Systems Biology Approach to Identify Novel Genomic Determinants for Pancreatic Cancer Pathogenesis

Indu Khatri,Sunandini Sharma,Sukhwinder Kaur,Surinder K Batra,Manoj K Bhasin,Joseph Carmicheal,Koelina Ganguly

doi:10.1038/s41598-018-36328-w

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a 5-year survival rate of <8%. Its dismal prognosis stems from inefficient therapeutic modalities owing to the lack of understanding about pancreatic cancer pathogenesis. Considering the molecular complexity and heterogeneity of PDAC, identification of novel molecular contributors involved in PDAC onset and progression using global “omics” analysis will pave the way to improved strategies for disease prevention and therapeutic targeting. Meta-analysis of multiple miRNA microarray datasets containing healthy controls (HC), chronic pancreatitis (CP) and PDAC cases, identified 13 miRNAs involved in the progression of PDAC. These miRNAs showed dysregulation in both tissue as well as blood samples, along with progressive decrease in expression from HC to CP to PDAC. Gene-miRNA interaction analysis further elucidated 5 miRNAs (29a/b, 27a, 130b and 148a) that are significantly downregulated in conjunction with concomitant upregulation of their target genes throughout PDAC progression. Among these, miRNA-29a/b targeted genes were found to be most significantly altered in comparative profiling of HC, CP and PDAC, indicating its involvement in malignant evolution. Further, pathway analysis suggested direct involvement of miRNA-29a/b in downregulating the key pathways associated with PDAC development and metastasis including focal adhesion signaling and extracellular matrix organization. Our systems biology data analysis, in combination with real-time PCR validation indicates direct functional involvement of miRNA-29a in PDAC progression and is a potential prognostic marker and therapeutic candidate for patients with progressive disease.

Highlights

MiRNAs, a group of small non-coding RNAs, have emerged recently as potential molecular contributors in carcinogenesis including initiation, progression and metastasis[4]
We explored the combined potency of gene and miRNA datasets collected at different pancreas statuses (Healthy controls(HC), chronic pancreatitis (CP), Pancreatic ductal adenocarcinoma (PDAC) and metastatic PDAC (MPDAC)), to identify novel prognostic markers associated with the onset and progression of PDAC
We performed an integrative meta-analysis on miRNA and mRNA data from CP and PDAC cases to identify the miRNAs that are putatively associated with pathophysiology of CP to PDAC

Summary

Introduction

MiRNAs, a group of small non-coding RNAs, have emerged recently as potential molecular contributors in carcinogenesis including initiation, progression and metastasis[4]. Cancer-related miRNAs, apart from regulating the expression of known protein-coding oncogenes and tumor suppressors, behave as oncogenes themselves (referred to as oncomirs) as well as acting as tumor suppressors. MiRNAs have previously been reported to exhibit exclusively distinct expression profiles in PDAC, chronic pancreatitis (CP) and normal pancreas with each www.nature.com/scientificreports/ Cancer-related miRNAs, apart from regulating the expression of known protein-coding oncogenes and tumor suppressors, behave as oncogenes themselves (referred to as oncomirs) as well as acting as tumor suppressors5. miRNAs have previously been reported to exhibit exclusively distinct expression profiles in PDAC, chronic pancreatitis (CP) and normal pancreas with each www.nature.com/scientificreports/

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