Extracellular translationally controlled tumor protein promotes colorectal cancer invasion and metastasis through Cdc42/JNK/ MMP9 signaling
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Bin Xiao1,*, Daxiang Chen1, Shuhong Luo1,2,3, Wenbo Hao1, Fangyan Jing4, Tiancai Liu1, Suihai Wang1, Yan Geng5, Linhai Li6, Weiwen Xu1, Yajie Zhang7, Xiaoqing Liao1, Daming Zuo8, Yingsong Wu1, Ming Li1, Qiang Ma1,*
1State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
2RayBiotech, Inc., Guangzhou 510600, China
3RayBiotech, Inc., Norcross, GA 30092, USA
4Department of Anorectal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China
5Department of Intensive Care Unit, 303 Hospital of People’s Liberation Army, Nanning 530021, China
6Department of Laboratory Medicine, Guangzhou General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China
7Division of Clinical Immunology Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China
8Department of Immunology, School of Basic Medicine, Southern Medical University, Guangzhou, 510515, China
*These authors have contributed equally to this work
Yingsong Wu, email: email@example.com
Ming Li, email: firstname.lastname@example.org
Qiang Ma, email: email@example.com
Keywords: extracellular TCTP, metastasis, Cdc42, p-JNK
Received: February 11, 2016 Accepted: June 08, 2016 Published: June 28, 2016
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.
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