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

Abstract

// Bin Xiao 1, * , Daxiang Chen 1 , Shuhong Luo 1, 2, 3 , Wenbo Hao 1 , Fangyan Jing 4 , Tiancai Liu 1 , Suihai Wang 1 , Yan Geng 5 , Linhai Li 6 , Weiwen Xu 1 , Yajie Zhang 7 , Xiaoqing Liao 1 , Daming Zuo 8 , Yingsong Wu 1 , Ming Li 1 , Qiang Ma 1, * 1 State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China 2 RayBiotech, Inc., Guangzhou 510600, China 3 RayBiotech, Inc., Norcross, GA 30092, USA 4 Department of Anorectal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China 5 Department of Intensive Care Unit, 303 Hospital of People’s Liberation Army, Nanning 530021, China 6 Department of Laboratory Medicine, Guangzhou General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China 7 Division of Clinical Immunology Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China 8 Department of Immunology, School of Basic Medicine, Southern Medical University, Guangzhou, 510515, China * These authors have contributed equally to this work Correspondence to: Yingsong Wu, email: wg@smu.edu.cn Ming Li, email: mingli2006_2006@126.com Qiang Ma, email: mq@smu.edu.cn Keywords: extracellular TCTP, metastasis, Cdc42, p-JNK Received: February 11, 2016      Accepted: June 08, 2016      Published: June 28, 2016 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.