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Genome-wide CRISPR screen identifies DCK and CCNL1 as genes that contribute to gemcitabine resistance in pancreatic cancer

ABSTRACT: Gemcitabine Resistance in pancreatic cancer

PROVIDER: PRJEB51345 | ENA |

REPOSITORIES: ENA

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Genome-Wide CRISPR Screening Identifies DCK and CCNL1 as Genes That Contribute to Gemcitabine Resistance in Pancreatic Cancer.

Project description:Pancreatic cancer is one of the most lethal cancers. Due to the difficulty of early diagnosis, most patients are diagnosed with metastasis or advanced-stage cancer, limiting the possibility of surgical treatment. Therefore, chemotherapy is applied to improve patient outcomes, and gemcitabine has been the primary chemotherapy drug for pancreatic cancer for over a decade. However, drug resistance poses a significant challenge to the efficacy of chemotherapy. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) gene-editing system is a powerful tool, and researchers have developed CRISPR/Cas9 library screening as a means to identify the genes associated with specific phenotype changes. We performed genome-wide CRISPR/Cas9 knockout screening in the mouse pancreatic cancer cell line TB32047 with gemcitabine treatment and identified deoxycytidine kinase (DCK) and cyclin L1 (CCNL1) as the top hits. We knocked out DCK and CCNL1 in the TB32047 and PANC1 cell lines and confirmed that the loss of DCK or CCNL1 enhanced gemcitabine resistance in pancreatic cells. Many researchers have addressed the mechanism of DCK-related gemcitabine resistance; however, no study has focused on CCNL1 and gemcitabine resistance. Therefore, we explored the mechanism of CCNL1-related gemcitabine resistance and found that the loss of CCNL1 activates the ERK/AKT/STAT3 survival pathway, causing cell resistance to gemcitabine treatment.

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N6-methyladenosine modification of FZR1 mRNA promotes gemcitabine resistance in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with limited therapeutic options, and gemcitabine insensitivity remains a major challenge. N6-methyladenosine (m6A) is a prevalent nucleotide modification in mRNA that has been linked to various biological processes in human diseases, yet its role in drug sensitivity of cancer remains largely unknown. Herein, by detecting the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified the key role of hyper-m6A modification of the master G0/G1 regulator Fizzy and Cell Division Cycle 20 Related 1 (FZR1) in regulating gemcitabine sensitivity. Targeting m6A modification of FZR1 improves the gemcitabine treatment response of gemcitabine-insensitive PDAC cells in vitro and in vivo. Mechanistically, Gem Nuclear Organelle Associated Protein 5 (GEMIN5) was identified as a novel m6A mediator that specifically binds to m6A-modified FZR1 and recruits the eIF3 translation initiation complex to accelerate FZR1 translation. Upregulation of FZR1 maintains the G0/G1 quiescent state and impairs gemcitabine sensitivity of PDAC cells. Further clinical analysis showed that both high levels of FZR1 m6A modification and FZR1 protein indicated a poor response to gemcitabine. These findings unveil the critical function for m6A modification in regulating gemcitabine sensitivity in PDAC and identify the m6A-FZR1 axis as a potential target to enhance gemcitabine response.

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mRNA Expression profiles of parental Panc cell lines and Gemcitabine resistance Panc1cell lines

Project description:Gemcitabine (GEM) is a key drug for treating PDAC, and it is commonly used for adjuvant chemotherapy. Although the majority of PDAC is sensitive to GEM at first, GEM cannot control PDAC for very long, suggesting that PDAC develops resistance to GEM after prolonged exposure. No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma. This study assesses gemcitabine resistant PDAC for its specific mRNA expression pattern. Gemcitabine resistant variants of Panc1, a human pancreatic adenocarcinoma cell line, were established. mRNA screening was investigated by microarray.

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Transcription profiling of human pancreatic cancer treated with masitinib combined with standard gemcitabine chemotherapy

Project description:Masitinib is a tyrosine kinase inhibitor of c-Kit, PDGFRÎ± and Î², and to some extent Lyn of the Src kinase family. We evaluated the therapeutic potential of masitinib in vitro on human pancreatic tumour cell lines and in vivo in a mouse model of human pancreatic cancer. Experiment Overall Design: Expression patterns of masitinib tyrosine kinase targets including c-Kit, PDGFRÎ± and PDGFRÎ² were determined in four pancreatic tumour cell lines by PCR. Proliferation assays were performed with masitinib alone or in combination with gemcitabine. To determine the in vivo effects of masitinib, Nog-SCID mice were injected subcutaneously with MiaPacaÂ2 cells, randomised 28 days later and received one of the following treatments: vehicle control p.o., masitinib p.o., gemcitabine i.p., or a combination of masitinib plus gemcitabine. Additionally, the transcriptome of MiaPacaÂ2 cells for each of these conditions was determined with Affymetrix arrays.

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