Non-metabolic role of UCK2 links EGFR-AKT pathway activation to metastasis enhancement in hepatocellular carcinoma

Jie Cai,Han Guo,Hongting Huang,Chang Yu,Qiang Xia,Xiaoye Qu,Yueqiu Gao,Xiaoni Kong,Hailong Wu,Xuehua Sun

doi:10.1038/s41389-020-00287-7

Abstract

Up-regulation of Uridine-cytidine kinase 2 (UCK2), a rate-limiting enzyme of the pyrimidine salvage pathway, has been suggested in HCC, but the detailed molecular mechanisms and therapic role of UCK2 remain elusive. Bioinformatic analyses revealed that UCK2 might be a key up-regulated metabolic gene in HCCs. The expressional pattern and prognostic value of UCK2 were further examined in a large number of clinical samples. Functional assays based on site-directed mutagenesis showed that UCK2 promoted cell proliferation in a metabolic manner, but non-catalytically facilitates HCC metastasis. Mechanistically, in response to EGF, UCK2 interacted with EGFR to block EGF-induced EGFR ubiquitination and degradation, which resulted in elevated EGFR-AKT pathway activation and metastasis enhancement in HCCs. Concurrent pharmacological targeting on UCK2 and EGFR showed synergistic effects on HCC treatment. This study disclosed the non-metabolic role of UCK2 and suggested the therapeutic potential of concurrent blocking the metabolic and non-metabolic roles of UCK2 in HCC treatment.

Highlights

China reports over half of the new cases and deaths of liver cancer[10]
In present study, we confirm up-regulated Uridine-cytidine kinase 2 (UCK2) serves as an independent risk factor of poor prognosis in Hepatocellular carcinoma (HCC)
UCK2 plays a pro-oncogenic role by promoting tumor cell proliferation and metastasis

Summary

Introduction

Hepatocellular carcinoma (HCC), which accounts for 85–90% of primary liver cancers, affects more than 700,000 patients every year[17]. Despite the multiple curative treatments available[29], the prognosis is still poor in HCC patients mainly due to the high recurrence rate of HCC18, which is closely related to tumor invasion and metastasis. Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase, whose overexpression overexpression and activation in various types of cancers, including glioblastoma[14], oligodendroglioma[11], non-smallcell lung cancer[9] and gastric carcinomas[32], such genomic alterations of EGFR are barely reported in HCCs8,13, suggesting the existence of other mechanisms leading to the high frequency of EGFR overexpression and activation in HCCs. Uridine-cytidine kinase (UCK) is a type of rate-limiting enzymes in the salvage pathway of pyrimidine-nucleotide biosynthesis.

Methods

Results

Conclusion