Protein expression of ABCC2 and SLC22A3 associates with prognosis of pancreatic adenocarcinoma

Lenka Cervenkova,Ondrej Vycital,Ondrej Daum,Pavel Soucek,Vaclav Liska,Beatrice Mohelnikova-Duchonova,Richard Palek,Jachym Rosendorf,Jan Bruha

doi:10.1038/s41598-019-56059-w

Abstract

ATP-binding cassette (ABC) and solute carrier (SLC) transporters translocate diverse substances across cellular membranes and their deregulation may cause drug resistance of cancers. This study investigated significance of protein expression and cellular localization of the previously suggested putative prognostic markers ABCC2 and SLC22A3 in pancreatic cancer patients. Protein localization and brush border staining intensity of ABCC2 and SLC22A3 was assessed in tumor tissue blocks of 65 pancreatic cancer patients and associated with clinical data and survival of patients with regard to therapy. Negative SLC22A3 brush border staining in pancreatic tumors significantly increased the risk of both disease progression and patient´s death in univariate analyses. Multivariate analyses confirmed the association of SLC22A3 expression with progression-free survival of patients. A subgroup analysis of patients treated with regimens based on nucleoside analogs suggested that patients with negative brush border staining or apical localization of SLC22A3 in tumor cells have worse overall survival. The combination of positive ABCC2 and negative SLC22A3 brush border staining predicted worst overall survival and patients with positive brush border staining of both proteins had best overall and progression-free survival. The present study shows for the first time that the protein presence and to some extent also localization of SLC22A3 significantly associate with prognosis of pancreatic cancer in both unstratified and chemotherapy-treated patients. The combination of ABCC2 and SLC22A3 brush border staining also needs further attention in this regard.

Highlights

Pancreatic ductal adenocarcinoma (PDAC, OMIM: 260350) incidence ranks 12th among cancer diagnoses worldwide, but its mortality is predicted to become the second leading cause of cancer death in the USA within the decade[1,2]
Positive IHC brush border staining was observed in 45% and 29% of patients for ABCC2 and SLC22A3, respectively
Our data clearly show that presence of SLC22A3 protein associates with prognosis of PDAC patients

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC, OMIM: 260350) incidence ranks 12th among cancer diagnoses worldwide, but its mortality is predicted to become the second leading cause of cancer death in the USA within the decade[1,2]. We have found dysregulation of transcript levels of several ABC and SLC transporters in tumor tissues of PDAC patients compared to paired adjacent non-tumorous control tissues. Main goal of the present study was to validate on the protein level the previously suggested putative prognostic role of this combination in independent series of PDAC patients. Characteristics Age (median ± S.D.) Gender Female Male UICC stage Stage IA Stage IB Stage IIA Stage IIB Stage III Unknown Tumor size (pT) pT1 pT2 pT3 pT4 pTx Lymph node metastasis (pN) pN0 pN1-2 pNx Distant metastasis (cM) cM0 cMx Grade G1 G2 G3 Gx Resection margins (R) R0 R1 Chemotherapy None Adjuvant Unknown www.nature.com/scientificreports biomarkers in a larger cohort of PDAC patients and compared it with the patientsurvival in order to substantiate further mechanistic studies behind this association

Methods

Results

Conclusion