Inhibition of DTYMK significantly restrains the growth of HCC and increases sensitivity to oxaliplatin

Fengze Sun,Qijing Wang,Desheng Weng,Qiuzhong Pan,Ting-Ting Gong ,Jia He,Yongqiang Li,Yu Han ,Chih Ping Yang ,Han Li,Yuanyuan Chen,Mengjia Song,Yue Huang,Hao Chen,Tong Xiang,Yan Tang,Jin-Hao Yang ,Yuanyuan Liu,Jingjing Zhao,Ruiqing Peng

doi:10.1038/s41419-021-04375-3

Abstract

Most patients with hepatocellular carcinoma (HCC) are in the middle or advanced stage at the time of diagnosis, and the therapeutic effect is limited. Therefore, this study aimed to verify whether deoxythymidylate kinase (DTYMK) increased in HCC and was an effective therapeutic target in HCC. The findings revealed that the DTYMK level significantly increased and correlated with poor prognosis in HCC. However, nothing else is known, except that DTYMK could catalyze the phosphorylation of deoxythymidine monophosphate (dTMP) to form deoxythymidine diphosphate (dTDP). A number of experiments were performed to study the function of DTYMK in vitro and in vivo to resolve this knowledge gap. The knockdown of DTYMK was found to significantly inhibit the growth of HCC and increase the sensitivity to oxaliplatin, which is commonly used in HCC treatment. Moreover, DTYMK was found to competitively combine with miR-378a-3p to maintain the expression of MAPK activated protein kinase 2 (MAPKAPK2) and thus activate the phospho-heat shock protein 27 (phospho-HSP27)/nuclear factor NF-kappaB (NF-κB) axis, which mediated the drug resistance, proliferation of tumor cells, and infiltration of tumor-associated macrophages by inducing the expression of C-C motif chemokine ligand 5 (CCL5). Thus, this study demonstrated a new mechanism and provided a new insight into the role of mRNA in not only encoding proteins to regulate the process of life but also regulating the expression of other genes and tumor microenvironment through the competing endogenous RNA (ceRNA) mechanism.

Highlights

The 5‐year relative survival rate of liver cancer is only 20%, and the incidence rate is rising annually [1]
deoxythymidylate kinase (DTYMK) was found to increase in HepG2, Hun7, and Hep3B Hepatocellular carcinoma (HCC) cell lines compared with LO2 hepatic epithelial cells and in most HCC tissues (Fig. 1F–H)
Huh7 and Hep3B cells became more sensitive to oxaliplatin, which was a commonly used chemotherapeutic drug for HCC, after DTYMK knockdown (Fig. 2G and H)

Summary

Introduction

The 5‐year relative survival rate of liver cancer is only 20%, and the incidence rate is rising annually [1]. Hepatocellular carcinoma (HCC) is the most common type of all liver cancers (comprising 80% of cases). Chronic HBV infection accounts for ~50% of all cases of HCC [2]. Most patients with HCC are in the middle or advanced stage at the time of diagnosis, with a high degree of malignancy, easy recurrence, and poor prognosis, which seriously threatens their health and life [3, 4]. The long-term therapeutic effect of HCC remains unsatisfactory, especially in patients with advanced unresectable disease. Oxaliplatin is one of the most commonly used chemotherapeutic drugs in transcatheter arterial chemoembolization, hepatic arterial infusion, and systemic administration of HCC [9,10,11], oxaliplatin resistance is an important reason for poor therapeutic effect and recurrence of HCC [12, 13].

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