FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7.
FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7.
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DOI：
10.18632/oncotarget.1581
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Mao JH
中科院分区：
文献类型：
--
作者：
Wang Z;Liu Y;Zhang P;Zhang W;Wang W;Curr K;Wei G;Mao JH
摘要染色体20 q的扩增在包括乳腺癌在内的多种人类癌症中经常被发现。在过去的十年中，20 q中的候选致癌基因名单已经扩大。在这里，我们调查是否FAM 83 D（家庭与序列相似性83，成员D）在染色体20 q发挥任何作用，在乳腺癌的发展。FAM 83 D的表达水平在乳腺癌细胞系和原发性人乳腺癌中显著升高。FAM 83 D的高表达水平与乳腺癌患者的不良临床结局和远处转移显著相关。我们发现FAM 83 D在人乳腺上皮细胞中的异位表达促进细胞增殖、迁移和侵袭，沿着上皮-间质转化（EMT）。乳腺癌细胞中FAM 83 D的消融诱导细胞凋亡并因此抑制细胞增殖和集落形成。机制研究表明，FAM 83 D的过表达通过物理相互作用下调FBXW 7表达水平，这导致FBXW 7下游致癌底物（如mTOR）的蛋白水平升高，雷帕霉素对其的抑制可以抑制FAM 83 D诱导的细胞迁移和侵袭。结果表明，FAM 83 D对乳腺癌患者具有预后价值，并且是乳腺癌发展中的一种新癌基因，其至少部分地通过抑制FBXW 7通过mTOR超活化起作用。
Abstract Amplification of chromosome 20q is frequently found in various types of human cancers, including breast cancer. The list of candidate oncogenes in 20q has expanded over the past decade. Here, we investigate whether FAM83D (family with sequence similarity 83, member D) on chromosome 20q plays any role in breast cancer development. The expression level of FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers. High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients. We show that ectopic expression of FAM83D in human mammary epithelial cells promotes cell proliferation, migration and invasion along with epithelial-mesenchymal transition (EMT). Ablation of FAM83D in breast cancer cells induces apoptosis and consequently inhibits cell proliferation and colony formation. Mechanistic studies reveal that overexpression of FAM83D downregulates FBXW7 expression levels through a physical interaction, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as mTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion. The results demonstrate that FAM83D has prognostic value for breast cancer patients and is a novel oncogene in breast cancer development that at least in part acts through mTOR hyper-activation by inhibiting FBXW7.
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影响因子：
3.7
作者：
Ramakrishna M;Williams LH;Boyle SE;Bearfoot JL;Sridhar A;Speed TP;Gorringe KL;Campbell IG
通讯作者：
Campbell IG
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
24.5
作者：
Carvalho, B.;Postma, C.;Meijer, G. A.
通讯作者：
Meijer, G. A.
影响因子：
3.8
作者：
Chen, Dung-Tsa;Nasir, Aejaz;Culhane, Aedin;Venkataramu, Chinnambally;Fulp, William;Rubio, Renee;Wang, Tao;Agrawal, Deepak;McCarthy, Susan M.;Gruidl, Mike;Bloom, Gregory;Anderson, Tove;White, Joe;Quackenbush, John;Yeatman, Timothy
通讯作者：
Yeatman, Timothy
影响因子：
50.3
作者：
Chin, Koei;DeVries, Sandy;Gray, Joe W.
通讯作者：
Gray, Joe W.