Molecular characterization of pro-metastatic functions of β4-integrin in colorectal cancer
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Wanguang Zhang1,3,*, Bixiang Zhang1,3,*, Trung Vu2, Guandou Yuan1,2,4, Binhao Zhang1,3, Xiaoping Chen3, Upender Manne5 and Pran K. Datta1,2
1Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
2Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
3Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
4Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
5Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
*These authors have contributed equally to this work
Pran K. Datta, email: [email protected]
Keywords: colorectal cancer, liver metastasis, affymetrix microarray, β4-integrin, tissue microarray
Received: February 25, 2017 Accepted: August 15, 2017 Published: September 27, 2017
The β4-integrin subunit has been implicated in development and progression of several epithelial tumor types. However, its role in metastases of colorectal cancer (CRC) remains elusive. To study CRC metastasis, we generated a highly invasive, metastatic cell line MC38-LM10 (LM10) by passaging mouse CRC MC38 cells ten times, using a splenic injection model of liver metastasis. Affymetrix microarray analyses of LM10 and MC38 cell lines and their corresponding liver metastases generated a gene signature for CRC metastasis. This signature shows strong upregulation of β4-integrin in LM10 cells and corresponding metastases. Upregulation of β4-integrin in highly aggressive LM10 cells is associated with increased migration, invasion, and liver metastases. Furthermore, stable knockdown of β4-integrin in human CRC SW620 cells reduces Bcl-2 expression, increases apoptosis, and decreases invasion, tumorigenicity, and liver metastasis, thus resulting in significantly increased survival of mice (hazard ratio = 0.32, 95% confidence interval = 0.15-0.66, P<0.01). Patients with CRC tumors display higher β4-integrin levels in stages 1-4 and significantly lower survival rate. Collectively, β4-integrin plays a critical role in CRC progression, invasion, and metastasis, suggesting that it could be a potential therapeutic target for CRC patients.
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