Abstract
BackgroundTo clarify the effects of cylcin E1 expression on HCC tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition.MethodsWestern blotting for caspase-3 and Hoechst 33225 staining was used to measure the expression level of apoptosis-related proteins under drug treatment.ResultsOur results showed that enhanced expression of cyclin E1 after transfection compromised apoptosis in HCC cells induced by regorafenib or sorafenib. Conversely, down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase (CDK) inhibitors dinaciclib (DIN) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis. The expression of Mcl-1, which is modulated by STAT3, plays a key role in regulating the therapeutic effects of CDK inhibitors. Xenograft experiments conducted to test the efficacy of regorafenib combined with DIN showed dramatic tumor inhibitory effects due to induction of apoptosis. Our results suggested that the level of cyclin E1 expression in HCCs may be used as a pharmacodynamic biomarker to assess the antitumor effects of regorafenib or sorafenib.ConclusionsCombining regorafenib and CDK inhibitors may enhance the clinical efficiency of the treatment of HCCs.
Highlights
To clarify the effects of cylcin E1 expression on Hepatocellular carcinoma (HCC) tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition
To further study its role in liver malignancy, we examined the expression of several cyclin family members in large scale cancer datasets provided by The Cancer Genome Atlas (TCGA), including CCNA1, CCND1, and cyclin E1 (CCNE1)
By analyzing 6 different HCC cell lines, we found that cyclin E1 expression was lower in Huh7, HepG2, SNU475, but higher in SK-Hep1, SNU398, and Hep3B cells (Fig. 1c)
Summary
To clarify the effects of cylcin E1 expression on HCC tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition. Cyclin-dependent kinase (CDK) inhibitors and other molecular agents that regulate the cell cycle have been widely studied, the role of these agents in tumor therapy was unclear until a CDK inhibitor, palbociclib, was shown to extend the life span of breast cancer patients who were treated with hormones [12, 13]. Data from both preclinical and clinical studies indicate that the combination of cell-cycle regulators and current anticancer treatments may improve tumor treatment efficacy [14]. It is still unclear whether the expression of cyclin E1 has similar effects on regorafenib sensitivity in HCC
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