Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

Abstract

E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.

Prognostic significance ofSOCS1andSOCS3tumor suppressors in hepatocellular carcinoma and its correlation to key oncogenic signaling pathways

“…CDK2 and other CDKs are considered potential therapeutic targets in many cancers including HCC [57]. While high CDK2 expression correlated with poor survival in our study, Sonntag et al, [55] did not find significant prognostic value for CDK2, possibly because the latter used the median value to separate the low and high expression groups, whereas in our study we compared the high one-quartile group and the remaining with low/medium expression.…”

“…Under conditions of increased cyclin D1 availability, for example from increased growth factor signaling, CDK2 promotes hepatocyte proliferation. CDK2 is needed for the initiation of HCC, although not for progression as HCC may acquire CDK2 independence [54][55][56]. CDK2 and other CDKs are considered potential therapeutic targets in many cancers including HCC [57].…”

Long Noncoding RNA RAET1K Enhances CCNE1 Expression and Cell Cycle Arrest of Lung Adenocarcinoma Cell by Sponging miRNA-135a-5p

“…The dynamic progression of the cell cycle consists of four sequential phases: S (chromosome replication), M (chromosome segregation), and G1 and G2 (gap), which are regulated by cyclin/cyclin-dependent kinases (Dai et al, 2018). In particular, cyclin E/Cdk2 interacts and forms complexes that promote G1 progression and G1/S transition (Sonntag et al, 2018). The amplification of cyclin E, which functions in cell cycle progression, inhibition of apoptosis, transcription, and replication, and DNA repair, has been observed in various types of cancer (Kanska et al, 2016;Vijayaraghavan et al, 2017).…”

CCT6A, a novel prognostic biomarker for Ewing's sarcoma

“…Meanwhile, the CCT2 gene has also been shown to reduce the survival rate of colorectal cancer patients with higher levels of gene expression [35] . Elevated expression levels of The CCNE2 gene coincided with shorter overall survival in patients with hepatocellular carcinoma [36] . Thus, the results presented by the network of protein interactions suggest that all of these genes linked to CCT6A are associated with the development of cancer.…”