SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer

Yan Huang,Hailong Jiang,Wenjun Chang,Lei Qiu,Jianzhong Li,Jie Wang,Yamin Pan,Fuao Cao,An Li,Yiming Lu,Hao Shen,Chuanxiang Zhou

doi:10.1038/s41598-017-17604-7

Abstract

Tyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman’s rho = −0.408, P ≤ 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165–0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227–0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199–4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC.

Highlights

Colorectal cancer (CRC) is the third most frequent cancer in men and second in women worldwide[1]
We demonstrated that SHP2 reduced the aggressiveness of colorectal cancer (CRC) cells in vitro, and had a robust capability of inhibiting STAT3 activation in CRC cells
Bard-Chapeau et al demonstrated that mice with hepatocyte-specific deletion of SHP2 are more sensitive to diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC), and STAT3 is required for the promotion of HCC development induced by SHP2 deletion[11]

Summary

Introduction

Colorectal cancer (CRC) is the third most frequent cancer in men and second in women worldwide[1]. Depending on the cell or tissue type, SHP2 enhanced or antagonized PI3K-AKT or RHO activation[8,9], increased STAT5 phosphorylation[10], but decreased STAT3 phosphorylation[11], and might affect NF-кB12 or NFAT13 pathways. Such a complexity makes it difficult to identify SHP2 functions. (M)Transwell assay showing blockade of SHP2 phosphatase activity by PHPS1 improved CRC cell migratory ability. We evaluated the prognostic value of the combination of SHP2 and STAT3 in tumor samples from a cohort of CRC patients with known clinical history

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