Perturbation of epithelial apicobasal polarity by rhomboid family-1 gene overexpression
Perturbation of epithelial apicobasal polarity by rhomboid family-1 gene overexpression
复制标题
菱形家族 1 基因过表达对上皮顶端基底极性的扰动
DOI：
10.1096/fj.201800016r
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发表时间：
2018-10-01
期刊：
影响因子：
4.8
通讯作者：
Li, Lu-Yuan
中科院分区：
文献类型：
--
作者：
Peng, Xue-Mei;Gao, Shan;Li, Lu-Yuan
人菱形家族（RHBDF）1基因在临床条件下的乳腺癌中高表达，但在正常乳腺组织中不表达。沉默乳腺癌异种移植肿瘤中的RHBDF 1基因导致肿瘤生长的抑制。我们在这项研究中表明，人工提高乳腺上皮细胞MCF-10A中的RHBDF 1蛋白水平导致细胞形成含腔腺泡的能力严重紊乱，无论是在三维细胞培养中还是植入小鼠乳腺脂肪垫中。用短发夹（sh）RNA敲低RHBDF 1导致腺泡形成的恢复。一致地，RHBDF 1过表达引起极性标记物GM 130和层粘连蛋白-5的无序分布，否则它们分别位于腺泡的顶端和基底位置。进一步的研究表明，RHBDF 1直接结合到Par 6a，一个蛋白质复合物的组成部分，由分区缺陷支架蛋白（Par）6，Par 3，肾素-血管紧张素系统相关的C3肉毒杆菌毒素底物（Rac）1，和细胞分裂周期（Cdc）42，这是结构上的顶基极性的形成至关重要。RHBDF 1与Par 6a的结合导致蛋白质复合物的崩溃，从而破坏极性形成。由于乳腺癌的早期阶段的特征在于乳腺上皮细胞极性的丧失，我们的研究结果表明，高水平的RHBDF 1对顶基底极性的扰动是乳腺瘤形成发展的重要属性。M.，Gao，S.，邓，H- T.，蔡，H.- X.，周志，湘河，缅-地张，Q.- Z.，李湖，澳-地Y.菱形家族-1基因过表达对上皮顶基极性的干扰。
The human rhomboid family (RHBDF)1 gene is highly expressed in breast cancer under clinical conditions but not in normal mammary gland tissues. Silencing the RHBDF1 gene in breast cancer xenograft tumors leads to inhibition of tumor growth. We show in this study that artificially raising RHBDF1 protein levels in the mammary epithelial cells MCF-10A results in severe perturbations of the ability of the cells to form lumen-containing acini, either in 3-dimensional cell cultures or implanted in mouse mammary fat pads. Knocking down RHBDF1 with short hairpin (sh)RNA leads to restoration of acinus formation. Consistently, RHBDF1 overexpression gives rise to disordered distribution of polarity markers GM130 and laminin-5, which otherwise are located in apical and basal positions, respectively, in the acini. Further investigations reveal that RHBDF1 directly binds to Par6a, a component of a protein complex consisting of partitioning-defective scaffold protein (Par)6, Par3, renin-angiotensin system-related C3 botulinum toxin substrate (Rac)1, and cell-division cycle (Cdc)42, which is structurally critical to the formation of apicobasal polarity. RHBDF1 binding to Par6a results in collapse of the protein complex and thus disruption of polarity formation. Since early stages of breast cancer are characterized by the loss of mammary gland epithelial cell polarity, our findings indicate that perturbations of apicobasal polarity by high levels of RHBDF1 is a significant attribute in the development of breast neoplasia.Peng, X.-M., Gao, S., Deng, H.-T., Cai, H.-X., Zhou, Z., Xiang, R., Zhang, Q.-Z., Li, L.-Y. Perturbation of epithelial apicobasal polarity by rhomboid family-1 gene overexpression.