Journal
MOLECULAR CARCINOGENESIS
Volume 57, Issue 11, Pages 1608-1615Publisher
WILEY
DOI: 10.1002/mc.22883
Keywords
cancer therapy; colorectal cancer; drug resistance; YAP; 5-fluorouracil (5-FU)
Categories
Funding
- National Cancer Institute [R01CA155086]
- Wells Center for Pediatric Research
- Riley Children Foundation
- Jeff Gordon Research Laboratory, AGA, Healthcare Initiatives, Inc.
- IU Simon Cancer Center
- National Natural Science foundation of China [81672823, 81472641]
- Key Projects in the National Science & Technology Pillar Program of China [2014BAI09B03]
- CTSI Indiana
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Colorectal cancer is a leading cause of cancer-related death worldwide. While early stage colorectal cancer can be removed by surgery, patients with advanced disease are treated by chemotherapy, with 5-Fluorouracil (5-FU) as a main ingredient. However, most patients with advanced colorectal cancer eventually succumb to the disease despite some responded initially. Thus, identifying molecular mechanisms responsible for drug resistance will help design novel strategies to treat colorectal cancer. In this study, we analyzed an acquired 5-FU resistant cell line, LoVo-R, and determined that elevated expression of YAP target genes is a major alteration in the 5-FU resistant cells. Hippo/YAP signaling, a pathway essential for cell polarity, is an important regulator for tissue homeostasis, organ size, and stem cells. We demonstrated that knockdown of YAP1 sensitized LoVo-R cells to 5-FU treatment in cultured cells and in mice. The relevance of our studies to colorectal cancer patients is reflected by our discovery that high expression of YAP target genes in the tumor was associated with an increased risk of cancer relapse and poor survival in a larger cohort of colorectal cancer patients who underwent 5-FU-related chemotherapy. Taken together, we demonstrate a critical role of YAP signaling for drug resistance in colorectal cancer.
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