PO.MCB09.05 · 分子与细胞生物学
PDLIM2下调通过调控致癌代谢物和HIF-1alpha通路促进肿瘤生长
Downregulation of PDLIM2 promotes tumor growth through regulation of oncometabolites and HIF-1alpha pathway
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症越来越被认为是一种由细胞代谢失调驱动的疾病，阐明这些代谢改变背后的分子机制对于开发有效的靶向治疗至关重要。在本研究中，我们研究了PDLIM2（PDZ和LIM结构域2）下调在肺癌进展中的促肿瘤作用，特别关注其对线粒体代谢和缺氧诱导因子-1alpha（HIF-1alpha）信号的影响。我们的分析显示，PDLIM2表达在肺癌组织中显著下调，且这一降低与患者不良预后相关。转录组分析表明，PDLIM2调控一组与线粒体功能相关的基因网络。机制上，PDLIM2下调损害了三羧酸（TCA）循环基因的表达，尤其是编码琥珀酸脱氢酶（SDH）亚基的基因。这一破坏导致线粒体功能障碍、琥珀酸和其他致癌代谢物的积累。这些代谢紊乱促进了HIF-1alpha的稳定和激活，HIF-1alpha是一种已知在缺氧条件下驱动肿瘤进展的转录因子。进一步研究表明，HIF-1alpha表达在肺癌各个分期中均升高，且其水平在患者样本中与PDLIM2表达呈负相关。为进一步验证这一轴，我们使用口服生物可利用的HIF-1alpha抑制剂PX-478在癌症动物模型中进行了体内研究。PX-478治疗显著减弱了由PDLIM2敲低促进的肿瘤生长，支持HIF-1alpha激活在介导PDLIM2缺失致癌后果中的功能相关性。总之，这些发现突显了肺癌中PDLIM2、线粒体代谢与HIF-1alpha信号之间一种新的调控联系。它们强调了PDLIM2下调的促肿瘤效应，并提示对HIF-1alpha的治疗性抑制可能代表针对PDLIM2缺陷型肿瘤患者的一种有前景的精准策略。
查看英文原文 English abstract
Cancer is increasingly recognized as a disease driven by dysregulated cellular metabolism, and elucidating the molecular mechanisms behind these metabolic alterations is essential for developing effective targeted therapies. In present study, we investigated the pro-tumorigenic role of PDLIM2 (PDZ and LIM domain 2) downregulation in lung cancer progression, with a particular focus on its impact on mitochondrial metabolism and hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. Our analysis revealed that PDLIM2 expression is significantly downregulated in lung cancer tissues, and this reduction correlates with unfavorable patient prognosis. Transcriptomic profiling indicated that PDLIM2 regulates a network of genes associated with mitochondrial function. Mechanistically, PDLIM2 downregulation impaired the expression of tricarboxylic acid (TCA) cycle genes, notably those encoding succinate dehydrogenase (SDH) subunits. This disruption led to mitochondrial dysfunction, accumulation of succinate and other oncometabolites. These metabolic disturbances contributed to the stabilization and activation of HIF-1alpha, a transcription factor known to drive tumor progression under hypoxic conditions. Further studies indicated that HIF-1alpha expression is elevated across all stages of lung cancer, and its levels are inversely correlated with PDLIM2 expression in patient samples. To further validate this axis, we performed an in vivo study with cancer animal model using PX-478, an orally bioavailable HIF-1alpha inhibitor. Treatment with PX-478 significantly attenuated the tumor growth promoted by PDLIM2 knockdown, supporting the functional relevance of HIF-1alpha activation in mediating the oncogenic consequences of PDLIM2 loss. Collectively, these findings highlight a novel regulatory link between PDLIM2, mitochondrial metabolism, and HIF-1alpha signaling in lung cancer. They emphasize the tumor-promoting effects of PDLIM2 downregulation and suggest that therapeutic inhibition of HIF-1alpha may represent a promising precision strategy for patients with PDLIM2-deficient tumors.
利益披露 Disclosure
T. Chuang, None..
J. Yang, None..
Y. Chuang, None..
J. Tseng, None..
Y. Liu, None..
C. Lai, None.