Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

MicroRNA profiling by array of gemcitabine sensitive BxPC-3 pancreatic cancer cell lines and their derived resistant subclones, Bx-GEM

ABSTRACT: This experiment describes the differential microRNA expression between parental gemcitabine-sensitive BxPC-3 cells and their resistant subclones, Bx-GEM. To select for the resistant subclones, parental BxPC-3 cells were treated with increasing concentrations of gemcitabine (10, 25, 50, 100 and 200 nM) for more than one year. Cells resistant at each stage of drug dosing were re-cultured in the subsequent dose, and their resistance confirmed via cell viability assays. Subclones resistant to 200 nM gemcitabine, in additon to the parental cells were used for microRNA profiling by array. Total RNA was extracted from the cells using the miRNeasy Mini Kit (Qiagen). Fluorescently-labeled miRNA were prepared according to Agilent protocol miRNA Complete Labeling and Hyb Kit. Labeled miRNA sample were hybridized for at least 20 hr at 55C on Agilent human miRNA Microarray Release 19.0, 8x60k. Gene Expression Microarrays were scanned using the Agilent Scanner G2505C.

ORGANISM(S): Homo sapiens

SUBMITTER: Prince Amponsah

PROVIDER: E-MTAB-4927 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

microRNA-210 overexpression inhibits tumor growth and potentially reverses gemcitabine resistance in pancreatic cancer.

Amponsah Prince Saforo PS Fan Pei P Bauer Nathalie N Zhao Zhefu Z Gladkich Jury J Fellenberg Joerg J Herr Ingrid I

Cancer letters 20161207

Resistance to first-line chemotherapies like gemcitabine contributes to high disease lethality in pancreatic cancer. By microarray and qRT-PCR, we observed significant downregulation of microRNA-210 in gemcitabine-resistant cells. The overexpression of microRNA-210 was toxic to gemcitabine-resistant cells and enhanced gemcitabine sensitivity. MicroRNA-210 overexpression induced caspase-3-mediated apoptosis, and inhibited colony formation. Computationally, ABCC5, a highly expressed gene in our ar ...[more]

PMID: 27940128

Publication: 1/2

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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.

Dataset Information

MicroRNA profiling by array of gemcitabine sensitive BxPC-3 pancreatic cancer cell lines and their derived resistant subclones, Bx-GEM

Publications

microRNA-210 overexpression inhibits tumor growth and potentially reverses gemcitabine resistance in pancreatic cancer.

Similar Datasets

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