Pancreatic cancer is unresectable in over 80 % of patients owing to difficulty in early diagnosis.
Chemotherapy is the most frequently adopted
therapy for advanced
pancreatic cancer. The development of drug resistance to
gemcitabine (GEM), which is always used in standard
chemotherapy, often results in therapeutic failure. However, the molecular mechanisms underlying the
gemcitabine resistance remain unclear. Therefore, we sought to explore the
microRNA-
mRNA network that is associated with the development of
gemcitabine resistance and to identify molecular targets for overcoming the
gemcitabine resistance. By exposing SW1990
pancreatic cancer cells to long-term
gemcitabine with increasing concentrations, we established a
gemcitabine-resistant cell line (SW1990/GEM) with a high IC50 (the concentration needed for 50 % growth inhibition, 847.23 μM). The
mRNA and
microRNA expression profiles of SW1990 cells and SW1990/GEM cells were determined using
RNA-seq analysis. By comparing the results in control SW1990 cells, 507 upregulated genes and 550 downregulated genes in SW1990/GEM cells were identified as differentially expressed genes correlated with
gemcitabine sensitivity. Gene ontology (GO) analysis showed that the differentially expressed genes were related to diverse biological processes. The upregulated genes were mainly associated with drug response and apoptosis, and the downregulated genes were correlated with cell cycle progression and RNA splicing. Concurrently, the differentially expressed
microRNAs, which are the important player in drug resistance development, were also examined in SW1990/GEM cells, and 56 differential
microRNAs were identified. Additionally, the expression profiles of selected genes and
microRNAs were confirmed by using Q-PCR assays. Furthermore, combining the differentially expressed
microRNAs and mRNAs as well as the predicted targets for these
microRNAs, a core
microRNA-
mRNA regulatory network was constructed, which included hub
microRNAs, such as hsa-miR-643,
hsa-miR-4644, hsa-miR-4650-5p, hsa-miR-4455, hsa-miR-1261, and hsa-miR-3676. The predicted targets of these hub
microRNAs in the
microRNA-
mRNA network were also observed in the identified differential genes. As a result, a differential gene and
microRNA expression pattern was constructed in
gemcitabine-resistant
pancreatic cancer cells. Therefore, these data may be useful for the detection and treatment of drug resistance in
pancreatic cancer patients, and the
microRNA-
mRNA network-based analysis is expected to be more effective and provides deep insights into the molecular mechanism of drug resistance.