Abstract
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.
Highlights
Colorectal cancer (CRC) patients have benefited from research advancements in early screening and preventative measures in life styles
These results indicate that more YAP1 protein is accumulated in the nucleus in the 5-FU resistant cells, suggesting elevated YAP signaling in the 5-FU resistant cells
Through RNA-seq analyses, we discovered elevated YAP1 target gene expression as the major alteration in the 5-FU resistant cells
Summary
Colorectal cancer (CRC) patients have benefited from research advancements in early screening and preventative measures in life styles. The overall incidence of CRC has significantly declined in the last two decades CRC is still the leading cause of cancer-related deaths, with nearly 1.4 million cases a year and ~774,000 deaths worldwide [1]. Chemotherapy, 5-Fluorouracil (5-FU) -based adjuvant chemotherapy, has been widely used to treat CRC since early 1990s. Addition of oxaliplatin to 5-FU-based regiment has resulted in risk reduction (~20%) for disease-free survival. The first line treatment of CRC includes mFOLFOX6 with or without targeted drugs bevacizumab or cetuximab [2,3]. The mFOLFOX6 regimen contains leucovorin calcium (folinic acid), 5-fluorouracil, and oxaliplatin. Many advanced CRC patients eventually develop relapsed disease despite of initial response to chemotherapy. Drug resistance is a major barrier to achieve effective CRC treatment
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