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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells
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Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells

机译：瘦素受体（OB-R）的多能因子介导的表达将肥胖与肿瘤发生通过肿瘤引发的干细胞联系起来

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摘要

Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tumor-initiating stem cells (TISCs) through poorly understood mechanisms. We demonstrate that robust and selective expression of the receptor for the adipocyte-derived peptide hormone leptin (OB-R) is a characteristic feature of TISCs and of a broad array of embryonic and induced pluripotent stem cells and is mediated directly by the core pluripotency-associated transcription factors OCT4 and SOX2. TISCs exhibit sensitized responses to leptin, including the phosphorylation and activation of the pluripotency-associated oncogene STAT3 and induction of Oct4 and Sox2, thereby establishing a self-reinforcing signaling module. Exposure of cultured mouse embryonic stem cells to leptin sustains pluripotency in the absence of leukemia inhibitory factor. By implanting TISCs into leptin-deficient ob/ob mice or into comparably overweight Lepr~(ab/db) mice that produce leptin, we provide evidence of a central role for the leptin-TISC-signaling axis in promoting obesity-induced tumor growth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis.
机译：成人组织中多能性相关转录因子网络的失调与罕见的，高度恶性的肿瘤起始干细胞（TISCs）的扩展有关，但机制尚不清楚。我们证明，脂肪细胞源性肽激素瘦素（OB-R）受体的强大且选择性的表达是TISCs和众多胚胎和诱导多能干细胞的特征，并且直接由核心多能性介导-相关的转录因子OCT4和SOX2。 TISC表现出对瘦蛋白的敏感反应，包括多能性相关癌基因STAT3的磷酸化和激活以及Oct4和Sox2的诱导，从而建立了自我增强的信号传导模块。在没有白血病抑制因子的情况下，将培养的小鼠胚胎干细胞暴露于瘦蛋白可维持多能性。通过将TISCs植入瘦素缺陷型ob / ob小鼠或相当超重的产生瘦素的Lepr〜（ab / db）小鼠中，我们提供了瘦素-TISC信号转导轴在促进肥胖诱导的肿瘤生长中的重要作用的证据。对外在的，来自脂肪细胞的提示的不同反应可能促进肿瘤细胞亚群的扩展，并促进肿瘤的发生。

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    Douglas Edmund Feldman; Chialin Chen; Vasu Punj; Hidekazu Tsukamoto; Keigo Machida;

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    Department of Molecular Microbiology and Immunology,University of Southern California Keck School of Medicine, Los Angeles,CA 90033;

    Department of Molecular Microbiology and Immunology,University of Southern California Keck School of Medicine, Los Angeles,CA 90033;

    Bioinformatics Core, Norris Comprehensive Cancer Center at University of Southern California Epigenome Center and Division of Hematology, and University of Southern California Keck School of Medicine, Los Angeles,CA 90033;

    Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles,CA 90033,Southern California Research Center for ALPD and Cirrhosis,Veterans Affairs Medical Center, Los Angeles, CA 90033;

    Department of Molecular Microbiology and Immunology,University of Southern California Keck School of Medicine, Los Angeles,CA 90033,Bioinformatics Core, Norris Comprehensive Cancer Center at University of Southern California Epigenome Center and Division of Hematology, and University of Southern California Keck School of Medicine, Los Angeles,CA 90033;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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