Cyclin-dependent kinase 19 upregulation correlates with an unfavorable prognosis in hepatocellular carcinoma

Xiaopeng Cai,Huiqiang Cai,Jiaming Zhou,Zhi Chen,Jingwen Deng

doi:10.1186/s12876-021-01962-8

Abstract

ObjectivesCyclin-dependent kinase 19 (CDK19) is a component of the mediator coactivator complex, which is required for transcriptional activation. In this study, we utilized public databases and wet-bench hepatic cell line experiments to elucidate the potential roles of CDK19 in hepatocellular cancer (HCC).Materials and methodsWe studied the relationships between CDK19 expression and several clinical features related to HCC via the Oncomine and UALCAN databases. The prognostic value of CDK19 was tested using the Kaplan–Meier Plotter database. We presented the mutations of CDK19 and addressed the relation of CDK19 expression with immune cell infiltration by means of the cBioPortal, Catalogue of Somatic Mutations in Cancer (COSMIC) and Tumor IMmune Estimation Resource (TIMER) databases. Hub genes were obtained and further analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. To test the in silico findings, we knocked down CDK19 with short hairpin RNA (shRNA) technology in two hepatic cell lines and conducted several functional characterization experiments.ResultsMarked CDK19 upregulation was found in HCC tissues versus normal liver tissues, and CDK19 mRNA expression had high diagnostic value in HCC patients. Subgroup analysis showed that CDK19 overexpression was associated with sex, tumor stage and TP53 mutation status. The prognostic value of CDK19 upregulation for overall survival (OS) was significant in patients with stage 2–3, stage 3–4, and grade 2 disease. One percent of the patients had CDK19 mutations, but no relationship between CDK19 mutation and prognosis was observed. CDK19 was positively correlated with the abundances of CD4 + T cells, macrophages and dendritic cells. We identified 10 genes correlated with CDK19, 8 of which presented excellent prognostic value in HCC. These hub genes were directly involved in cell division and regulation of the G2/M cell cycle transition. Protein–protein interaction (PPI) and pathway predictions indicated that CDK19 is highly likely to be involved in several cellular functions, such as proliferation, migration, and invasion. These functions were strongly interfered from two independent hepatic cell lines after CDK19 knockdown.ConclusionsCDK19 could be a prognostic marker in HCC, and its therapeutic potential in HCC needs further study.

Highlights

Hepatocellular carcinoma (HCC), accounting for 75–85% of primary liver cancers, ranks as the 6th most commonly diagnosed cancer and the 3rd most common cause of cancer-related death globally [1]
We identified 10 genes correlated with Cyclin-dependent kinase 19 (CDK19), 8 of which presented excellent prognostic value in HCC
Protein–protein interaction (PPI) and pathway predictions indicated that CDK19 is highly likely to be involved in several cellular functions, such as proliferation, migration, and invasion

Summary

Introduction

Hepatocellular carcinoma (HCC), accounting for 75–85% of primary liver cancers, ranks as the 6th most commonly diagnosed cancer and the 3rd most common cause of cancer-related death globally [1]. Several novel therapeutic options for HCC are emerging and have been shown to improve survival rates, but the overall prognosis is still unsatisfactory [3]. CDK19 or CDK8 reversibly regulates RNA polymerase II to control transcriptional activity. CDK8 has been reported to be involved in the development of malignancies, including cancers of the colon, breast and pancreas [5,6,7]. The role of CDK19 in carcinogenesis is rarely studied and only sporadically reported in prostate cancer, colorectal cancer, breast cancer, etc. Some small-molecule CDK8/19 inhibitors have been found to possess beneficial effects on tumor treatment, and a clinical trial (ClinicalTrials.gov Identifier: NCT03065010) with estrogen receptor-positive breast cancer has been on its way [11]. We performed bioinformatics analysis of HCC patients treated with sorafenib and found that they had a better prognosis than those not treated with sorafenib (Additional file 1: Fig. S1)

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