癌症轉移是一連串包含基因改變的複雜的序列事件，包括週邊組織侵襲、穿透至血液或淋巴組織中、定位在遠端組織的血管內皮細胞上、穿出血管並引起血管新生作用，最後在遠端轉移組織長成次發的腫瘤。MTA1( metastasis- associated protein 1)首先是從老鼠轉移乳腺腫瘤cDNA庫(cDNA library from rat metastatic mammary adenocarcinoma)中首先選殖出來，並發現MTA1的mRNA表現量在老鼠乳癌腫瘤和人類乳癌細胞中有上升的傾向。先前的幾個研究顯示MTA1 mRNA表現量似乎也和具侵襲性的人類腫瘤有關，包括結腸直腸癌、胃癌食道癌及胸腺瘤。MTA1剪裁變異型(MTA1s)是MTA1經過選擇性接合作用（alternative splicing）去除外顯子-14的47對核苷酸，造成框移突變(frame shift mutation)產生了一個提前終止訊號(stop codon)而得到MTA1 C端截切產物。值得注意的是MTA1s缺乏核內定位信號（nuclear localization signal），MTA1s能和雌激素受體交互作用，並將雌激素受體捕捉在細胞質中。最近研究顯示，MTA1s過度表現在乳癌細胞中可能與anchorage-independent及tumorigenic的表現型有關。首先，在本研究中，我們測試MTA1及MTA1s與乳癌轉移及侵襲相關之假說，我們利用即時偵測同步定量之聚合酶連鎖反應器（real-time polymerase chain reaction），定量乳癌組織中MTA1及MTA1s之表現量。我們發現在病人的腫瘤組織中，在淋巴結轉移≧2（n=13）的病人其腫瘤組織的MTA1s/ MTA1比值比鄰近週邊正常組織來的高，並且也有顯著差異(p=0.041)。其次，我們利用EGFP-N1、EGFP- MTA1及EGFP- MTA2瞬時轉染老鼠胚胎細胞NIH3T3並進行細胞移行及細胞侵襲性分析。在細胞移行實驗中，EGFP-MTA1、EGFP-MTA2分別比EGFP-N1控制組高1.4及1.3倍;在細胞侵襲試驗(n=6)中，EGFP- MTA1，EGFP-MTA2分別比EGFP- N1控制組高1.6及 1.4倍。我們結果顯示乳癌患者腫瘤組織MTA1s/ MTA1比值越高，其臨床的表現越不佳。我們認為定量分析MTA1和MTA1s有潛力成為乳癌轉移的生物指標。

　Metastasis is a complex series of events that involves several gene products, including those for the invasion and detachment of neoplastic cells from the primary tumor, penetration into blood and lymphatics, arrest at distant sites by adhesion to endothelial cells, extravasation, induction of angiogenesis, invasion from host antitumor responses, and growth at metastatic sites. The metastasis-associated gene 1 (mta1) was identified by differential cDNA screening using cell lines derived from highly metastatic mammary adenocarcinomas. Enhanced expression of mta1 mRNA was also found in a variety of other human cancerous tissues and carcinoma cell lines, including in colorectal, gastric, or oesophageal carcinomas and thymoma. A naturally occurring variant of MTA1 was recently discovered. This variant, named MTA1s (for short version of MTA1), is a C-terminal truncated form of MTA1, generated by alternative splicing at a cryptic splice site in exon 14, resulting in a deletion of 47 base-pair nucleotides. The underlying mechanism of MTA1s-mediated repression of the estrogen receptor (ER) transactivation function involves nuclear exclusion and sequestration of ER in the cytoplasm. Results of studies involving MTA1s overexpression suggest a role of MTA1s in conferring anchorage independent and tumorigenic phenotypes in breast cancer cells. In this study, we tested the hypothesis that the expression of MTA1 and MTA1s was correlated with the invasive and metastatic potential of breast cancer. First, we used quantitative real-rime PCR to detect mRNA expression levels of mta1 and mta1s in breast cancer tissue. The result revealed that mta1s/mta1 mRNA ratio was significantly higher in metastasis≧2 breast cancer tissue than adjacent normal tissue (p=0.041). Second, we also used migration assay and invasion assay with Boyden chamber and transwell to analysis the association between the level of mta1 and cancer metastasis. We found that transient transfection of NIH3T3 by EGFP-MTA1, EGFP-MTA2, and EGFP-N1 caused a 1.4-fold and 1.3-fold increased migration and 1.6-fold and 1.4-fold increased invasion, compared to the corresponding EGFP-N1 cells. Our results suggest that the patients with breast cancer that have a more aggressive clinical behavior may have higher mta1s/mta1 mRNA ratio. We conclude that expression of mta1 and mta1s may act as a potential biological marker in breast cancer progression.

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