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Mechanism Comparison of Gemcitabine and Dasatinib-Resistant Pancreatic Cancer by Integrating mRNA and miRNA Expression Profiles by Zongjing Chen, Liang Zhao, Keqing Shi, Bicheng Chen

Background: Pancreatic cancer is one of the most lethal cancers with limited treatment options. Gemcitabine has been the standard drug for patients with advanced pancreatic cancer. Dasatinib is a competitive inhibitor of Src kinase, which has shown promise in treatment of pancreatic cancer. Several studies have revealed the drug resistant mechanism of gemcitabine or dasatinib in human cancers; however, few reports focused on the different mechanisms of gemcitabine and dasatinib resistance in pancreatic cancer. Here, we integrate mRNA and miRNA expression profiles to achieve it.
Methods: Two mRNA expression profiles were downloaded from GEO database. The differentially expressed genes (DEGs) were identified with |fold change| ≥ 2 and p-value ≤ 0.05. Further function of the DEGs were annotated with GO and KEGG pathway enrichment. Finally, the mRNA-miRNA interaction networks were constructed to explore the molecular mechanism.
Results: Results showed that 116 and 238 DEGs were detected in gemcitabine-resistant cell lines and dasatinib-resistant cell lines respectively. Meanwhile, 4 common DEGs were identified in both resistant cell lines, which can clearly divide all cell lines into different sub-groups. KEGG pathway enrichment analysis displayed that the DEGs of both gemcitabine-resistant cell lines and dasatinib-resistant cell lines can map to drug metabolism-cytochrome P450 and metabolism of xenobiotics by cytochrome P450, while DEGs of gemcitabine-resistant cell lines can also map to several metabolism related pathways and dasatinib-resistant cell lines for several cancer related pathways. GO annotation analysis showed that the DEGs of gemcitabine-resistant cell lines and dasatinib-resistant cell lines can also be categorized into drug metabolism. Additionally, the miRNA-mRNA regulation network of gemcitabine-resistant cell lines revealed 16 DEGs were regulated by 6 miRNAs, indicating that these miRNAs may play a key role in gemcitabine treatment of pancreatic cancer.
Conclusions: The difference of gemcitabine resistance in pancreatic cancer were explored by mechanism comparison via the mRNA and miRNA expression profile. These findings support strategies to target molecules and relevant pathways for improving the efficacy of chemotherapy in pancreatic cancer patients.

DOI: 10.7754/Clin.Lab.2018.171124