Analysis of therapeutic miRNA against KRAS mutant colorectal cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE60370 | GEO | 2015/09/01
SECONDARY ACCESSION(S): PRJNA258123
REPOSITORIES: GEO
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Project description:We compared the profile of miRNAs expressed in HEK293 and MRC5 cells that overexpressed KRASG12V to those expressed in parental cells that harbored wild-type KRAS. The results indicated that a subset of miRNAs was significantly down-regulated in KRASG12V transfected two cells. To address the functional relevance of miRNAs in KRAS mutant cancers, we transfected exogenous KRASG12V into HEK293 and MRC5 cells with wild type KRAS genes, and we comprehensively profiled the dysregulated miRNAs.
2015-09-01 | E-GEOD-60370 | biostudies-arrayexpress
Project description:KRAS mutation is one of the major genetic alterations in colorectal cancer (CRC). Treating patients with KRAS mutant CRC remains one of the biggest challenges in oncology. In this study, we aimed to discover an effective therapeutic microRNA (miRNA) that could target KRAS mutant CRC. For this purpose, we investigated the functional relevance of dysregulated miRNAs in KRAS mutant cancers. We transfected exogenous KRASG12V into human embryonic kidney 293 (HEK293) cells and human lung fibroblasts (MRC5) cells, and performed comprehensive microRNA expression profiling by microarray analysis. The results showed that 6 miRNAs are significantly upregulated in KRAS-transfected HEK293 and MRC5 cells. Among 6 miRNAs, we identified mature miRNA-29b-1-5p as potent growth inhibitor in CRC cell proliferation. However, miRNA-29b-1-5p was found to be a passenger strand with a star form (miRNA-29b-1-5p*), and did not function in CRC cells. Proliferation assay revealed that completely opposite complementary strand to miRNA-29b-1-5p possessed a potent anti-tumor effect. We named this novel anti-tumor siRNA sequence “MIRTX”. MIRTX induced apoptosis and significantly inhibited cell proliferation in KRAS mutant CRC in vitro. In addition, MIRTX suppressed NF-κB signaling pathway, which is downstream effector of KRAS in CRC. Furthermore, MIRTX directly targeted 3'-UTR of PIK3R1 and CXCR2 mRNA, and indirectly suppressed KRAS itself. In vivo xenograft mouse models, systemic administration of MIRTX significantly inhibited the tumor growth with no particular toxicity, using carbonate apatite as a vehicle. These findings indicate that inhibition of NF-κB signaling by siRNA-based therapeutic could be a promising strategy against KRAS mutant CRC.
2018-03-17 | GSE83634 | GEO
Project description:We used doxycycline (dox) treatment to generate a larval model of hepatocellular carcinoma (HCC)22. In this model, we induced the expression of a single EGFP-krasG12V transgene, denoted TO(krasG12V)T/+ in developing livers by treating with doxycycline between 2-7 days post-fertilisation (dpf). This led to the accumulation of a constitutively active, EGFP-tagged, potently oncogenic form of Kras specifically in hepatocytes, causing hepatocyte hyperplasia and a substantial increase in total liver volume. We used RNA sequencing to analyse the gene expression patterns of hepatocytes expressing the krasG12V transgene compared to wildtype (WT) livers expressing no transgene. We detected more than 6000 significantly upregulated genes in dox-treated TO(krasG12V)T/+ livers compared WT livers, and a further 6000+ genes were significantly downregulated. Of the upregulated genes, many were significantly enriched in KEGG pathways associated with highly proliferative cancers, including DNA replication, cell cycle and DNA damage repair. Geneset enrichment analysis identified a positive correlation between the differential gene expression data from the dox-treated TO(krasG12V)T/+ versus WT livers and the differential gene expression data for the HCC (LIHC) and healthy liver subsets available from The Cancer Genome Atlas. We also found a positive correlation between the DEGs from the dox-treated TO(krasG12V)T/+ versus WT livers and a small HCC expression signature based on four patient samples carrying KRAS G12 or KRAS G13 mutations. These observations build on previous reports that dox-treated TO(krasG12V)T/+ zebrafish provide an authentic model of human HCC.
