The mRNA of TCTP functions as a sponge to maintain homeostasis of TCTP protein levels in hepatocellular carcinoma

Zhiying He,Rongzhi Zou,Fu Wang,Zhibin Lin,Xisheng Yang,Beilei Zhang,Meng Pu,Xia Li,Kefeng Dou,Wei Liu,Qi Liu

doi:10.1038/s41419-020-03149-7

Abstract

Translationally controlled tumor protein (TCTP) is a highly conserved protein that accumulated in the tumorigenesis of various malignancies. Despite the important role of TCTP protein in tumor progression, the precise function and underlying mechanistic regulation of TCTP mRNA in hepatocellular carcinoma (HCC) remain unclear. In this study, we found that TCTP protein was overexpressed in HCC patients but TCTP mRNA expression levels were reversed. TCTP knockout HCC cells exhibited attenuated abilities of proliferation, migration, and invasion. The knockdown of TCTP by siRNA effectively reduced TCTP mRNA levels but not protein levels in HCC cells. Moreover, although the constitutive knockdown of TCTP inhibited almost 80% of TCTP protein expression levels in tumors of wildtype transgenic mice (TCTP KD/WT), partial restoration of TCTP protein expression was observed in the tumors of heterozygous TCTP mice (TCTP KD/TCTP±). The blockage of mRNA synthesis with ActD stimulated TCTP protein expression in HCC cells. In contrast, combined treatment with ActD and CHX or MG132 treatment alone did not lead to the TCTP protein accumulation in cells. Furthermore, following the introduction of exogenous TCTP in cells and orthotopic HCC tumor models, the endogenous TCTP protein did not change with the recombinational TCTP expression and kept a rather stable level. Dual-luciferase assays revealed that the coding sequence of TCTP mRNA functions as a sponge to regulate the TCTP protein expression. Collectively, our results indicated that the TCTP mRNA and protein formed a closed regulatory circuit and works as a buffering system to keep the homeostasis of TCTP protein levels in HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading cause of death in the world for years[1]
We found that the increase of phosphorylation of ERK and AKT was associated with Translationally controlled tumor protein (TCTP) overexpression in HCC tumors (Supplementary Fig. S1A), confirming that TCTP expression is regulated through PI3-K/Akt/mTORC1 signaling pathway[22]
The accumulation of TCTP mRNA has been reported without an increase in its corresponding protein level[26]

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading cause of death in the world for years[1]. Other risk factors, including inherited metabolic diseases, nonalcoholic steatohepatitis, and tobacco smoking, have been proposed to induce HCC3. Due to the high recurrence rates of 70–80% within 5 years and low longterm survival rate of 7% within 10 years after resection[4], the identification of specific targets for early diagnosis and therapy of HCC is imperative and urgent. Factors that can induce HCC reversion, which means expelling HCC cells to quit the malignancy, have been highly desired and explored for HCC therapy in clinic[5,6]. Controlled tumor protein (TCTP), a highly conserved protein, has been implicated as one of the most important biomarkers and targets for tumor reversion[7,8].

Methods

Results

Conclusion