Increased CD44 expression in low-dose chemotherapeutic treated colon cancer cells is controlled by ELF3
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE193865 | GEO | 2022/01/21
REPOSITORIES: GEO
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Project description:One of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU), the most commonly used drug in CRC patients. Whilst some mechanisms of resistance are well-known, it is clear from the stasis in therapy success rate, that much is still unknown. Here a proteomics approach is taken towards identification using 5-FU resistant sublines of human CRC cell lines generated in-house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) proteomics strategy, the resistant cell lines, and equivalently passaged 5-FU-sensitive cell lines were compared to parent cell lines grown in Heavy medium using 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis.
2024-06-16 | PXD047672 | Pride
Project description:Colorectal cancer（CRC）is a commonly diagnosed cancer of the digestive system worldwide. Although chemotherapeutic agents and targeted therapeutic drugs are currently available for CRC treatment, drug resistance is a problem that cannot be ignored and needs to be solved. 5-Fluorouracil (5-Fu) is a first-line chemotherapeutic agent for colorectal cancer, to explore the role of circular RNA (circRNA) in 5-Fu resistance, we performed the circRNA expression profile in two CRC cell lines and their homologous 5-Fu resistant cells by high-throughput sequencing. We validated the differentially expressed circRNAs in other two paired CRC cells, confirmed that circ_0002813 and circ_0000236 could have a potential ceRNA mechanism and be involved in the formation of 5-Fu resistance. And we combined the sequencing results of mRNA to construct the regulatory network of circRNA-miRNA-mRNA. Our study revealed that circ_0002813 and circ_0000236 may as the biomarkers to predict the occurrence of 5-Fu resistance in CRC.
2024-08-05 | GSE181537 | GEO
Project description:The radio-chemotherapy with 5-fluorouracil (5-FU) is the standard of care treatment for patients with locally advanced rectal cancer (LARC) but it is only effective for a third of them. The proteomic and transcriptomic response of three colorectal cancer (CRC) cell lines to 5-FU and radiation was assessed and correlated with their genetic background. The induction of a 5-FU-resistance in those cell lines negatively affects the levels of transcripts corresponding to Krüppel-associated box (KRAB)-containing zinc finger proteins (ZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter are down-regulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights possible new mechanisms involved in resistance to treatment and therefore potential new therapeutic targets to overcome this resistance.
2022-05-19 | PXD020000 | Pride
Project description:Claret2009 - Predicting phase III overall survival in colorectal cancer
This model is described in the article:
Model-based prediction of
phase III overall survival in colorectal cancer on the basis of
phase II tumor dynamics.
Claret L, Girard P, Hoff PM, Van
Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R.
J. Clin. Oncol. 2009 Sep; 27(25):
4103-4108
Abstract:
PURPOSE: We developed a drug-disease simulation model to
predict antitumor response and overall survival in phase III
studies from longitudinal tumor size data in phase II trials.
METHODS: We developed a longitudinal exposure-response
tumor-growth inhibition (TGI) model of drug effect (and
resistance) using phase II data of capecitabine (n = 34) and
historical phase III data of fluorouracil (FU; n = 252) in
colorectal cancer (CRC); and we developed a parametric survival
model that related change in tumor size and patient
characteristics to survival time using historical phase III
data (n = 245). The models were validated in simulation of
antitumor response and survival in an independent phase III
study (n = 1,000 replicates) of capecitabine versus FU in CRC.
RESULTS: The TGI model provided a good fit of longitudinal
tumor size data. A lognormal distribution best described the
survival time, and baseline tumor size and change in tumor size
from baseline at week 7 were predictors (P < .00001).
Predicted change of tumor size and survival time distributions
in the phase III study for both capecitabine and FU were
consistent with observed values, for example, 431 days (90%
prediction interval, 362 to 514 days) versus 401 days observed
for survival in the capecitabine arm. A modest survival
improvement of 39 days (90% prediction interval, -21 to 110
days) versus 35 days observed was predicted for capecitabine.
CONCLUSION: The modeling framework successfully predicted
survival in a phase III trial on the basis of capecitabine
phase II data in CRC. It is a useful tool to support
end-of-phase II decisions and design of phase III studies.
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2017-08-31 | MODEL1708310001 | BioModels
Project description:Purpose: Preoperative 5-fluorouracil (5-FU) based radiochemotherapy (RCT) represents the standard treatment for locally advanced rectal cancer. Both, tumor response and progression vary considerably. MicroRNAs represent master regulators of gene expression, and may therefore contribute to this heterogeneity. Results: Thirty-six miRNAs were identified to significantly correlate with sensitivity of CRC cell lines to RCT (q < 0.05). This list included miR320a as most significantly correlated as well as other miRNAs involved in the MAPK-, TGF- and Wnt-pathway. Importantly, transfection of selected miRNAs (let7g, miR-132, miR-224, miR-320a and miR-429) each induced a shift of sensitivity (p<0.00001). Moreover, high expression of miR-224 was associated with a poor prognosis in rectal cancer patients (p=0.043). Experimental design: Genome-wide microRNA (miRNA) profiling was performed from 12 colorectal cancer (CRC) cell lines. To establish an in vitro signature of radiochemosensitivity, these profiles were correlated to the individual sensitivities of each cell line to 5-FU and radiation. The functional relevance of selected miRNAs was validated by transfecting miRNA-mimics into SW480 cells, followed by treatment with 5-FU and radiation. 12 Samples with 3 replicates each.
