TP53INP1 Downregulation Activates a p73-Dependent DUSP10/ERK Signaling Pathway to Promote Metastasis of Hepatocellular Carcinoma

Kai-Yu Ng; Lok-Hei Chan; Stella Chai; Man Tong; Xin-Yuan Guan; Nikki P Lee; Yunfei Yuan; Dan Xie; Terence K Lee; Nelson J Dusetti; Alice Carrier; Stephanie Ma

doi:10.1158/0008-5472.CAN-16-3456

TP53INP1 Downregulation Activates a p73-Dependent DUSP10/ERK Signaling Pathway to Promote Metastasis of Hepatocellular Carcinoma

Cancer Res. 2017 Sep 1;77(17):4602-4612. doi: 10.1158/0008-5472.CAN-16-3456. Epub 2017 Jul 3.

Authors

Kai-Yu Ng¹, Lok-Hei Chan¹, Stella Chai¹, Man Tong¹, Xin-Yuan Guan^{2

3}, Nikki P Lee⁴, Yunfei Yuan⁵, Dan Xie⁵, Terence K Lee⁶, Nelson J Dusetti⁷, Alice Carrier⁷, Stephanie Ma^{8

3}

Affiliations

¹ School of Biomedical Sciences, The University of Hong Kong, Hong Kong.
² Department of Clinical Oncology, The University of Hong Kong, Hong Kong.
³ State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
⁴ Department of Surgery, The University of Hong Kong, Hong Kong.
⁵ State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
⁶ Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
⁷ Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France.
⁸ School of Biomedical Sciences, The University of Hong Kong, Hong Kong. stefma@hku.hk.

PMID: 28674078
DOI: 10.1158/0008-5472.CAN-16-3456

Abstract

Identifying critical factors involved in the metastatic progression of hepatocellular carcinoma (HCC) may offer important therapeutic opportunities. Here, we report that the proapoptotic stress response factor TP53INP1 is often selectively downregulated in advanced stage IV and metastatic human HCC tumors. Mechanistic investigations revealed that TP53INP1 downregulation in early-stage HCC cells promoted metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway. The DUSP10 promoter included putative binding sites for p73 directly implicated in modulation by TP53INP1. Overall, our findings show how TP53INP1 plays a critical role in limiting the progression of early-stage HCC, with implications for developing new therapeutic strategies to attack metastatic HCC. Cancer Res; 77(17); 4602-12. ©2017 AACR.

MeSH terms

Animals
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Dual-Specificity Phosphatases / genetics
Dual-Specificity Phosphatases / metabolism*
Gene Expression Profiling
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism*
Humans
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / secondary*
Mice
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / metabolism*
Mitogen-Activated Protein Kinase Phosphatases / genetics
Mitogen-Activated Protein Kinase Phosphatases / metabolism*
Neoplasm Metastasis
Prognosis
Protein Array Analysis
Signal Transduction
Tumor Cells, Cultured
Tumor Protein p73 / genetics
Tumor Protein p73 / metabolism*
Xenograft Model Antitumor Assays

Substances

Carrier Proteins
Heat-Shock Proteins
TP53INP1 protein, human
TP73 protein, human
Tumor Protein p73
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
DUSP10 protein, human
Mitogen-Activated Protein Kinase Phosphatases
Dual-Specificity Phosphatases