IGFBP1 orchestrates metabolic reprogramming to drive clear cell renal cell carcinoma progression through NR1H4-mediated lipid homeostasis disruption.

IF 6 2区 医学 Q1 ONCOLOGY
Yanning Sun, Yuhu Hao, Fan Peng, Hongju Ling, Kai Sun, Jiechuan Qiu, Tianmin Yang, Leizuo Zhao, Qinghua Xia
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引用次数: 0

Abstract

The hallmark lipid accumulation phenotype observed in clear cell renal cell carcinoma (ccRCC) serves as a critical pathophysiological driver of tumor progression. Our investigation revealed that IGFBP1 expression was significantly elevated in ccRCC versus matched normal renal tissues, with increased levels correlating with poorer patient survival outcomes. IGFBP1 knockdown not only suppressed tumor proliferation and invasiveness in vitro but also provoked substantial lipidomic remodeling, as validated through comprehensive lipidomic profiling. Specifically, IGFBP1-deficient cells demonstrated marked reductions in triglycerides (TGs), diacylglycerols (DAGs), free fatty acids (FFA), and cholesterol esters (CEs), thereby establishing IGFBP1 as a key regulator of the metabolic derangements' characteristic of ccRCC pathogenesis. Mechanistic exploration identified NR1H4 as a potential transcriptional regulator operating downstream of IGFBP1-mediated signaling pathways. A thorough interrogation of these pathways established mechanistic links between IGFBP1 activity and endoplasmic reticulum stress, revealing an integrated network that coordinates lipid homeostasis within malignant renal epithelium. These findings substantiated the role of IGFBP1 as a central node in the metabolic reprogramming associated with ccRCC and propose actionable targets for therapeutic intervention through modulation of lipid metabolic pathways.

IGFBP1协调代谢重编程,通过nr1h4介导的脂质稳态破坏驱动透明细胞肾细胞癌的进展。
透明细胞肾细胞癌(ccRCC)中观察到的标志性脂质积累表型是肿瘤进展的关键病理生理驱动因素。我们的研究显示,与匹配的正常肾组织相比,IGFBP1在ccRCC中的表达显著升高,且水平升高与较差的患者生存结果相关。IGFBP1基因敲低不仅在体外抑制肿瘤的增殖和侵袭性,而且引起大量的脂质组重塑,这一点通过全面的脂质组学分析得到了证实。具体来说,IGFBP1缺陷的细胞表现出甘油三酯(tg)、二酰基甘油(dag)、游离脂肪酸(FFA)和胆固醇酯(CEs)的显著减少,从而确立了IGFBP1作为ccRCC发病机制中代谢紊乱特征的关键调节因子。机制探索发现NR1H4是igfbp1介导的信号通路下游的潜在转录调节因子。对这些途径的深入研究建立了IGFBP1活性和内质网应激之间的机制联系,揭示了一个协调恶性肾上皮内脂质稳态的综合网络。这些发现证实了IGFBP1在与ccRCC相关的代谢重编程中作为中心节点的作用,并提出了通过调节脂质代谢途径进行治疗干预的可行靶点。
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来源期刊
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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