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Activation of multiple cancer pathways and tumor maintenance function of the 3q amplified oncogene FNDC3B

机译：3q扩增癌基因FNDC3B的多种癌症途径的激活和肿瘤维持功能

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FNDC3B was recently identified in an oncogenomic screen for amplified oncogenes in hepatocellular carcinoma. It is located at 3q26 and is amplified in over 20% of cancers, usually as part of a broad amplified region encompassing the entire 3q arm. Consistent with an oncogenic role in multiple cancer types, we show here that overexpression of FNDC3B is capable of malignantly transforming mammary and kidney epithelial cells in addition to hepatocytes. To explore how FNDC3B transforms cells, we determined the cellular localization of its gene product and the cancer pathways that it activates. We found that the FNDC3B oncoprotein localizes to the Golgi network, and that its correct localization is essential for its transforming function. We found that overexpression of FNDC3B induces the epithelial-to-mesenchymal transition (EMT) and activates several cancer pathways, including PI3-kinase/Akt, Rb1 and TGFβ signaling. For TGFβ signaling, we analyzed the point in the pathway at which FNDC3B operates and obtained evidence that it induces expression of all three TGFβ ligands and also promotes TGFBR1 cell-surface localization. We found that RNAi-mediated knockdown of FNDC3B in cancer cells with 3q amplification suppressed their clonogenicity and tumorigenicity, but that the same RNAi knockdown had no effect on single-copy 3q cancer cells. These results indicate that FNDC3B is an important oncogenic driver gene of the 3q amplicon, adding to the growing list of oncogenic drivers within this commonly amplified region.
机译：FNDC3B最近在肿瘤基因筛查中被鉴定为肝细胞癌中扩增的癌基因。它位于3q26，在超过20％的癌症中被扩增，通常是围绕整个3q臂的广泛扩增区域的一部分。与多种癌症类型中的致癌作用一致，我们在这里显示FNDC3B的过度表达除肝细胞外，还能够恶性转化乳腺和肾脏上皮细胞。为了探索FNDC3B如何转化细胞，我们确定了其基因产物的细胞定位及其激活的癌症途径。我们发现FNDC3B癌蛋白定位于高尔基网络，并且其正确的定位对于其转化功能至关重要。我们发现FNDC3B的过表达诱导上皮到间充质转化（EMT）并激活几种癌症途径，包括PI3-激酶/ Akt，Rb1和TGFβ信号传导。对于TGFβ信号传导，我们分析了FNDC3B起作用的途径中的点，并获得证据表明它诱导了所有三种TGFβ配体的表达，并且还促进了TGFBR1细胞表面的定位。我们发现，RNAi介导的3q扩增癌细胞中FNDC3B的敲低抑制了其克隆性和致瘤性，但相同的RNAi敲低对单拷贝3q癌细胞没有影响。这些结果表明，FNDC3B是3q扩增子的重要致癌驱动基因，在这个通常被扩增的区域内，致癌驱动基因的列表不断增加。

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