國家衛生研究院 NHRI:Item 3990099045/15904
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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/15904


    Title: Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1alpha activation
    Other Titles: Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1α activation
    Authors: Yang, JX;Chuang, YC;Tseng, JC;Liu, YL;Lai, CY;Lee, AYL;Huang, CYF;Hong, YR;Chuang, TH
    Contributors: Immunology Research Center;National Institute of Cancer Research
    Abstract: Background Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing targeted therapies. In this study, we investigated the pro-tumoral effect of PDZ and LIM domain 2 (PDLIM2) downregulation in lung cancer growth and its association with the accumulation of mitochondrial ROS, oncometabolites and the activation of hypoxia-inducible factor-1 (HIF-1) alpha in the process.Methods Databases and human cancer tissue samples were analyzed to investigate the roles of PDLIM2 and HIF-1 alpha in cancer growth. DNA microarray and gene ontology enrichment analyses were performed to determine the cellular functions of PDLIM2. Seahorse assay, flow cytometric analysis, and confocal microscopic analysis were employed to study mitochondrial functions. Oncometabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). A Lewis lung carcinoma (LLC) mouse model was established to assess the in vivo function of PDLIM2 and HIF-1 alpha.Results The expression of PDLIM2 was downregulated in lung cancer, and this downregulation correlated with poor prognosis in patients. PDLIM2 highly regulated genes associated with mitochondrial functions. Mechanistically, PDLIM2 downregulation resulted in NF-kappa B activation, impaired expression of tricarboxylic acid (TCA) cycle genes particularly the succinate dehydrogenase (SDH) genes, and mitochondrial dysfunction. This disturbance contributed to the accumulation of succinate and other oncometabolites, as well as the buildup of mitochondrial reactive oxygen species (mtROS), leading to the activation of hypoxia-inducible factor 1 alpha (HIF-1 alpha). Furthermore, the expression of HIF-1 alpha was increased in all stages of lung cancer. The expression of PDLIM2 and HIF-1 alpha was reversely correlated in lung cancer patients. In the animal study, the orally administered HIF-1 alpha inhibitor, PX-478, significantly reduces PDLIM2 knockdown-promoted tumor growth.Conclusion These findings shed light on the complex action of PDLIM2 on mitochondria and HIF-1 alpha activities in lung cancer, emphasizing the role of HIF-1 alpha in the tumor-promoting effect of PDLIM2 downregulation. Additionally, they provide new insights into a strategy for precise targeted treatment by suggesting that HIF-1 alpha inhibitors may serve as therapy for lung cancer patients with PDLIM2 downregulation.
    Date: 2024-06-17
    Relation: Journal of Experimental and Clinical Cancer Research. 2024 Jun 17;43:Article number 169.
    Link to: http://dx.doi.org/10.1186/s13046-024-03094-9
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1756-9966&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001248050300001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85196093168
    Appears in Collections:[Tsung-Hsien Chuang] Periodical Articles
    [Alan Yueh-Luen Lee] Periodical Articles

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