Abstract
BackgroundPancreatic 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.MethodsYAP1 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.ResultsMass 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.ConclusionsOur 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.
Highlights
Pancreatic cancer is a major cause of cancer-related mortality
Yes-associated protein 1 (YAP1) is connected to mediators promoting remodeling of the extracellular matrix Subsequently, we explored the biological background of the obtained results with the aim to identify the most significant networks and relationships associated with YAP1 expression in pancreatic cancer
The results revealed that YAP1 is directly connected to secreted AREG, connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), fibroblast growth factor 1 (FGF1) and MSLN that are involved in fibrosis and other key signaling pathways involved in the tumor-stroma interactions [27,28,29,30,31]
Summary
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. We evaluate the biomarker potential of YAP1 in pancreatic cancer tissue. Zhou et al J Transl Med (2020) 18:77 the second leading cause by 2030 [2] Multiple factors, such as late diagnosis and resistance to conventional therapies, contribute to the overall poor prognosis. Large-scale genomic studies have been performed to determine molecular subtypes of pancreatic cancer requiring individualized treatments [3,4,5,6]. Such studies have massively increased our understanding of pancreatic cancer at the molecular level
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