Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors
Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors
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DOI：
10.1073/pnas.1214394109
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发表时间：
2012-11-20
影响因子：
11.1
通讯作者：
Nistico, Paola
中科院分区：
文献类型：
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作者：
Di Modugno, Francesca;Iapicca, Pierluigi;Nistico, Paola
人类 mena (hMENA) 是肌动蛋白细胞骨架调节因子 Ena/VASP 的成员，在高风险癌前病变和原发性乳腺肿瘤中过度表达，并已被确定在表达 HER2 的乳腺癌的侵袭性和不良预后中发挥作用。在这里，我们鉴定了一种独特的亚型，hMENA Delta v6，源自 hMENA 选择性剪接程序。在人类乳腺癌进展的等基因模型中，我们发现 hMENA(11a) 在癌前细胞中表达，而 hMENA Delta v6 表达仅限于侵袭性癌细胞。恶性表型的“逆转”导致所有 hMENA 亚型同时下调。在乳腺癌细胞系中，亚型特异性 hMENA 过表达或敲低表明，在 hMENA(11a) 缺失的情况下，hMENA Delta v6 的过表达会增加细胞侵袭，而 hMENA(11a) 的过表达会降低这些细胞的迁移和侵袭能力。 hMENA(11a) 剪接被证明依赖于剪接上皮调节因子 1 (ESRP1)，并且 ESRP1 在侵袭性间充质乳腺癌细胞中的强制表达引起表型转换，让人想起间充质到上皮转化 (MET)，其特征是细胞骨架结构的变化、hMENA(11a) 的重新表达和细胞侵袭的减少。与表达 hMENA(11a) 的肿瘤相比，hMENA 阳性的原发性乳腺肿瘤（hMENA(11a) 阴性）的 E-钙粘蛋白水平更常见。这些数据表明，极化和生长停滞的细胞结构与替代 hMENA 亚型表达的缺乏相关，并且 hMENA 剪接程序与侵袭性疾病的恶性进展相关。
Human mena (hMENA), a member of the actin cytoskeleton regulators Ena/VASP, is overexpressed in high-risk preneoplastic lesions and in primary breast tumors and has been identified as playing a role in invasiveness and poor prognosis in breast cancers that express HER2. Here we identify a unique isoform, hMENA Delta v6, derived from the hMENA alternative splicing program. In an isogenic model of human breast cancer progression, we show that hMENA(11a) is expressed in premalignant cells, whereas hMENA Delta v6 expression is restricted to invasive cancer cells. "Reversion" of the malignant phenotype leads to concurrent down-regulation of all hMENA isoforms. In breast cancer cell lines, isoform-specific hMENA overexpression or knockdown revealed that in the absence of hMENA(11a), overexpression of hMENA Delta v6 increased cell invasion, whereas overexpression of hMENA(11a) reduced the migratory and invasive ability of these cells. hMENA(11a) splicing was shown to be dependent on the epithelial regulator of splicing 1 (ESRP1), and forced expression of ESRP1 in invasive mesenchymal breast cancer cells caused a phenotypic switch reminiscent of a mesenchymal-to-epithelial transition (MET) characterized by changes in the cytoskeletal architecture, reexpression of hMENA(11a), and a reduction in cell invasion. hMENA-positive primary breast tumors, which are hMENA(11a)-negative, are more frequently E-cadherin low in comparison with tumors expressing hMENA(11a). These data suggest that polarized and growth-arrested cellular architecture correlates with absence of alternative hMENA isoform expression, and that the hMENA splicing program is relevant to malignant progression in invasive disease.