miR-205 regulates basement membrane deposition in human prostate: implications for cancer development
miR-205 regulates basement membrane deposition in human prostate: implications for cancer development
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DOI：
10.1038/cdd.2012.56
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发表时间：
2012-11-01
影响因子：
12.4
通讯作者：
Zaffaroni, N.
中科院分区：
文献类型：
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作者：
Gandellini, P.;Profumo, V.;Zaffaroni, N.
基底膜（BM）是一层特殊的细胞外基质，包围着正常的前列腺腺体并保持组织的完整性。BM的缺乏或不连续是肿瘤细胞侵入间质空间的先决条件，因此有利于转移。因此，BM维持代表了针对癌症发展和进展的屏障。在这项研究中，我们发现miR-205参与了一个涉及Delta Np 63 α的网络，这对前列腺上皮中BM的维持至关重要。在分子水平上，Delta Np 63 alpha能够通过与其启动子结合来增强miR-205的转录，而microRNA可以在转录后限制Delta Np 63 a蛋白的量，主要是通过影响Delta Np 63 alpha蛋白酶体的降解，而不是通过典型的miRNA/靶标相互作用。在功能上，miR-205能够控制层粘连蛋白-332及其受体整合素-β 4的沉积。因此，如在前列腺癌中广泛观察到的，miR-205的病理性丢失可能通过在BM中产生不连续性而有利于肿瘤发生。在这里，我们证明了在前列腺癌（PCa）细胞中治疗性替换miR-205可以将BM沉积和3D组织恢复为正常样腺泡结构，从而阻碍癌症进展。Cell Death and Differentiation（2012）19，1750-1760; doi：10.1038/cdd.2012.56; 2012年5月4日在线发表
The basement membrane (BM) is a layer of specialized extracellular matrix that surrounds normal prostate glands and preserves tissue integrity. Lack or discontinuity of the BM is a prerequisite for tumor cell invasion into interstitial spaces, thus favoring metastasis. Therefore, BM maintenance represents a barrier against cancer development and progression. In the study, we show that miR-205 participates in a network involving Delta Np63 alpha, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, Delta Np63 alpha is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of Delta Np63a protein, mostly by affecting Delta Np63 alpha proteasomal degradation rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor integrin-beta 4. Hence, pathological loss of miR-205, as widely observed in prostate cancer, may favor tumorigenesis by creating discontinuities in the BM. Here we demonstrate that therapeutic replacement of miR-205 in prostate cancer (PCa) cells can restore BM deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression. Cell Death and Differentiation (2012) 19, 1750-1760; doi:10.1038/cdd.2012.56; published online 4 May 2012