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MiRNA profile of radioresistant pancreatic cancer cell lines

ABSTRACT: We established radioresistant cell sublines, named as BxPC3/RR1 and BxPC3/RR2 which were derived from parental human pancreatic cancer cell line BxPC3. The miRNA expression profiles of the radioresistant pancreatic cancer cells were then compared with their parental cells.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE41249 | GEO | 2013/07/01

SECONDARY ACCESSION(S): PRJNA176334

REPOSITORIES: GEO

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Project description:Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic cancer patients. In recent years, technical advances have developed experimental methods that unveiled a high degree of inter- and intratumoral heterogeneity in pancreatic cancer. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Experimental Design: We addressed the effect of ITH on response to gemcitabine treatment using single cell-derived cell lines (SCDCL) from the classical-like cell line BxPC3 and the basal-like cell line Panc-1 which were analyzed by mRNA-seq and mass spectrometry. Results: Individual SCDCLs of the parental tumor cell populations of BxPC3 and Panc-1 showed considerable heterogeneity in response to gemcitabine. Unsupervised principal component analysis (PCA) including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this clustering was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance to gemcitabine. Feature extraction of proteomes again identified less proteins whose expression was associated with the response of individual SCDCLs in Panc-1 compared to BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusions: Our model system of SCDCLs identified gemcitabine-resistant subclones within a parental tumor population and provides evidence for the critical role of ITH for treatment response in pancreatic cancer. Through molecular profiling, we identified specific signaling pathways and protein signatures that might help to explain the differential response to treatment among clones. We exploited these molecular differences for an improved and more targeted therapy of resistant subclones of a heterogeneous tumor.

Project description:The molecular mechanisms underlying exceptional radioresistance in pancreatic cancer remain elusive. In the present study, we established a stable radioresistant pancreatic cancer cell line MIA PaCa-2-R by exposing the parental MIA PaCa-2 cells to fractionated ionizing radiation (IR). Systematic proteomics and bioinformatics comparison of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor- and cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT and MAPK/ERK pathways, were activated in the radioresistant cells, leading to enhanced cell migration, invasion and epithelial-mesenchymal transition (EMT), and inhibition of apoptosis. We focused functional analysis on one of the most upregulated proteins in the radioresistant cells, CD73, which is a cell surface protein that is overexpressed in a variety types of cancer. Ectopic overexpression of CD73 in the parent cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 resensitized the radioresistant cells to IR and IR-induced apoptosis. The effect of CD73 on radioresistance and apoptosis is independent of the enzymatic activity of CD73. Further studies suggest that CD73 confers acquired radioresistance in pancreatic cancer cells at least in part through inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136. Furthermore, we found that knockdown of CD73 in the radioresistant cells alone reverted the gene expression and phenotype of the radioresistant cells from those of mesenchymal-like cells to the ones of epithelial cells, demonstrating that CD73 upregulation is required for maintaining EMT in the radioresistant cells. Our results support the notion that the enhanced growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity, and acquisition of cancer stem-like cell properties contributes to acquired radioresistance in the residual surviving cells after fractionated irradiation, and that CD73 is a novel downstream factor of those enhanced signaling and acts to confers acquired radioresistance and maintains EMT in the radioresistant pancreatic cancer cells.

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MiRNA profile of radioresistant pancreatic cancer cell lines

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