell carcinoma [23]. In clinical level, Song et al [24] utilized TCGA database to found ovarian cancer patients with high SCAMP1 level had poorer overall survival rates than those with low SCAMP1. The expression level of SCAMP1 was positively correlated with the pathological grades of glioma and higher SCAMP1 expression indicated poorer overall survival [22]. These results indicated that SCAMP1 might be a potential biomarker in clinical application.
Our in vitro experiments showed that SCAMP1 knockdown suppressed cell proliferation, induced cell cycle G0/G1 phase arrest and promoted apoptosis in two HCC cell lines (HepG2 and SNU-182), which suggested that SCAMP1 can be used as an oncogene to promote HCC cell proliferation. In fact, SCAMP1 also plays oncogenic role in other tumors. For instance, inhibition of SCAMP1 significantly restrained the cell proliferation, migration and invasion, as well as promoted apoptosis in glioma [22]. SCAMP1 depletion attenuated cell viability and promoted apoptosis under H2O2 treatment in pediatric renal cell carcinoma [23]. Downregulation of SCAMP1 suppressed the pancreatic and gallbladder cancer proliferation, migration, and invasion [25].
In terms of molecular mechanism, our data further demonstrated that SCAMP1 knockdown reduced the expression of CDK4, Cyclin D1 and Bcl-2, but promoted the expression of p21, p53 and Bax in both HepG2 and SNU-182 cells. Three protein families, including cyclin-dependent kinases (CDKs), Cyclins and CDK inhibitors (CDKIs) regulate the progress of the cell cycle in cancer cells, of which CDK4/Cyclin D1 and p21 are the key regulators of G1/S transition [26, 27]. Here, SCAMP1 knockdown induced cell cycle G0/G1 phase arrest, which might be correlated with decreased CDK4/Cyclin D1 and increased p21 expression induced by depletion of SCAMP1. P53, the tumor suppressor gene product, can directly regulate the p21 gene, which encodes a universal inhibitor of CDKs, to inhibit the cell cycle progression [28]. In addition to p21, Bcl-2 and Bax are the downstream target genes of p53. As our best knowledge, the tumor suppressor protein p53 has a critical role in regulation of the Bcl-2 family, including antiapoptotic protein Bcl-2 and proapoptotic protein Bax [29, 30]. Our findings revealed that SCAMP1 knockdown induced apoptosis via downregulating Bcl-2 and upregulating Bax expression.
In conclusion, our work demonstrated for the first time that SCAMP1 was overexpressed in HCC tissues and predicted poor prognosis. Moreover, SCAMP1 positively regulated HCC cell growth and proliferation via activation of p53 signaling pathway. Our data provide new insight into the oncogenic roles of SCAMP1 in HCC progression, which may become a potential therapeutic target for HCC.