Date Published: May 31, 2019
Publisher: Public Library of Science
Author(s): Tainara F. Felix, Rainer M. Lopez Lapa, Márcio de Carvalho, Natália Bertoni, Tomas Tokar, Rogério A. Oliveira, Maria A. M. Rodrigues, Cláudia N. Hasimoto, Walmar K. Oliveira, Leonardo Pelafsky, César T. Spadella, Juan C. Llanos, Giovanni F. Silva, Wan L. Lam, Silvia Regina Rogatto, Luciana Schultz Amorim, Sandra A. Drigo, Robson F. Carvalho, Patricia P. Reis, Surinder K. Batra.
Despite progress in treatment strategies, only ~24% of pancreatic ductal adenocarcinoma (PDAC) patients survive >1 year. Our goal was to elucidate deregulated pathways modulated by microRNAs (miRNAs) in PDAC and Vater ampulla (AMP) cancers. Global miRNA expression was identified in 19 PDAC, 6 AMP and 25 paired, histologically normal pancreatic tissues using the GeneChip 4.0 miRNA arrays. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated pathways. Target gene expression was validated in 178 pancreatic cancer and 4 pancreatic normal tissues from The Cancer Genome Atlas (TCGA). 20 miRNAs were significantly deregulated (FC≥2 and p<0.05) (15 down- and 5 up-regulated) in PDAC. miR-216 family (miR-216a-3p, miR-216a-5p, miR-216b-3p and miR-216b-5p) was consistently down-regulated in PDAC. miRNA-modulated pathways are associated with innate and adaptive immune system responses in PDAC. AMP cancers showed 8 down- and 1 up-regulated miRNAs (FDR p<0.05). Most enriched pathways (p<0.01) were RAS and Nerve Growth Factor signaling. PDAC and AMP display different global miRNA expression profiles and miRNA regulated networks/tumorigenesis pathways. The immune response was enriched in PDAC, suggesting the existence of immune checkpoint pathways more relevant to PDAC than AMP.
Pancreatic cancer is the fourth most frequent cause of cancer death, worldwide [1,2]. The majority of pancreatic cancers (~96%) comprise exocrine ductal adenocarcinomas (PDAC) . Other pancreatic tumors include periampullary carcinomas; of these, ~12% are adenocarcinomas of Vater ampulla (AMP). AMP patients have a better prognosis (5-year survival of >45%) [3,4] compared to PDAC, mainly due to early disease detection.
Recently studies have provided evidence of an immune-related component of PDAC tumors. Here, we provide novel data on the potential role of miRNAs in the regulation of immune-related gene networks including pathways of adaptive and innate immune response involved in PDAC. We validated an inverse correlation in miRNA and target gene expression in these pathways using the pancreatic cancer TCGA dataset; these data suggest a potential role of miRNAs in the regulation of immune-related genes in PDAC tumorigenesis.
Our data provide a comprehensive picture of distinct pathways modulated by miRNAs in different subtypes of pancreatic tumors. Adaptive and innate immune response pathways modulated by miRNAs may be useful as potential therapeutic strategies specifically benefiting patients with PDAC.