Abstract
BackgroundNo reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC). MicroRNAs (miR) are epigenetic gene regulators with tumorsuppressive or oncogenic roles in various carcinomas. This study assesses chemoresistant PDAC for its specific miR expression pattern.MethodsGemcitabine-resistant variants of two mutant p53 human PDAC cell lines were established. Survival rates were analyzed by cytotoxicity and apoptosis assays. Expression of 1733 human miRs was investigated by microarray and validated by qRT-PCR. After in-silico analysis of specific target genes and proteins of dysregulated miRs, expression of MRP-1, Bcl-2, mutant p53, and CDK1 was quantified by Western blot.ResultsBoth established PDAC clones showed a significant resistance to gemcitabine (p<0.02) with low apoptosis rate (p<0.001) vs. parental cells. MiR-screening revealed significantly upregulated (miR-21, miR-99a, miR-100, miR-125b, miR-138, miR-210) and downregulated miRs (miR-31*, miR-330, miR-378) in chemoresistant PDAC (p<0.05). Bioinformatic analysis suggested involvement of these miRs in pathways controlling cell death and cycle. MRP-1 (p<0.02) and Bcl-2 (p<0.003) were significantly overexpressed in both resistant cell clones and mutant p53 (p = 0.023) in one clone.ConclusionConsistent miR expression profiles, in part regulated by mutant TP53 gene, were identified in gemcitabine-resistant PDAC with significant MRP-1 and Bcl-2 overexpression. These results provide a basis for further elucidation of chemoresistance mechanisms and therapeutic approaches to overcome chemoresistance in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal entity among human visceral cancers with increasing incidence and mortality in the United States and Europe
No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC)
Both established PDAC clones showed a significant resistance to gemcitabine (p
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal entity among human visceral cancers with increasing incidence and mortality in the United States and Europe. Despite advances in clinical management and multimodal therapeutic regimens, 6-month progressionfree survival remains below 15% [1]. The advances in cancer research that have led to improved prognosis in many hematological and solid cancers could not be translated into clinical benefits for PDAC patients so far. The poor prognosis of PDAC is mainly attributed to rapid disease progression, late diagnosis at advanced unresectable stages, and poor response to the current single first-line chemotherapeutic agent gemcitabine with objectified tumor remission in only 5–11% of patients [2]. Chemotherapy remains a central asset in PDAC treatment and deciphering the mechanisms underlying the disease’s high level of chemoresistance is critical. No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC). This study assesses chemoresistant PDAC for its specific miR expression pattern
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