MicroRNA-30a調控上皮/間質細胞轉換抑制乳癌進程之角色探討

上皮間質細胞轉換(epithelial-to-mesenchymal transition : EMT)是腫瘤進程中給予轉移潛能的必要條件，microRNA-30a(miR-30a)在侵襲性乳癌細胞株的表現量明顯低於非侵襲性乳癌細胞株和非惡性乳腺上皮細胞株，相對的，高度表達miR-30a能將間質型態的癌細胞反轉成鵝卵石狀上皮細胞的型態，我們使用電腦比對預測鑑定出EMT的主要調節者之一，Slug，是miR-30a的目標基因，由冷光報導基因實驗(luciferase reporter assay)確認miR-30a會結合到Slug mRNA的3端UTR，再者，我們銜接了miR-30a與緊密接合(tight junctions)膜蛋白Claudins(CLDNs)表現增加的關聯，當miR-30a高度表達時能減少Snail、Slug與Claudin promoter上E box的結合量，更加導致線狀偽足(filopodia)形成減少和降低乳癌細胞侵襲轉移的能力，相同的，在異種移植(xenograft model)的小鼠中，miR-30a能抑制腫瘤的侵襲和轉移，在乳癌病人中，我們發現miR-30alow /CLDN2 low/FSCN high 是一種有較高風險的基因型，導致較大的腫瘤，淋巴結轉移和晚期癌症，最後，miR-30a調控Snail、Slug干擾轉移性癌細胞的編程，在抑制間質性腫瘤發展中扮演著重要角色，或許能在乳癌的治療策略發展上成為一個有潛力的標的。

關鍵字

乳癌轉移；上皮間質細胞轉換；微小RNA-30a ； Snail ； Slug ； Claudin

並列摘要

The epithelial-to-mesenchymal transition (EMT) is a prerequisite for conferring metastatic potential during tumor progression. microRNA-30a (miR-30a) expression was significantly lower in aggressive breast cancer cell lines compared with non-invasive breast cancer and non-malignant mammary epithelial cell lines. In contrast, miR-30a overexpression reversed the mesenchymal appearance of cancer cells to yield a cobblestone-like epithelial phenotype. We identified Slug, one of the master regulators of EMT, as a target of miR-30a using in silico prediction. We confirmed this with reporter assays, which revealed that miR-30a could bind to the 3’-untranslted region of Slug mRNA. Furthermore, we linked miR-30a to increased expression of Claudins, a family of tight junction transmembrane proteins. An interaction between Snail, Slug and E-box in the Claudin promoter sequences was reduced upon miR-30a overexpression, further leading to reduction of filopodia formation and decreased invasiveness/ metastasis capabilities of breast cancer cells. Consistently, delivery of miR-30a in xenografted mice decreased tumor invasion and migration. In patients with breast cancer, we observed a significantly elevated risk of the miR-30alow/CLDN2low/FSCNhigh genotype, leading to a phenotypic manifestation of larger tumor size, lymph node metastasis, and advanced tumor stage among patients. In conclusion, the miR-30a/Snail,Slug axis plays a central role in inhibiting mesenchymal tumor development to interfere with metastatic cancer cell programming and may be a potential target for therapeutic development in breast cancer.

並列關鍵字

Breast cancer metastasis ； EMT ； miR-30a ； Snail ； Slug ； Claudin

參考文獻

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MicroRNA-30a調控上皮/間質細胞轉換抑制乳癌進程之角色探討

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