Extracellular translationally controlled tumor protein promotes colorectal cancer invasion and metastasis through Cdc42/JNK/ MMP9 signaling

Bin Xiao,Suihai Wang,Daming Zuo,Wenbo Hao,Tiancai Liu,Shuhong Luo,Fangyan Jing,Qiang Ma,Yan Geng,Xiaoqing Liao,Ming Li,Daxiang Chen,Yajie Zhang,Linhai Li,Yingsong Wu,Weiwen Xu

doi:10.18632/oncotarget.10315

Abstract

The translationally controlled tumor protein (TCTP) can be secreted independently of the endoplasmic reticulum/Golgi pathway and has extrinsic activities when it is characterized as the histamine releasing factor (HRF). Despite its important role in allergies and inflammation, little is known about how extracellular TCTP affects cancer progression. In this study, we found that TCTP was overexpressed in the interstitial tissue of colorectal cancer (CRC) and its expression correlated with poor survival, high pathological grades and metastatic TNM stage in CRC patients. TCTP expression was greater in metastatic liver tissue than in primary tumors and was increased in highly invasive CRC cells. We demonstrated that the expression of TCTP was regulated by HIF-1α and its release was increased in response to low serum and hypoxic stress. Recombinant human TCTP (rhTCTP) promoted the migration and invasiveness of CRC cells in vitro and contributed to distant liver metastasis in vivo. Furthermore, rhTCTP activated Cdc42, phosphorylated JNK (p-JNK), increasing the translocation of p-JNK from the cytoplasm to the nucleus, as well as the secretion of MMP9. In addition, the expression of TCTP positively correlated with that of Cdc42 and p-JNK in clinical CRC samples. The silencing of Cdc42, JNK and MMP9 significantly inhibited the Matrigel invasion of rhTCTP-enhanced CRC cells. Collectively, these results identify a new role for extracellular TCTP as a promoter of CRC progression and liver metastases via Cdc42/JNK/MMP9 activation.

Highlights

Colorectal cancer (CRC) is one of the most common malignancies with high rates of morbidity and mortality
Analysis of translationally controlled tumor protein (TCTP) expression according to the clinical parameters of colorectal cancer (CRC) patients, such as age, gender, lymphoma metastasis, tumor size, pathological grade, American Joint Committee On Cancer (AJCC) stage, and Tumor Node Metastasis (TNM) stage showed that TCTP expression was positively associated with high pathological grades (P=0.014) and metastatic TNM stage (Table 1)
TCTP expression at the protein and mRNA levels correlated with increased metastatic potential in the six CRC cell lines [12,13,14], which was consistent with our previous report [6] (Figure 1G and Figure 1H)

Summary

Introduction

Colorectal cancer (CRC) is one of the most common malignancies with high rates of morbidity and mortality. More than half of CRC patients will suffer from systemic tumor metastases, most commonly liver metastases, which is the leading cause of death [1]. Controlled tumor protein (TCTP), a highly conserved protein, is implicated in the tumorigenesis of various malignances [2]. TCTP inhibits cell apoptosis by binding to Mcl and blocking its ubiquitination [4, 5]. Our previous work showed that TCTP participated in CRC progression. Down-regulation of TCTP inhibited proliferation, migration and invasion activities of LoVo cells [6]. Lee et al [7] reported that TCTP can induce epithelial to mesenchymal transition and promotes cell migration, invasion and metastasis. Efforts to elucidate the direct role of TCTP in tumor cells and the underlying molecular mechanisms are imperative

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Conclusion