PTP1B Contributes to Calreticulin-Induced Metastatic Phenotypes in Esophageal Squamous Cell Carcinoma

Xiao-Min Wang,Yu Zhang,Ming-Rong Wang,Tong-Tong Zhang,Jia-Jie Hao,Qi-Min Zhan,Yang Yang,Zhi-Hua Liu,Li Shang,Wei Luo,Bo-Shi Wang,Feng Shi

doi:10.1158/1541-7786.mcr-12-0704

Abstract

Calreticulin (CRT) is a Ca(2+)-binding chaperone protein that alters cellular Ca(2+)-homeostasis in the endoplasmic reticulum (ER). Previously it was shown that CRT was overexpressed in esophageal squamous cell carcinoma (ESCC), and elevated CRT expression promoted the migration and invasion of ESCC cells. In the present study, the mechanisms underlying the role of CRT in esophageal carcinoma progression were investigated. Critically, depletion of CRT or protein-tyrosine phosphatase 1B (PTP1B) reduced ESCC cell migration and metastasis to the lung, whereas restoration of PTP1B protein levels rescued cell migration in CRT-silenced cells. Knockdown of CRT decreased PTP1B protein expression by reducing phosphorylation at the Y694 site of STAT5A, whereas knockdown of PTP1B reduced ERK1/2 phosphorylation at T204. Immunohistochemical analysis of CRT and PTP1B expression in ESCC patient tissues was strongly correlated. Importantly, PTP1B expression was associated with poor survival in patients with CRT overexpression. Overall, these data indicate a novel signaling pathway connecting CRT, STAT5A, PTP1B, and ERK1/2 in the regulation of ESCC cell migration. These findings suggest that PTP1B is a downstream effector of CRT signaling, promotes tumor progression, and can potentially be used as a new drug target for ESCC.

Highlights

Squamous cell carcinoma is the predominant esophageal cancer occurring in the Chinese population and is correlated with a poor prognosis and a 5-year survival rate of 15% to 25% [1]
These results indicate that CRT regulates protein-tyrosine phosphatase 1B (PTP1B) expression in esophageal squamous cell carcinoma (ESCC) cells
We showed that PTP1B, an important member of PTP family, is involved downstream of the CRT-dependent ESCC cell motility pathway

Summary

Introduction

Squamous cell carcinoma is the predominant esophageal cancer occurring in the Chinese population and is correlated with a poor prognosis and a 5-year survival rate of 15% to 25% [1]. One reason for the poor prognosis is that esophageal squamous cell carcinoma (ESCC) already exhibits extensive local invasion and distant metastasis at the time of initial diagnosis [2]. Having a better understanding of the molecular pathogenesis of ESCC is important for early diagnosis and effective treatment of the disease. The metastatic process consists of a number of distinct steps. Tumor invasion and migration are parts of these sequential steps. A multitude of molecular changes in tumor cells could enable these cells to acquire highly motile properties that overcome cell–cell contacts and cell–extracellular matrix barriers. We showed that one of such molecular alterations is the overexpression of calreticulin (CRT) in ESCCs [3]

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Results

Conclusion