Research Article: The G Protein-Coupled Receptor RAI3 Is an Independent Prognostic Factor for Pancreatic Cancer Survival and Regulates Proliferation via STAT3 Phosphorylation

Date Published: January 23, 2017

Publisher: Public Library of Science

Author(s): Elisabeth Jahny, Hai Yang, Bin Liu, Beatrix Jahnke, Franziska Lademann, Thomas Knösel, Petra Rümmele, Robert Grützmann, Daniela E. Aust, Christian Pilarsky, Axel Denz, Ilse Rooman.

http://doi.org/10.1371/journal.pone.0170390

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest tumors worldwide. Understanding the function of gene expression alterations is a prerequisite for developing new strategies in diagnostic and therapy. GPRC5A (RAI3), coding for a seven transmembrane G protein-coupled receptor is known to be overexpressed in pancreatic cancer and might be an interesting candidate for therapeutic intervention. Expression levels of RAI3 were compared using a tissue microarray of 435 resected patients with pancreatic cancer as well as 209 samples from chronic pancreatitis (CP), intra-ductal papillary mucinous neoplasm (IPMN) and normal pancreatic tissue. To elucidate the function of RAI3 overexpression, siRNA based knock-down was used and transfected cells were analyzed using proliferation and migration assays. Pancreatic cancer patients showed a statistically significant overexpression of RAI3 in comparison to normal and chronic pancreatitis tissue. Especially the loss of apical RAI3 expression represents an independent prognostic parameter for overall survival of patients with pancreatic cancer. Suppression of GPRC5a results in decreased cell growth, proliferation and migration in pancreatic cancer cell lines via a STAT3 modulated pathway, independent from ERK activation.

Partial Text

Pancreatic cancer is one of the most perilous and lethal solid malignancies and the five-year relative survival rate, is one of the lowest for all cancers with 8% [1]. Typical alterations in the molecular signaling include mutations in KRAS in 95% of PDACs and in tumor suppressor’s genes like p16/CDKN2A, p53 or SMAD4 [2]. Besides these, many other changes in different pathways have been described, which are caused by gene mutations as well as epigenetic mechanisms [2, 3].

In PDAC and IPMN the percentage of RAI3 expressing cells is highly elevated (median = 90%) compared to normal (median = 40%) and CP tissue (median = 60%) and PDAC cells show mostly a strong expression. Apical expression was detected in 100% of stained normal and CP tissue as well as in 90% of the stained IPMNs. PDAC-tissue showed an obvious loss of apical expression (median = 30%) (Fig 1A–1F and Fig 2A and 2B) (Kruskal-Wallis-test p<0.001 for all parameters). The results in TMA show clearly, that RAI3/GPRC5a is over-expressed in PDAC in comparison to normal pancreas or CP tissue. Interestingly, in IPMN, a cystic neoplasm that is considered to be a precursor lesion for pancreatic cancer, also high intensity and expression levels of RAI3 were observed. Compared to other tissues the loss of apical staining in PDACs was revealed as an independent parameter for the overall survival of patients with pancreatic carcinoma. A possible background for this is the increasing loss of cell polarity and architecture with the dedifferentiation of the tumors. This could be detected earlier by immunohistochemistry than by conventional methods as seen with other marker [22].   Source: http://doi.org/10.1371/journal.pone.0170390

 

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