Goto Yoko, Zeng Lihua, Yeom Chan Joo, Zhu Yuxi, Morinibu Akiyo, Shinomiya Kazumi, Kobayashi Minoru, Hirota Kiichi, Itasaka Satoshi, Yoshimura Michio, Tanimoto Keiji, Torii Masae, Sowa Terumasa, Menju Toshi, Sonobe Makoto, Kakeya Hideaki, Toi Masakazu, Date Hiroshi, Hammond Ester M, Hiraoka Masahiro, Harada Hiroshi
1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan.
1] Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Kyoto 606-8501, Japan [3] Department of Radiation Medicine, Fourth Military Medical University, 17 Changle West Road, Shaanxi 710032, China.
Nat Commun. 2015 Jan 23;6:6153. doi: 10.1038/ncomms7153.
Hypoxia-inducible factor 1 (HIF-1) plays a role in tumour metastases; however, the genes that activate HIF-1 and subsequently promote metastases have yet to be identified. Here we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1) abrogates the von Hippel-Lindau-mediated ubiquitination of HIF-1α, the regulatory subunit of HIF-1, and consequently promotes metastasis. The aberrant overexpression of UCHL1 facilitates distant tumour metastases in a HIF-1-dependent manner in murine models of pulmonary metastasis. Meanwhile, blockade of the UCHL1-HIF-1 axis suppresses the formation of metastatic tumours. The expression levels of UCHL1 correlate with those of HIF-1α and are strongly associated with the poor prognosis of breast and lung cancer patients. These results indicate that UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1α, which justifies exploiting it as a prognostic marker and therapeutic target of cancers.
缺氧诱导因子1（HIF-1）在肿瘤转移中发挥作用；然而，激活HIF-1并随后促进转移的基因尚未被确定。在此我们表明，泛素C末端水解酶-L1（UCHL1）消除了希佩尔-林道蛋白介导的HIF-1α（HIF-1的调节亚基）的泛素化，从而促进转移。在肺转移的小鼠模型中，UCHL1的异常过表达以HIF-1依赖的方式促进远处肿瘤转移。同时，阻断UCHL1-HIF-1轴可抑制转移性肿瘤的形成。UCHL1的表达水平与HIF-1α的表达水平相关，并且与乳腺癌和肺癌患者的不良预后密切相关。这些结果表明，UCHL1作为HIF-1α的去泛素化酶促进转移，这证明将其用作癌症的预后标志物和治疗靶点是合理的。
Zotero 插件
