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首页> 外文期刊>Oncogene >Basement membrane component laminin-5 is a target of the tumor suppressor Smad4
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Basement membrane component laminin-5 is a target of the tumor suppressor Smad4

机译：基底膜成分层粘连蛋白5是肿瘤抑制物Smad4的靶标

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The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon. Functional inactivation of Smad4 is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth. Smad4 encodes an intracellular messenger common to all signalling cascades induced by members of the transforming growth factor- (TGF-) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-/Smad signal transduction, little is known about Smad4 targets involved in the transition to malignancy. The hallmark of invasive growth is a breakdown of the basement membrane (BM), a specialized sheet of extracellular matrix produced through cooperation of epithelial and stromal cells. Laminin-5, a heterotrimeric epithelial-derived BM component, is commonly lost in carcinomas but not in premalignant tumors. Herein, we report that in human colon and pancreatic tumor cells, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-5. Coordinate re-expression of the three laminin-5 chains induced by reconstitution of Smad4 leads to secretion and deposition of the heterotrimeric molecule in BM-like structures. These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4.
机译：肿瘤抑制因子Smad4主要参与胰腺和结肠的癌变过程。 Smad4的功能失活是遗传上的晚期事件，发生于从恶变前阶段到侵袭性和转移性生长的过渡期。 Smad4编码由细胞因子的转化生长因子-（TGF-）超家族成员诱导的所有信号级联所共有的细胞内信使。尽管对TGF- / Smad信号转导的机制有广泛的了解，但对参与向恶性肿瘤转化的Smad4靶标的了解却很少。侵袭性生长的标志是基底膜（BM）的分解，基底膜是通过上皮细胞和基质细胞的合作而产生的专门的细胞外基质薄片。层粘连蛋白5（Laminin-5）是异源三聚体上皮衍生的BM成分，通常在癌症中丢失，而在恶变前肿瘤中不丢失。在此，我们报道在人类结肠和胰腺肿瘤细胞中，Smad4充当编码层粘连蛋白5的所有三个基因的正转录调节因子。通过重组Smad4诱导的三个层粘连蛋白5链的坐标重新表达导致异三聚体分子在BM样结构中分泌和沉积。这些数据将必需的BM成分的表达控制定义为肿瘤抑制物Smad4的新功能。

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