2023-02-03 | GSE220282 | GEO
Project description:Appendiceal adenocarcinoma (AA) is a rare cancer with limited treatment options. KRAS is the most commonly mutated gene in AA and a promising therapeutic target, but its preclinical and translational relevance in AA remains unclear. We evaluated KRASG12D–specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRASmut organoid and PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. MRTX1133 was highly effective for KRASG12D organoids (IC50 = 4.1 nM); both KRASG12D and KRASG12V organoids were sensitive to RMC-6236 (IC50 = 4.4 nM vs. 0.5 nM, respectively). In PDX models of peritoneal carcinomatosis from AA, MRTX1133 reduced tumor growth in the KRASG12D model TM00351, and RMC-6236 reduced tumor growth in KRASG12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Set Enrichment Analysis (GSEA) demonstrated consistent downregulation of E2F targets and RAS/ERK signaling across both models, confirming on-target KRAS inhibition, alongside upregulation of EMT (Epithelial-to-Mesenchymal Transition), suggesting a shared resistance-associated transcriptional program. Interferon-alpha and interferon-gamma signaling were significantly upregulated following pan-KRAS inhibition, implicating TME (Tumor Microenvironment) immunomodulation as a downstream consequence of KRAS inhibition in AA. scRNA-seq analysis of the TME showed a dramatic shift from normal to inflammatory cancer-associated fibroblasts (iCAFs) following KRAS inhibition. Upregulation of interferon alpha and gamma pathways was also observed, suggesting that KRAS inhibition can activate innate immune response in the setting of peritoneal metastases. While effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of the EMT pathway may mediate resistance in KRASmut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support the continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.
2026-06-25 | GSE336609 | GEO
Project description:To elucidate the molecular basis of the HR deficiency induced by KRASG12D inhibition, we conducted RNA sequencing (RNA-seq) on KRASG12D -mutant PDAC cells (AsPC-1, PANC-1, SW1990) treated with MRTX1133 and KRASG12V -mutant CFPAC-1 cell treated with pan-KRAS inhibitor BI-2865. To futher verified the molecular alternation, we also conducted RNA-seq on KRASG12D-mutant Patient-derived xenograft treated with MRTX1133.
2025-12-28 | GSE279749 | GEO
Project description:Description: (Supplemental data for Project PXD035399) “Analysis of context-specific KRAS-effectors (sub)complexes in Caco-2 cells”. Proteome of Caco-2 cells, transfected with KRAS-G12D and stimulated with different conditions.
2023-02-23 | PXD039404 | Pride
Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 metastisized colorectal cancer patients in a phase III trial (CKTO 2005-02; ClinTrials.gov NCT00208546) of the Dutch Colorectal Cancer Group (DCCG), who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab.
2012-01-01 | E-GEOD-32048 | biostudies-arrayexpress
Project description:We used Kras/Hras/Nras-triple knockout MEFs expressing recombinant Nras to test the off-target effect of 2 Kras siRNAs at different transfection concentrations. Gene expression profiles were generated using Affimymetrix Mouse Gene ST 2.0 microarrays. Cells were transfected with Kras siRNAs and gene expression profiles were generated to identify genes up or down regulated by each siRNA at different transfection concentrations.
2014-09-01 | E-GEOD-59823 | biostudies-arrayexpress
Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software
2012-01-01 | GSE32048 | GEO
Project description:The transcriptional repressor Capicua (CIC) is negatively regulated by KRAS/MAPK signaling. To characterize the impact of CIC loss on KrasG12V/Trp53-KO-driven lung adenocarcinomas in mice, the transcriptome of tumors from Kras (+/LSLG12V); Trp53 (lox/lox) [KP] and Kras (+/LSLG12V); Trp53 (lox/lox); Cic (lox/lox) [KPCic] mice are compared.
2025-09-11 | GSE303269 | GEO