YAP1 is an independent prognostic marker in pancreatic cancer and associated with extracellular matrix remodeling
Open Access
- 13 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Translational Medicine
- Vol. 18 (1), 1-10
- https://doi.org/10.1186/s12967-020-02254-7
Abstract
Pancreatic cancer is a major cause of cancer-related mortality. The identification of effective biomarkers is essential in order to improve management of the disease. Yes-associated protein 1 (YAP1) is a downstream effector of the Hippo pathway, a signal transduction system implicated in tissue repair and regeneration, as well as tumorigenesis. Here we evaluate the biomarker potential of YAP1 in pancreatic cancer tissue. YAP1 was selected as a possible biomarker for pancreatic cancer from global protein sequencing of fresh frozen pancreatic cancer tissue samples and normal pancreas controls. The prognostic utility of YAP1 was evaluated using mRNA expression data from 176 pancreatic cancer patients in The Cancer Genome Atlas (TCGA), as well as protein expression data from immunohistochemistry analysis of a local tissue microarray (TMA) cohort comprising 140 pancreatic cancer patients. Ingenuity Pathway Analysis was applied to outline the interaction network for YAP1 in connection to the pancreatic tumor microenvironment. The expression of YAP1 target gene products was evaluated after treatment of the pancreatic cancer cell line Panc-1 with three substances interrupting YAP–TEAD interaction, including Super-TDU, Verteporfin and CA3. Mass spectrometry based proteomics showed that YAP1 is the top upregulated protein in pancreatic cancer tissue when compared to normal controls (log2 fold change 6.4; p = 5E−06). Prognostic analysis of YAP1 demonstrated a significant correlation between mRNA expression level data and reduced overall survival (p = 0.001). In addition, TMA and immunohistochemistry analysis suggested that YAP1 protein expression is an independent predictor of poor overall survival [hazard ratio (HR) 1.870, 95% confidence interval (CI) 1.224–2.855, p = 0.004], as well as reduced disease-free survival (HR 1.950, 95% CI 1.299–2.927, p = 0.001). Bioinformatic analyses coupled with in vitro assays indicated that YAP1 is involved in the transcriptional control of target genes, associated with extracellular matrix remodeling, which could be modified by selected substances disrupting the YAP1-TEAD interaction. Our findings indicate that YAP1 is an important prognostic biomarker for pancreatic cancer and may play a regulatory role in the remodeling of the extracellular matrix.This publication has 42 references indexed in Scilit:
- The Hippo Effector Yorkie Controls Normal Tissue Growth by Antagonizing Scalloped-Mediated Default RepressionDevelopmental Cell, 2013
- Insights into the regulation of protein abundance from proteomic and transcriptomic analysesNature Reviews Genetics, 2012
- Structural Analysis of the Cancer-specific Promoter in Mesothelin and in Other Genes Overexpressed in CancersOnline Journal of Public Health Informatics, 2011
- Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitorsOncogene, 2009
- Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic AnalysesScience, 2008
- Connective tissue growth factor (CTGF) and cancer progressionJournal of Biomedical Science, 2008
- TEAD mediates YAP-dependent gene induction and growth controlGenes & Development, 2008
- Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategiesThe Esophagus, 2008
- High Cancer-Specific Expression of Mesothelin (MSLN) Is Attributable to an Upstream Enhancer Containing a Transcription Enhancer Factor–Dependent MCAT MotifCancer Research, 2007
- REporting recommendations for tumour MARKer prognostic studies (REMARK)British Journal of Cancer, 2005