Premila D Leiphrakpam1, Audrey J Lazenby2, Sanjib Chowdhury3, Lynette M Smith4, Michelle Mathiesen5, Michael G Brattain6, Jing Wang7, Jennifer D Black6, Chandrakanth Are8. 1. Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. 2. Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. 3. Section of Gastroenterology, College of Medicine, Boston University Medical Center, Boston, Massachusetts. 4. Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska. 5. Diagnostic Laboratory, Phibro Animal Health Corporation, Omaha, Nebraska. 6. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. 7. Department of Cancer Biology and Genetics, College of Medicine, Ohio State University, Columbus, Ohio. 8. Division of Surgical Oncology, Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
Abstract
BACKGROUND: Na+ /H+ exchanger regulatory factor 1 (NHERF1) has been implicated in the tumorigenesis of several cancer types and is a potential therapeutic target. The current study evaluated the relationship between NHERF1 expression and clinical outcome in colorectal cancer (CRC). METHODS: NHERF1 expression was evaluated by immunohistochemistry in 167 patients with CRC primary tumors, 37 patients with no disease, and 27 patients with metastatic CRC (mCRC); and in the orthotopically implanted tumors in mice. NHERF1 expression was manipulated in CRC cells using inducible short hairpin RNAs to determine its biological functions. RESULTS: High expression of NHERF1 correlated with CRC progression and metastasis, as well as significantly worse overall survival, recurrence-free survival, and disease-specific survival. Orthotopic implantation studies demonstrated increased NHERF1 expression in liver metastases. Treatment of CRC xenografts with insulin-like growth factor 1 receptor (IGF1R) inhibitors downregulated NHERF1 expression, indicating NHERF1 is downstream of IGF1R signaling. Knockdown of NHERF1 increased apoptosis and reduced X-linked inhibitor of apoptosis protein (XIAP) and survivin expression, indicating NHERF1 is critical for CRC cell survival. CONCLUSION: NHERF1 expression levels correlated with worse prognosis in patients with CRC and plays a critical role in CRC cell survival. Together, our findings establish NHERF1 as a novel potential marker for increased risk of CRC-specific mortality and identify NHERF1 as an attractive therapeutic target for mCRC treatment.
BACKGROUND:Na+ /H+ exchanger regulatory factor 1 (NHERF1) has been implicated in the tumorigenesis of several cancer types and is a potential therapeutic target. The current study evaluated the relationship between NHERF1 expression and clinical outcome in colorectal cancer (CRC). METHODS:NHERF1 expression was evaluated by immunohistochemistry in 167 patients with CRC primary tumors, 37 patients with no disease, and 27 patients with metastatic CRC (mCRC); and in the orthotopically implanted tumors in mice. NHERF1 expression was manipulated in CRC cells using inducible short hairpin RNAs to determine its biological functions. RESULTS: High expression of NHERF1 correlated with CRC progression and metastasis, as well as significantly worse overall survival, recurrence-free survival, and disease-specific survival. Orthotopic implantation studies demonstrated increased NHERF1 expression in liver metastases. Treatment of CRC xenografts with insulin-like growth factor 1 receptor (IGF1R) inhibitors downregulated NHERF1 expression, indicating NHERF1 is downstream of IGF1R signaling. Knockdown of NHERF1 increased apoptosis and reduced X-linked inhibitor of apoptosis protein (XIAP) and survivin expression, indicating NHERF1 is critical for CRC cell survival. CONCLUSION:NHERF1 expression levels correlated with worse prognosis in patients with CRC and plays a critical role in CRC cell survival. Together, our findings establish NHERF1 as a novel potential marker for increased risk of CRC-specific mortality and identify NHERF1 as an attractive therapeutic target for mCRC treatment.
Authors: Xiao-Ning Guo; Ashwani Rajput; Rebecca Rose; Jennie Hauser; Alexander Beko; Karen Kuropatwinski; Charles LeVea; Robert M Hoffman; Michael G Brattain; Jing Wang Journal: Cancer Res Date: 2007-06-15 Impact factor: 12.701
Authors: Jing Wang; Karen Kuropatwinski; Jennie Hauser; Michael R Rossi; Yunfei Zhou; Alexis Conway; Julie L C Kan; Neil W Gibson; James K V Willson; John K Cowell; Michael G Brattain Journal: Mol Cancer Ther Date: 2007-03 Impact factor: 6.261
Authors: Premila D Leiphrakpam; Audrey J Lazenby; Lynette M Smith; Michael G Brattain; Jennifer D Black; Jing Wang; Chandrakanth Are Journal: J Surg Oncol Date: 2020-11-12 Impact factor: 3.454