As colorectal cancer remains the second highest cause of cancer-related deaths in much of the industrialised world, identifying novel strategies to prevent colorectal tumour development remains an important challenge. BAG-1 is a multi-functional protein, the expression of which is up-regulated at relatively early stages in colorectal tumorigenesis. Importantly, BAG-1 is thought to enhance colorectal tumour progression through promoting tumour cell survival. Here, we report for the first time a novel role for BAG-1, establishing it as a suppressor of transforming growth factor β (TGF-β1) expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-β1 expression, a key cytokine in normal colonic tissue homoeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by small interfering RNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and chromatin immunoprecipitation assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated that the levels of BAG-1 and TGF-β1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF-β1 production. In vitro studies showed that the change in TGF-β1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-β1-dependent normal rat kidney fibroblasts and regulation of SMAD2 phosphorylation in TGF-β1-sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-β1, suggesting that high expression of BAG-1 can impact on a number of the hallmarks of cancer, of potential importance in promoting the early stages of colorectal tumorigenesis. Establishing BAG-1 as a repressor of TGF-β1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis.

译文

:由于在大多数工业化国家中,结直肠癌仍然是与癌症相关的死亡的第二大原因,因此,确定预防结直肠肿瘤发展的新策略仍然是一项重要的挑战。 BAG-1是一种多功能蛋白,其表达在大肠肿瘤发生的相对早期阶段就被上调。重要的是,BAG-1被认为通过促进肿瘤细胞的存活来增强结直肠肿瘤的进展。在这里,我们首次报道了BAG-1的新作用,确立了它作为大肠肿瘤细胞中转化生长因子β(TGF-β1)表达的抑制剂。微阵列分析首先凸显了BAG-1可能调节TGF-β1表达的可能性,TGF-β1是正常结肠组织稳态中的关键细胞因子。 Q-RT-PCR和ELISA结果表明,当小干扰RNA降低BAG1水平时,TGFB1 mRNA和蛋白表达显着增加。另外,BAG-1L的诱导导致结直肠肿瘤细胞中TGFB1 mRNA的抑制。使用报道分子和染色质免疫沉淀测定法,鉴定了BAG-1与TGFB1基因调控区的直接关联。免疫组织化学和Weiser分数数据表明,体内正常结肠上皮中BAG-1和TGF-β1的含量呈负相关,这与BAG-1介导的抑制TGF-β1产生的作用一致。体外研究表明,操纵BAG-1后TGF-β1产生的变化在功能上是相关的。通过诱导TGF-β1依赖的正常大鼠肾成纤维细胞中不依赖贴壁的生长以及调节TGF-β1敏感的腺瘤细胞中SMAD2磷酸化。综上所述,这项研究确定了抗凋亡蛋白BAG-1是抑制生长因子TGF-β1的抑制剂,这表明BAG-1的高表达可以影响多种癌症,对促进癌症的发展具有潜在的重要意义。大肠癌发生的早期阶段。建立BAG-1作为TGF-β1的阻遏物具有重要的生物学意义,并突出了BAG-1在结直肠肿瘤发生中的新作用。

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