Smad4 inactivation promotes malignancy and drug resistance of colon cancer.
Smad4 inactivation promotes malignancy and drug resistance of colon cancer.
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DOI：
10.1158/0008-5472.can-09-3269
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Thiagalingam S
中科院分区：
文献类型：
--
作者：
Papageorgis P;Cheng K;Ozturk S;Gong Y;Lambert AW;Abdolmaleky HM;Zhou JR;Thiagalingam S
SMAD 4定位于染色体18 q21，这是晚期结肠癌中杂合性丢失（洛）的常见位点。尽管Smad 4被认为是TGFβ信号通路的信号介导剂，但其作为结直肠癌进展的主要抑制剂的作用以及该现象背后的分子事件仍然难以捉摸。在这里，我们描述了结肠癌细胞系模型系统的建立和使用，以剖析TGFβ和Smad 4失活在恶性表型表现中的功能作用。我们发现SMAD 4的缺失和完整TGFβ受体的保留可以协同增加VEGF的水平，VEGF是一种主要的促血管生成因子。药理学抑制研究表明，TGFβ诱导的MEK-Erk和p38-MAPK辅助途径的过度激活参与了SMAD 4缺失细胞中VEGF表达的诱导。总体而言，SMAD 4缺陷导致结肠癌细胞迁移增强，MMP 9相应增加，缺氧诱导的GLUT 1表达增强，有氧糖酵解增加和对5′-氟尿嘧啶介导的凋亡的抵抗。有趣的是，Smad 4在缺氧条件下特异性地与HIF 1 α相互作用，为靶基因的差异调节提供了分子基础，以抑制恶性表型。总之，我们的研究结果定义了一种分子机制，解释了肿瘤抑制因子Smad 4的缺失如何促进结直肠癌的进展。这些发现也与靶向SMAD 4缺陷型肿瘤中TGFβ诱导的辅助途径（如MEK-ERK、p38-MAPK和糖酵解级联）作为治疗干预的有吸引力的策略一致。
SMAD4 is localized to chromosome 18q21, a frequent site for loss of heterozygosity (LOH) in advanced stage colon cancers. Although Smad4 is regarded as a signaling mediator of the TGFβ signaling pathway, its role as a major suppressor of colorectal cancer progression and the molecular events underlying this phenomenon, remain elusive. Here, we describe the establishment and use of colon cancer cell line model systems to dissect the functional roles of TGFβ and Smad4 inactivation in the manifestation of a malignant phenotype. We found that loss of SMAD4 and retention of intact TGFβ receptors could synergistically increase the levels of VEGF, a major pro-angiogenic factor. Pharmacological inhibition studies suggest that overactivation of the TGFβ-induced MEK-Erk and p38-MAPK auxiliary pathways are involved in the induction of VEGF expression in SMAD4 null cells. Overall, SMAD4 deficiency was responsible for the enhanced migration of colon cancer cells with a corresponding increase in MMP9, enhanced hypoxia-induced GLUT1 expression, increased aerobic glycolysis and resistance to 5′-fluoruracil-mediated apoptosis. Interestingly, Smad4 specifically interacts with HIF1α under hypoxic conditions providing a molecular basis for the differential regulation of target genes to suppress a malignant phenotype. In summary, our results define a molecular mechanism that explains how loss of the tumor suppressor Smad4 promotes colorectal cancer progression. These findings are also consistent with targeting TGFβ-induced auxiliary pathways, such as MEK-ERK, p38-MAPK and the glycolytic cascade, in SMAD4-deficient tumors as attractive strategies for therapeutic intervention.