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Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment.

ABSTRACT: Background:Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). Here we aimed to evaluate the (phospho)proteome of gemcitabine-sensitive and gemcitabine-resistant PDAC cells to identify novel therapeutic targets and predictive biomarkers. Methods:The oncogenic capabilities of gemcitabine-sensitive and resistant PDAC cells were evaluated in vitro and in vivo. Cultured cells were analyzed by label-free proteomics. Differential proteins and phosphopeptides were evaluated by gene ontology and for their predictive or prognostic biomarker potential with immunohistochemistry of tissue microarrays. Results:Gemcitabine-resistant cells had increased potential to induce xenograft tumours (p value < 0.001). Differential analyses showed that proteins associated with gemcitabine resistance are correlated with microtubule regulation. Indeed, gemcitabine-resistant cells displayed an increased sensitivity for paclitaxel in vitro (p < 0.001) and nab-paclitaxel had a strong anti-tumour efficacy in vivo. Microtubule-associated protein 2 (MAP2) was found to be highly upregulated (p = 0.002, fold change = 10) and phosphorylated in these resistant cells. Expression of MAP2 was correlated with a poorer overall survival in patients treated with gemcitabine in the palliative (p = 0.037) and adjuvant setting (p = 0.014). Conclusions:These data show an explanation as to why the combination of gemcitabine with nab-paclitaxel is effective in PDAC patients. The identified gemcitabine-resistance marker, MAP2, emerged as a novel prognostic marker in PDAC patients treated with gemcitabine and warrants further clinical investigation.

SUBMITTER: Le Large TYS

PROVIDER: S-EPMC6535709 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment.

Le Large Tessa Ya Sung TYS El Hassouni Btissame B Funel Niccola N Kok Bart B Piersma Sander R SR Pham Thang V TV Olive Kenneth P KP Kazemier Geert G van Laarhoven Hanneke W M HWM Jimenez Connie R CR Bijlsma Maarten F MF Giovannetti Elisa E

Therapeutic advances in medical oncology 20190510

<h4>Background</h4>Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). Here we aimed to evaluate the (phospho)proteome of gemcitabine-sensitive and gemcitabine-resistant PDAC cells to identify novel therapeutic targets and predictive biomarkers.<h4>Methods</h4>The oncogenic capabilities of gemcitabine-sensitive and resistant PDAC cells were evaluated <i>in vitro</i> and <i>in vivo</i>. Cultured cells were analyzed by label-free proteomics. Di ...[more]

PMID: 31205498

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Project description:Background:To identify key microRNAs (miRNAs) and their target mRNAs related to gemcitabine-resistant pancreatic cancer (PC) and investigate the association between gemcitabine-resistant-related miRNAs and mRNAs and immune infiltration. Methods:Expression profiles of miRNAs and mRNAs were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs and mRNAs (referred to as "DEmiRNAs" and "DEmRNAs", respectively) were distinguished between gemcitabine-resistant PC cells and its parental cells. The DEmRNAs targeted by the DEmiRNAs were retrieved using miRDB, microT, and Targetscan. Furthermore, GO and KEGG pathway enrichment analysis and GSEA were performed. The Kaplan-Meier plotter was used to analyze the prognosis of key DEmiRNAs and DEmRNAs on PC patients. The relationship between the key DEmRNAs and tumor-infiltrating immune cells in PC was investigated using CIBERSORT method using the LM22 signature as reference. Key infiltrating immune cells were further analyzed for the associations with prognosis of TCGA PAAD patients. Results:Four DEmiRNAs, including hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p, and hsa-miR-584-5p, were identified to target seven DEmRNAs, including MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6, individually, in gemcitabine-resistant PC cells versus parental cells. Gemcitabine-resistant PC cells were enriched in proteasome-related, immune-related, and memory CD4+ T cell-related pathways, indicating a gemcitabine therapeutic effect on PC cells. All four DEmiRNAs and almost all DEmRNAs had an impact on the prognosis of PC patients. All seven DEmRNAs had remarkable effects on CD4+ memory T cells, which were affected by the gemcitabine therapeutic effect. Effector memory CD4+ T cells rather than central memory CD4+ T cells predicted a good prognosis according to the TCGA PAAD dataset. Conclusions:Gemcitabine resistance can alter the fraction of memory CD4+ T cells via hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p and hsa-miR-584-5p targeted MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6 network in PC.

Dataset Information

Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment.

Publications

Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment.

Similar Datasets

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