Prohibitin attenuates colitis-associated tumorigenesis in mice by modulating p53 and STAT3 apoptotic responses.
Prohibitin attenuates colitis-associated tumorigenesis in mice by modulating p53 and STAT3 apoptotic responses.
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DOI：
10.1158/0008-5472.can-12-0603
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发表时间：
2012-11-15
期刊：
影响因子：
11.2
通讯作者：
Theiss AL
中科院分区：
文献类型：
--
作者：
Kathiria AS;Neumann WL;Rhees J;Hotchkiss E;Cheng Y;Genta RM;Meltzer SJ;Souza RF;Theiss AL
虽然炎症性肠病与结直肠癌的高风险相关，但这种相关性的确切致病机制尚未完全了解。抑制素1（PHB），一种参与增殖，凋亡和转录调节的蛋白质，在肠道炎症中减少。在这项研究中，我们已经建立了一个关键的功能，为聚羟基丁酸酯在介导结肠炎相关的癌症。对在肠上皮细胞中特异性过表达PHB的野生型和转基因（Tg）小鼠进行结肠炎相关致癌作用的经典两阶段方案。此外，使用野生型和p53缺失人类细胞模型来评估PHB与STAT 3和p53的相互作用。野生型小鼠在结肠炎相关癌变过程中表现出粘膜PHB蛋白表达降低。Tg小鼠表现出与增加的细胞凋亡、p53、Bax和Bad表达以及减少的Bcl-xL和Bcl-2表达相关的方式的易感性降低。在野生型而非p53缺失的人细胞中，PHB过表达增加Bax、Bad和caspase-3裂解的表达。在野生型p53细胞中，PHB过表达降低了基础和IL-6诱导的STAT 3激活以及STAT 3应答基因Bcl-xL和Bcl-2的表达。在培养的细胞裂解物和结肠粘膜中，除了p53之外，PHB还与磷酸化STAT 3共免疫沉淀。这是第一个研究显示在体内PHB和STAT 3之间的相互作用。总之，我们的研究结果表明，PHB通过调节p53和STAT 3介导的细胞凋亡来预防结肠炎相关癌症。调节肠上皮细胞中的PHB表达可能提供一种潜在的治疗方法来预防结肠炎相关的癌变。
Although inflammatory bowel disease is associated with higher risk of colorectal cancer, the precise pathogenic mechanisms underlying this association are not completely understood. Prohibitin 1 (PHB), a protein implicated in the regulation of proliferation, apoptosis, and transcription, is decreased in intestinal inflammation. In this study, we have established a key function for PHB in mediating colitis-associated cancer. Wild-type and transgenic (Tg) mice specifically overexpressing PHB in intestinal epithelial cells were subjected to a classical two-stage protocol of colitis-associated carcinogenesis Additionally, wild-type and p53 null human cell models were used to assess PHB interaction with STAT3 and p53. Wild-type mice exhibited decreased mucosal PHB protein expression during colitis-associated carcinogenesis. Tg mice exhibited decreased susceptibility in a manner associated with increased apoptosis, p53, Bax and Bad expression plus decreased Bcl-xL and Bcl-2 expression. PHB overexpression in wild-type but not p53 null human cells increased expression of Bax, Bad and caspase-3 cleavage. In wild-type p53 cells, PHB overexpression decreased basal and IL-6-induced STAT3 activation and expression of the STAT3 responsive genes Bcl-xL and Bcl-2. PHB co-immunoprecipitated with phospho-STAT3 in addition to p53 in cultured cell lysates and colon mucosa. This is the first study to show interaction between PHB and STAT3 in vivo. In summary, our findings suggest that PHB protects against colitis-associated cancer by modulating p53- and STAT3-mediated apoptosis. Modulation of PHB expression in intestinal epithelial cells may offer a potential therapeutic approach to prevent colitis-associated carcinogenesis.