Abstract
The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. We detected GNA15 expression in pre-neoplastic pancreatic lesions and throughout progression. The analysis of biological data sets, primary and xenografted human tumor samples, and clinical follow-up shows that elevated expression is associated with poor prognosis for GNA15, but not any other GNA gene. Demethylation of the 5′ GNA15 promoter region was associated with ectopic expression of Gα15 in pancreatic neoplastic cells, but not in adjacent dysplastic or non-transformed tissue. Down-modulation of Gα15 by shRNA or CRISPR/Cas9 affected oncogenic signaling, and reduced adenocarcimoma cell motility and invasiveness. We conclude that de novo expression of wild-type GNA15 characterizes transformed pancreatic cells. The methylation pattern of GNA15 changes in preneoplastic lesions coincident with the release a transcriptional blockade that allows ectopic expression to persist throughout PDAC progression. Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11.
Highlights
The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells
We found Gα15 was expressed in human pancreatic ductal adenocarcinoma (PDAC) biopsies, even after malignant cells were selectively expanded in nude m ice[10]
We suggest that ectopic expression of wild-type Gα15 is sufficient to divert G protein coupled receptors (GPCRs) signaling towards pancreatic oncogenisis[4,10] because wild-type Gα15 promiscuously and persistently[6] couples most GPCRs and may activate Kras19, PKD110 and other oncogenic drivers in PDAC progression
Summary
The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. Ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11. The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing as the disease remains a major challenge in oncology Risk factors, such as chronic inflammation, stimulate oncogenic transformation over many years prior to presentation of symptoms. Driver mutations in GNAS, the gene encoding Gαs that activates adenylyl cyclase, are associated with cystic lesions termed intraductal papillary mucinous neoplasms (IPMNs), the second most frequent precursor of PDAC3 after pancreatic intraepithelial neoplasia (PanIN). Constitutive Gα activation hyperstimulates persistent downstream signaling, and this may explain why driver mutations in Gα family members are not tolerated in most cellular contexts but are advantageous in only a few well-defined neoplasia
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