2013-09-01 | E-GEOD-40976 | biostudies-arrayexpress
Project description:5-fluorouracil (5‑FU) based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. METTL14 is a core subunit of the m6A methyltransferase complex and has been reported to regulate the drug resistance of cancers. Here, we demonstrated that METTL14 is significantly downregulated in 5-FU-resistant CRC and METTL14 overexpression inhibits the proliferation and 5-FU resistance of CRC cells in vitro and in vivo. In addition, we found that MIB1 catalyzes the K63-linked ubiquitination of METTL14 and induces its degradation through the autolysosome pathway, while AURKA-mediated phosphorylation enhances METTL14 stability by inhibiting its ubiquitination. Moreover, we first discovered that METTL14 functions in 5-FU-resistant CRC cells by directly participating in the translation initiation of non-m6A-modified mRNAs independently of METTL3, rather than cooperating with METTL3 to methylate adenosine residues of targets. Further analysis indicated that METTL14 regulates the cell cycle process in 5-FU-resistant CRC cells. Collectively, our study not only identified METTL14 as a potential therapeutic target for 5-FU resistance in CRC but also revealed a novel translation-facilitating role of METTL14.
2023-12-01 | GSE219172 | GEO
Project description:5-fluorouracil (5‑FU) based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. METTL14 is a core subunit of the m6A methyltransferase complex and has been reported to regulate the drug resistance of cancers. Here, we demonstrated that METTL14 is significantly downregulated in 5-FU-resistant CRC and METTL14 overexpression inhibits the proliferation and 5-FU resistance of CRC cells in vitro and in vivo. In addition, we found that MIB1 catalyzes the K63-linked ubiquitination of METTL14 and induces its degradation through the autolysosome pathway, while AURKA-mediated phosphorylation enhances METTL14 stability by inhibiting its ubiquitination. Moreover, we first discovered that METTL14 functions in 5-FU-resistant CRC cells by directly participating in the translation initiation of non-m6A-modified mRNAs independently of METTL3, rather than cooperating with METTL3 to methylate adenosine residues of targets. Further analysis indicated that METTL14 regulates the cell cycle process in 5-FU-resistant CRC cells. Collectively, our study not only identified METTL14 as a potential therapeutic target for 5-FU resistance in CRC but also revealed a novel translation-facilitating role of METTL14.
2023-12-01 | GSE219171 | GEO
Project description:The radio-chemotherapy with 5-fluorouracil (5-FU) is the standard of care treatment for patients with locally advanced rectal cancer (LARC) but it is only effective for a third of them. The proteomic and transcriptomic response of three colorectal cancer (CRC) cell lines to 5-FU and radiation was assessed and correlated with their genetic background. The induction of a 5-FU-resistance in those cell lines negatively affects the levels of transcripts corresponding to Krüppel-associated box (KRAB)-containing zinc finger proteins (ZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter are down-regulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights possible new mechanisms involved in resistance to treatment and therefore potential new therapeutic targets to overcome this resistance.
2022-04-13 | GSE153412 | GEO
Project description:Background: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard protocol for treating patients with locally advanced non-metastatic colorectal cancer (CRC) is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU), but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. Methods: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic CRC patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-two patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. Results: We have highlighted 384 differentially expressed proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially expressed proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Conclusions: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic CRC. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.
2018-06-25 | PXD008440 | Pride
Project description:Colorectal cancer (CRC) is one of the most frequently diagnosed and lethal malignancy. Several key factors including poor dietary habits, smoking, alcohol consumption, genetic predisposition, obesity, diabetes mellitus, and sedentary lifestyle – all result in a significantly increased risk for developing CRC. Current treatment modalities for patients with CRC include surgery, which is often followed with adjuvant chemotherapy, especially in patients with a stage II and III disease. Most patients with advanced CRC are generally treated with the chemotherapeutic drug, 5-fluorouracil (5-FU) – either given alone or in combination with oxaliplatin and other molecularly-targeted drugs. While such treatment regimens are effective at improving disease outcomes, their clinical usefulness is often hampered due to the considerable toxicity associated with these treatments, which often causes severe nausea, vomiting, weight loss, and risk of infectious complications due to immunosuppression. Furthermore, their therapeutic efficacy is limited due to the emergence of chemotherapeutic drug resistance. In this study we performed genomewide transcriptomic analysis of parental and 5-FU resistant cells to identify differentially expressed genes and its associated pathways in promoting chemoresistance in CRC.
2022-02-19 | GSE196900 | GEO