Integrin beta 4 (ITGB4) and its tyrosine-1510 phosphorylation promote pancreatic tumorigenesis and regulate the MEK1-ERK1/2 signaling pathway.

Xiangli Meng,Yunhao Wu,Haoyi Jin,Boqiang Yu,Jiahong Han,Xiaodong Tan,Xinlu Liu,Peng Liu,Yinpeng Huang

doi:10.17305/bjbms.2019.4255

Abstract

Pancreatic cancer is the fourth leading cause of cancer death, with a 5-year survival rate of only 1–4%. Integrin-mediated cell adhesion is critical for the initiation, progression, and metastasis of cancer. In this study we investigated the role of integrin β4 (ITGB4) and its phosphorylation at tyrosine Y1510 (p-ITGB4-Y1510) in the tumorigenesis of pancreatic cancer. We analyzed the expression of ITGB4 and p-ITGB4-Y1510 in pancreatic cancer tissue and cell lines using immunohistochemistry, Western blot, or semi-quantitative reverse transcription PCR. ITGB4 and p-ITGB4-Y1510 were highly expressed in pancreatic cancer (n = 176) compared with normal pancreatic tissue (n = 171). High p-ITGB4-Y1510 expression correlated with local invasion and distant metastasis of pancreatic cancer, and high ITGB4 was significantly associated with poor survival of patients. Inhibition of ITGB4 by siRNA significantly reduced migration and invasion of PC-1.0 and AsPC-1 cells. Overexpression of the mutant ITGB4-Y1510A (a mutation of tyrosine to alanine at 1510 position) in PC-1.0 and AsPC-1 cells not only blocked the ITGB4 phosphorylation at Y1510 but also suppressed the expression of ITGB4 (p < 0.05 vs. wild-type ITGB4). The transfection of PC-1.0 and AsPC-1 cells with ITGB4-Y1510A significantly decreased the level of p-mitogen-activated protein kinase kinase (MEK)1 (T292) and p-extracellular signal-regulated kinase (ERK)1/2 but did not affect the level of p-MEK1 (T386) and p-MEK2 (T394). Overall, our study showed that ITGB4 and its phosphorylated form promote cell migration and invasion in pancreatic cancer and that p-ITGB4-Y1510 regulates the downstream MEK1-ERK1/2 signaling cascades. Targeting ITGB4 or its phosphorylation at Y1510 may be a novel therapeutic option for pancreatic cancer.

Highlights

Pancreatic cancer accounts for only 1–3% of newly diagnosed cancer patients every year, with a 5-year survival rate of 1–4% it is the fourth leading cause of cancer death [1,2]
We found that ITGB4 was highly expressed in high-invasive metastatic pancreatic cancer cell www.bjbms.org line PC-1.0 compared to low-invasive cell line PC-1 [29], implying that ITGB4 may be functionally involved in the tumorigenicity of pancreatic cancer
Since the activation of mitogen-activated protein kinase (MAPK) cascades has shown to play a key role in pancreatic cell proliferation, differentiation, migration, senescence, and apoptosis [30,31] as well as in the tumorigenesis of pancreatic cancer, we examined whether the phosphorylation of ITGB4 at Y1510 is involved in the regulation of MAPK signaling cascades

Summary

Introduction

Pancreatic cancer accounts for only 1–3% of newly diagnosed cancer patients every year, with a 5-year survival rate of 1–4% it is the fourth leading cause of cancer death [1,2]. Surgery is a relatively effective treatment for pancreatic cancer, especially considering that most patients are in the advanced stage and with different degrees of distant

Objectives

Methods

Results

Discussion

Conclusion