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Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer
- Source :
- Molecular Carcinogenesis. 57:1608-1615
- Publication Year :
- 2018
- Publisher :
- Wiley, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Antimetabolites, Antineoplastic
Cancer Research
Colorectal cancer
medicine.medical_treatment
Cell Cycle Proteins
Kaplan-Meier Estimate
Disease
Drug resistance
Protein Serine-Threonine Kinases
Biology
Gene Knockout Techniques
Mice
03 medical and health sciences
0302 clinical medicine
Recurrence
Cell Line, Tumor
Biomarkers, Tumor
medicine
Animals
Humans
Hippo Signaling Pathway
RNA, Small Interfering
Molecular Biology
Tissue homeostasis
YAP1
Chemotherapy
Gene knockdown
Nuclear Proteins
Prognosis
medicine.disease
030104 developmental biology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
Fluorouracil
Stem cell
Colorectal Neoplasms
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 10982744 and 08991987
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Molecular Carcinogenesis
- Accession number :
- edsair.doi.dedup.....4917bf23801ed335a748aff7cdce7e4f