KRAS induces lung tumorigenesis through microRNAs modulation
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ABSTRACT:
PROVIDER: PRJNA433453 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We analyzed microRNAs modulated by KRAS wild type or KRAS mutant (G12D).
2018-02-08 | GSE110311 | GEO
Project description:Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.
| S-EPMC5833396 | biostudies-literature
Project description:Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCe, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCe expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCe-deficient, conditionally activatable allele of oncogenic Kras (LSL-Kras G12D ;PKCe -/- mice) we were able to demonstrate the requirement of PKCe for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCe-deficient KRAS-dependent NSCLC cells. Moreover, PKCe-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCe and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCe in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCe for lung cancer therapeutics.
2020-07-31 | GSE149205 | GEO
Project description:REQUIREMENT FOR PKC EPSILON IN KRAS-DRIVEN LUNG TUMORIGENESIS
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Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress
Project description:ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence
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Project description:Regulatory T cell depletion promotes oncogenic Kras driven pancreatic tumorigenesis.
| PRJNA492936 | ENA
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:Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor formation in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.
2022-02-01 | GSE194097 | GEO
Project description:Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. We investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct and GB. We demonstrated that simultaneous activation of the Kras–Akt and Notch pathways in EHBD and GB resulted in the formation of BilINs and biliary cancer in a mouse model. Mechanistically, the Kras/Notch–Myc axis activates mTORC1 through phosphorylation of TSC2 in biliary tumorigenesis.
2023-05-04 | GSE231369 | GEO