MicroRNA-100 and microRNA-21 as markers of survival and chemotherapy response in pancreatic ductal adenocarcinoma UICC stage II
Dhayat et al. Clinical Epigenetics
MicroRNA-100 and microRNA-21 as markers of survival and chemotherapy response in pancreatic ductal adenocarcinoma UICC stage II
Sameer Abdallah Dhayat 0
Baha Abdeen 0
Gabriele Köhler 2
Norbert Senninger 0
Jörg Haier 1
Wolf Arif Mardin 0
0 Department of General and Visceral Surgery, University Hospital Muenster , Albert-Schweitzer-Campus 1 (W1), 48149 Muenster , Germany
1 Comprehensive Cancer Center Muenster, University Hospital Muenster , Albert-Schweitzer-Campus 1 (W1), 48149 Muenster , Germany
2 Department of Pathology, University Hospital Muenster , Albert-Schweitzer-Campus 1 (D17), 48149 Muenster , Germany
Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly chemoresistant tumor entity for which no reliable molecular targets exist to predict or influence the success of chemotherapy. Recently, we identified a panel of microRNAs associated with induced gemcitabine chemoresistance in human PDAC cell lines. This clinical study evaluates these microRNAs and associated molecular markers as prognostic markers of outcome in 98 PDAC patients Union Internationale Contre le Cancer (UICC) stage II undergoing curative surgery with adjuvant gemcitabine chemotherapy. The primary end points of this study are recurrence-free survival and overall survival. Results: Poor response to chemotherapy was significantly correlated to overexpression of microRNA-21 (p = 0.029), microRNA-99a (p = 0.037), microRNA-100 (p = 0.028), and microRNA-210 (p = 0.021) in tissue samples of PDAC patients UICC stage II. Upregulation of these microRNAs was associated with a significantly shorter overall survival and recurrence-free survival (p < 0.05). Overexpression of phosphatase and tensin homolog (PTEN) (p = 0.039) and low expression of multidrug resistance (MDR)-1 (p = 0.043) and breast cancer resistance protein (BCRP)-1 (p = 0.038) were significantly correlated to improved response to adjuvant chemotherapy. Adjuvant gemcitabine treatment (p < 0.0001) and low tumor grading (p = 0.047) were correlated to better outcome. MicroRNA-100, microRNA-21, and its targets PTEN and MDR-1 were independent factors of survival in multivariate analysis. Conclusions: Multivariate survival analyses identified microRNA-21 and microRNA-100 as unfavorable prognostic factors in resected and adjuvant treated PDAC UICC stage II patients.
Pancreatic ductal adenocarcinoma; Chemoresistance; microRNA
Background
Pancreatic ductal adenocarcinoma (PDAC) remains one
of the most deadly cancers in western countries with a
median survival below 6 months and a dismal 5-year
overall survival rate of less than 5 % [
1
]. Despite
developments in novel diagnostic and surgical techniques
over the past decades, only morbidity and postoperative
mortality were improved, without significant impact on
survival. Lack of early symptoms combined with rapid
disease progression result in low resectability rates of
about 15 % of PDAC patients with 5-year survival rates
below 20 % [
2
].
Adjuvant first-line chemotherapy and palliative
treatment by gemcitabine have slightly improved the clinical
outcome. However, nearly half of the treated patients do
not benefit from gemcitabine-based therapies [
3, 4
].
Chemotherapy response markers are needed to identify
PDAC patients who may benefit from adjuvant
gemcitabine chemotherapy.
PDAC chemoresistance is acquired through multiple
molecular pathways and genetic alterations affecting cell
cycle, apoptosis, and intracellular drug accumulation.
Especially, members of the ATP binding cassette
(ABC) superfamily including multidrug resistance
(MDR)-1 P-glycoprotein, multidrug resistance protein
(MRP)-1, and breast cancer resistance protein (BCRP)-1
have been shown to mediate resistance against several
anticancer drugs by enhanced drug efflux across cellular
plasma membranes [
5
]. Deoxycytidine kinase (DCK), a
key activator of gemcitabine, and its regulator Hu antigen
R (HuR) have been identified as powerful independent
prognostic factors for PDAC patients undergoing adjuvant
gemcitabine therapy [
6–8
]. Further, mutations and
epigenetic downregulation of phosphatase and tensin homolog
(PTEN), a tumor suppressor and the most important
negative regulator of Akt/PI3K signaling, are regarded as
crucial for PDAC development and chemoresistance [
9
].
Although a number of molecular players have been
connected to chemoresistance, their clinical impact
remains controversial [
10
].
We previously identified a panel of microRNAs
associated with induced gemcitabine chemoresistance in
human PDAC cell lines: Two PDAC cell lines were treated
by repeated pulsatile gemcitabine treatment to induce
acquired chemoresistance. Global microRNA profiling
identified a panel of 16 significantly and concordantly
dysregulated microRNAs in both chemoresistant PDAC
cell clones [
11
].
In this clinical study, our aim was to validate these
microRNA candidates as prognostic markers of
chemotherapy response to (...truncated)