Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis
Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis
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作者：
Lei, R.;Tang, J.;Hu, G.
乳腺癌是全世界女性中最常见的癌症类型，转移是该疾病最具破坏性的阶段。近年来的研究表明，microRNAs （miRNA）在调节癌细胞的侵袭和转移中起着至关重要的作用。在这里，我们提出证据表明miR-182在乳腺癌转移中的作用。miR-182在人MCF10和小鼠4T1系列的恶性细胞系变异中均上调。miR-182的异位表达增强了乳腺癌细胞的运动性和侵袭性，而miR-182抑制则导致相反的变化。在裸鼠中，miR-182导致癌细胞在肺部定植增加。我们进一步证明了miR-182直接靶向MIM (Missing in Metastasis)，其通过抑制乳腺癌细胞中ras同源家族成员A （RhoA）的活性和应激纤维的形成来抑制转移。恢复MIM表达完全阻断了miR-182的促转移功能，而RhoA抑制逆转了miR-182过表达和MIM敲低的表型。在乳腺肿瘤样本中，miR-182诱导与MIM下调、RhoA激活和预后不良有关。因此，我们的数据描绘了miR-182促进乳腺癌侵袭和转移的分子途径，并可能对转移性癌症的治疗具有重要意义。
Breast cancer is the most common type of cancer among women worldwide, and metastasis represents the most devastating stage of the disease. Recent studies have revealed that microRNAs (miRNA) have critical roles to regulate cancer cell invasion and metastasis. Here we present evidence to show the role of miR-182 in breast cancer metastasis. miR-182 is upregulated in the malignant cell line variants of both human MCF10 and mouse 4T1 series. Ectopic expression of miR-182 enhanced breast cancer cell motility and invasiveness, whereas miR-182 inhibition resulted in opposite changes. In nude mice, miR-182 led to increased pulmonary colonization of cancer cells. We further demonstrated that miR-182 directly targets MIM (Missing in Metastasis), which suppresses metastasis by inhibiting ras homolog family member A (RhoA) activity and stress fiber formation in breast cancer cells. Restoring MIM expression completely blocked the pro-metastasis function of miR-182, while RhoA inhibition reversed the phenotypes of both miR-182 overexpression and MIM knockdown. In breast tumor samples, miR-182 induction is linked to downregulation of MIM, RhoA activation and poor prognosis. Hence, our data delineates the molecular pathway by which miR-182 promotes breast cancer invasion and metastasis, and may have important implication for the treatment of metastatic cancers.