Identification of chemoresistance-related mRNAs based on gemcitabine-resistant pancreatic cancer cell lines.
Jiarong ZhouLinshi ZhangHuilin ZhengWenhao GeYu HuangYingcai YanXiaohu ZhouWei ZhuYang KongYuan DingWei-Lin WangPublished in: Cancer medicine (2019)
Gemcitabine (GEM) alone and GEM-based chemotherapy are the preferred regimens for treating advanced unresectable and metastatic pancreatic cancer (PC). However, these treatments have limited efficacy due to acquired resistance of cancer cells to chemotherapy, the mechanisms of which are not fully understood. In this study, we established two stable multidrug-resistant cell lines, BxPC-3-GR and CFPAC-1-GR, from their corresponding parental cells through exposure to GEM following a stepwise incremental dosing strategy. The GEM IC50 values of BxPC-3-GR and CFPAC-1-GR increased 112-fold and 210-fold, respectively, compared to parental cell lines. In vitro and in vivo experiments confirmed that both GEM-resistant cell subgroups declined in proliferative capacity, but were more resistant to GEM. Unlike CFPAC-1-GR, BxPC-3-GR exhibited enhanced migratory and invasive properties compared with BxPC-3 in vitro. We also compared differentially expressed mRNA profiles between parental and GEM-resistant cells using transcriptome sequencing. RRM1, STIM1, and TRIM21 were significantly upregulated in both GEM-resistant cell lines and confirmed to be associated with the degree of GEM resistance by quantitative reverse-transcription polymerase chain reaction and western blot analysis. These three genes were more highly expressed in PC tissues and potentially regarded as prognostic biomarkers through database mining. Thus, our findings provide chemo-resistant cell models to better understand the underlying mechanisms of chemoresistance, and to explore potential biomarkers for GEM response in PC patients.
Keyphrases
- locally advanced
- single cell
- multidrug resistant
- induced apoptosis
- squamous cell carcinoma
- gene expression
- emergency department
- cell therapy
- photodynamic therapy
- newly diagnosed
- ejection fraction
- stem cells
- dna methylation
- escherichia coli
- rna seq
- prognostic factors
- radiation therapy
- pseudomonas aeruginosa
- endoplasmic reticulum stress
- drug delivery
- klebsiella pneumoniae
- combination therapy
- liver metastases
- electronic health record