Translational study reveals a two-faced role of RBM3 in pancreatic cancer and suggests its potential value as a biomarker for improved patient stratification.

Emelie Karnevi,Sven-Erik Olofsson,Karin Jirström,Margareta Heby,Mathias Uhlén,Adil Mardinoglu,Liv Ben Dror,William Gallagher,Jacob Elebro,Jakob Eberhard,Björn Nodin

doi:10.18632/oncotarget.23486

Abstract

Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumors with dismal prognosis, partially due to lack of reliable targetable and predictive biomarkers. RNA-binding motif protein 3 (RBM3) has previously been shown to be an independent prognostic and predictive biomarker in several types of cancer. Herein, we examined the prognostic value of RBM3 in periampullary adenocarcinoma, as well as the effects following RBM3 suppression in pancreatic cancer cells in vitro. RBM3 mRNA levels were examined in 176 pancreatic cancer patients from The Cancer Genome Atlas. Immunohistochemical expression of RBM3 was analyzed in tissue microarrays with primary tumors and paired lymph node metastases from 175 consecutive patients with resected periampullary adenocarcinoma. Pancreatic cancer cells were transfected with anti-RBM3 siRNA in vitro and the influence on cell viability following chemotherapy, transwell migration and invasion was assessed. The results demonstrated that high mRNA-levels of RBM3 were significantly associated with a reduced overall survival (p = 0.026). RBM3 protein expression was significantly higher in lymph node metastases than in primary tumors (p = 0.005). High RBM3 protein expression was an independent predictive factor for the effect of adjuvant chemotherapy and an independent negative prognostic factor in untreated patients (p for interaction = 0.003). After siRNA suppression of RBM3 in vitro, pancreatic cancer cells displayed reduced migration and invasion compared to control, as well as a significantly increased resistance to chemotherapy. In conclusion, the strong indication of a positive response predictive effect of RBM3 expression in pancreatic cancer may be highly relevant in the clinical setting and merits further validation.

Highlights

Periampullary adenocarcinomas can be found in the head of the pancreas in the region of the ampulla of Vater and comprise ampullary, pancreatic, bile duct and perivaterian duodenal cancer - a group of heterogeneous tumors all having a rather dismal prognosis [1, 2]
RNA-binding motif protein 3 (RBM3) expression could be assessed in 171/175 (97.7%) of primary tumors and in 83/105 (79.0%) of sampled lymph node metastases
In line with previous studies, RBM3 was mainly differentially expressed in the nucleus [7,8,9,10,11,12,13], and no significant associations were found between cytoplasmic RBM3 expression and survival or any clinicopathological parameters and the results hereafter will only refer to the nuclear RBM3 expression

Summary

Introduction

Periampullary adenocarcinomas can be found in the head of the pancreas in the region of the ampulla of Vater and comprise ampullary, pancreatic, bile duct and perivaterian duodenal cancer - a group of heterogeneous tumors all having a rather dismal prognosis [1, 2]. Advanced pancreatic and periampullary cancer is very complex to treat; whenever surgical resection is possible, adjuvant chemotherapy often follows and most commonly includes gemcitabine or 5-FU, a www.impactjournals.com/oncotarget management shown to improve survival [1, 4]. Since only 15–20% of patients are eligible for surgery, the 5-year overall survival for all patients with pancreatic adenocarcinoma is less than 5%, contributing to almost identical incidence and death rates. For periampullary cancer patients, excluding pancreatic cancer, the survival is somewhat better with a 5-year overall survival of approximately 20% [5]. There is an immense need for better molecular tools to assist in an improved prognostic and treatment predictive stratification of patients with these types of cancers

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