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.

Project description:BackgroundPhosphatidylcholine (PC) is a major lipid of the gastrointestinal mucus layer. We recently showed that mucus from patients suffering from ulcerative colitis has low levels of PC. Clinical studies reveal that the therapeutic addition of PC to the colonic mucus using slow release preparations is beneficial. The positive role of PC in this disease is still unclear; however, we have recently shown that PC has an intrinsic anti-inflammatory property. It could be demonstrated that the exogenous application of PC inhibits membrane-dependent actin assembly and TNF-alpha-induced nuclear NF-kappaB activation. We investigate here in more detail the hypothesis that the exogenous application of PC has anti-inflammatory properties.MethodsPC species with different fatty acid side chains were applied to differentiated and non-differentiated Caco-2 cells treated with TNF-alpha to induce a pro-inflammatory response. We analysed TNF-alpha-induced NF-kappaB-activation via the transient expression of a NF-kappaB-luciferase reporter system. Pro-inflammatory gene transcription was detected with the help of a quantitative real time (RT)-PCR analysis. We assessed the binding of TNF-alpha to its receptor by FACS and analysed lipid rafts by isolating detergent resistant membranes (DRMs).ResultsThe exogenous addition of all PC species tested significantly inhibited TNF-alpha-induced pro-inflammatory signalling. The expression levels of IL-8, ICAM-1, IP-10, MCP-1, TNF-alpha and MMP-1 were significantly reduced after PC pre-treatment for at least two hours. The effect was comparable to the inhibition of NF-kB by the NF-kB inhibitor SN 50 and was not due to a reduced binding of TNF-alpha to its receptor or a decreased surface expression of TNF-alpha receptors. PC was also effective when applied to the apical side of polarised Caco-2 cultures if cells were stimulated from the basolateral side. PC treatment changed the compartmentation of the TNF-alpha-receptors 1 and 2 to DRMs.ConclusionPC induces a prolonged inhibition of TNF-alpha-induced pro-inflammatory signalling. This inhibition may be caused by a shift of the TNF-alpha receptors at the surface to lipid rafts. Our results may offer a potential molecular explanation for the positive role of PC seen in clinical studies for the treatment of ulcerative colitis.

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.

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