最近一項(xiàng)用小鼠前列腺癌模型所做的實(shí)驗(yàn)研究，識(shí)別出了刺激轉(zhuǎn)移形成的一個(gè)信號(hào)通道,。當(dāng)一個(gè)蛋白配體占據(jù)一個(gè)被稱為RANK（receptor activator of nuclear factor κ B）的受體時(shí),，該通道被激發(fā),，并且它還依賴于這種激發(fā)和IKKα (IkB kinase a)的核轉(zhuǎn)位。一旦進(jìn)入細(xì)胞核中,，被激發(fā)的IKKα就會(huì)抑制maspin基因轉(zhuǎn)錄,，該轉(zhuǎn)錄的產(chǎn)物已被明確為前列腺癌和乳腺癌中細(xì)胞遷移和入侵的一個(gè)抑制成分。因此,，RANK可能是前列腺癌或乳房腫瘤細(xì)胞中都有的轉(zhuǎn)移行為的一個(gè)促進(jìn)劑（啟動(dòng)子）,。該研究成果被發(fā)表于4月5日出版的《自然》（Nature）雜志上。
部分英文原文：
Letter
Nature 446, 690-694 (5 April 2007) | doi:10.1038/nature05656; Received 5 December 2006; Accepted 2 February 2007; Published online 18 March 2007
Nuclear cytokine-activated IKK controls prostate cancer metastasis by repressing Maspin
Jun-Li Luo1, Wei Tan1, Jill M. Ricono2, Olexandr Korchynskyi1, Ming Zhang3, Steven L. Gonias2, David A. Cheresh2 & Michael Karin1
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA
Department of Pathology and the Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0803, USA
Baylor College of Medicine, Department of Molecular and Cellular Biology, One Baylor Plaza, Houston, Texas 77030, USA
Correspondence to: Michael Karin1 Correspondence and requests for materials should be addressed to M.K. (Email: [email protected]).
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Inflammation enhances tumour promotion through NF-B-dependent mechanisms1. NF-B was also proposed to promote metastatogenesis through epithelial–mesenchymal transition2. Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for IB kinase (IKK), activated by receptor activator of NF-B (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy3. Owing to similarities between mammary and prostate epithelia, we examined IKK involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKK activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium4. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin5, the ablation of which restored metastatic activity. IKK activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKK. The amount of active nuclear IKK in mouse and human prostate cancer correlates with metastatic progression, reduced Maspin expression and infiltration of prostate tumours with RANKL-expressing inflammatory cells. We propose that tumour-infiltrating RANKL-expressing cells lead to nuclear IKK activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.
