Dataset Information

CHUK/IKK-? loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation.

ABSTRACT: Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non-small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-? acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKK? ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKK? loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-? instead acts as a tumor promoter in this same context. IKK? knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKK? loss can result in the up-regulation of activated HIF-1-? protein to enhance NSCLC tumor growth under hypoxic conditions in vivo.

SUBMITTER: Chavdoula E

PROVIDER: S-EPMC6892436 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation.

Chavdoula Evangelia E Habiel David M DM Roupakia Eugenia E Markopoulos Georgios S GS Vasilaki Eleni E Kokkalis Antonis A Polyzos Alexander P AP Boleti Haralabia H Thanos Dimitris D Klinakis Apostolos A Kolettas Evangelos E Marcu Kenneth B KB

Life science alliance 20191202 6

Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non-small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) sole ...[more]

PMID: 31792060

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Project description:BackgroundThe non-canonical NF-?B activating kinase IKK?, encoded by CHUK (conserved-helix-loop-helix-ubiquitous-kinase), has been reported to modulate pro- or anti- inflammatory responses, cellular survival and cellular differentiation. Here, we have investigated the mechanism of action of IKK? as a novel effector of human and murine chondrocyte extracellular matrix (ECM) homeostasis and differentiation towards hypertrophy.Methodology/principal findingsIKK? expression was ablated in primary human osteoarthritic (OA) chondrocytes and in immature murine articular chondrocytes (iMACs) derived from IKK?(f/f):CreERT2 mice by retroviral-mediated stable shRNA transduction and Cre recombinase-dependent Lox P site recombination, respectively. MMP-10 was identified as a major target of IKK? in chondrocytes by mRNA profiling, quantitative RT-PCR analysis, immunohistochemistry and immunoblotting. ECM integrity, as assessed by type II collagen (COL2) deposition and the lack of MMP-dependent COL2 degradation products, was enhanced by IKK? ablation in mice. MMP-13 and total collagenase activities were significantly reduced, while TIMP-3 (tissue inhibitor of metalloproteinase-3) protein levels were enhanced in IKK?-deficient chondrocytes. IKK? deficiency suppressed chondrocyte differentiation, as shown by the quantitative inhibition of.Alizarin red staining and the reduced expression of multiple chondrocyte differentiation effectors, including Runx2, Col10a1 and Vegfa,. Importantly, the differentiation of IKK?-deficient chondrocytes was rescued by a kinase-dead IKK? protein mutant.Conclusions/significanceIKK? acts independent of its kinase activity to help drive chondrocyte differentiation towards a hypertrophic-like state. IKK? positively modulates ECM remodeling via multiple downstream targets (including MMP-10 and TIMP-3 at the mRNA and post-transcriptional levels, respectively) to maintain maximal MMP-13 activity, which is required for ECM remodeling leading to chondrocyte differentiation. Chondrocytes are the unique cell component in articular cartilage, which are quiescent and maintain ECM integrity during tissue homeostasis. In OA, chondrocytes reacquire the capacity to proliferate and differentiate and their activation results in pronounced cartilage degeneration. ????, our findings are also of potential relevance for defining the onset and/or progression of OA disease.

Dataset Information

CHUK/IKK-? loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation.

Publications

CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation.

Similar Datasets

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