ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer.
ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer.
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DOI：
10.1158/0008-5472.can-09-2641
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Wang JM
中科院分区：
文献类型：
--
作者：
Lin LF;Chuang CH;Li CF;Liao CC;Cheng CP;Cheng TL;Shen MR;Tseng JT;Chang WC;Lee WH;Wang JM
ZBRK 1是一种受BRCA 1调控的转录抑制因子，因其具有锌指结构和BRCA 1-interacting protein with KRAB domain-1（ZBRK 1）而得名。最近的证据还表明，ZBRK 1与BRCA 1/CtIP合作抑制血管生成素-1的表达，以防止肿瘤中血管的过度扩张，这表明ZBRK 1可能在肿瘤进展中发挥关键作用。然而，ZBRK 1在肿瘤发生和肿瘤进展中的直接作用仍然不清楚。我们发现ZBRK 1在高度恶性的宫颈癌细胞中的表达显著低于相应的正常组织。ZBRK 1在HeLa细胞中的异位表达显著抑制其肿瘤表型，包括细胞增殖、软琼脂集落形成和裸鼠肿瘤生长。为了探索其机制，对这些细胞的基因表达模式的分析揭示了不仅对细胞增殖而且对细胞运动性下调至关重要的基因组。一致地，ZBRK 1的异位表达在细胞迁移和侵袭测定中抑制HeLa细胞的迁移，在培养中抑制HeLa细胞的侵袭，在小鼠中抑制HeLa细胞的转移。重要的是，ZBRK 1直接抑制转移基因MMP 9的转录，并且ZBRK 1表达的丧失与宫颈癌标本中MMP 9的表达升高呈负相关。综上所述，这些结果表明，ZBRK 1可能通过直接调节转移基因（如MMP 9）而作为肿瘤抑制因子发挥关键作用，特别是在转移中。
ZBRK1, named after its structure of Zinc finger and BRCA1-interacting protein with KRAB domain-1 (ZBRK1), is a transcriptional repressor modulated by BRCA1. Recent evidence also indicated that ZBRK1 collaborated with BRCA1/CtIP to repress angiopoietin-1 expression in preventing over enlargement of blood vessels in tumors, suggesting that ZBRK1 may exert a critical role during tumor progression. However, a direct role of ZBRK1 in tumorigenesis and tumor progression remains obscure. Here we found that ZBRK1 expression was significantly lower in highly malignant cervical cancer cells than the counterpart normal tissue. Ectopic expression of ZBRK1 in HeLa cells significantly inhibits its neoplastic phenotypes including cell proliferation, soft-agar colony formation and tumor growth in nude mice. To explore its mechanisms, analyses of gene expression patterns of these cells revealed groups of genes not only critical for cell proliferation but also for cell motility being down regulated. Consistently, ectopic expression of ZBRK1 inhibits HeLa cells migration in cell migration and invasion assays in culture and metastatic assay in mice. Importantly, ZBRK1 directly represses transcription of the metastatic gene, MMP9, and the loss of ZBRK1 expression is inversely correlated to the elevated expression of MMP9 in cervical cancer specimens. Taken together, these results indicate that ZBRK1 may have a critical role as a tumor suppressor, especially in metastasis, through directly modulating metastatic genes such as MMP9.