Department of Oral and Craniofacial Biology, Louisiana State University Health Sciences Center-New Orleans, School of Dentistry, New Orleans, LA 70119, USA.
Biochem Biophys Res Commun. 2011 Mar 11;406(2):171-6. doi: 10.1016/j.bbrc.2011.01.109. Epub 2011 Feb 1.
Ligand engagement by integrins induces receptor clustering and formation of complexes at the integrin cytoplasmic face that controls cell signaling and cytoskeletal dynamics critical for adhesion-dependent processes. This study searches for a subset of integrin effectors that coordinates both tumor cell invasion and resistance to the chemotherapeutic drug cisplatin in oral carcinomas. Candidate integrin effectors were identified in a proteomics screen of proteins recruited to clustered integrin αβ1, α(v)β or α(6)β receptors in oral carcinomas. Proteins with diverse functions including microtubule and actin binding proteins, and factors involved in trafficking, transcription and translation were identified in oral carcinoma integrin complexes. Knockdown of effectors in the oral carcinoma HN12 cells revealed that p130Cas, Dek, Src and talin were required for invasion through Matrigel. Disruption of talin or p130Cas by RNA interference increased resistance to cisplatin, whereas targeting Dek, Src or zyxin reduced HN12 resistance to cisplatin. Analysis of the spreading of HN12 cells on collagen I and laminin I revealed that a decrease in p130Cas or talin expression inhibited spreading on both matrices. Interestingly, a reduction in zyxin expression enhanced spreading on laminin I and inhibited spreading on collagen I. Reduction of Dek, Src, talin or zyxin expression reduced HN12 proliferation by 30%. Proliferation was not affected by a reduction in p130Cas expression. We conclude that p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin.
整合素与配体的结合诱导受体聚集，并在整合素细胞质面形成复合物，从而控制细胞信号转导和细胞骨架动力学，这对于依赖黏附的过程至关重要。本研究旨在寻找一组整合素效应器，这些效应器既能协调口腔癌细胞的侵袭，又能抵抗化疗药物顺铂的作用。在口腔癌中，通过对募集到聚集的整合素 αβ1、α(v)β 或 α(6)β 受体的蛋白质进行蛋白质组学筛选，确定了候选整合素效应器。在口腔癌整合素复合物中鉴定出具有多种功能的蛋白质，包括微管和肌动蛋白结合蛋白，以及参与运输、转录和翻译的因子。在口腔癌 HN12 细胞中敲低效应器后发现，p130Cas、Dek、Src 和 talin 对于穿过 Matrigel 的侵袭是必需的。通过 RNA 干扰破坏 talin 或 p130Cas 会增加对顺铂的耐药性，而靶向 Dek、Src 或 zyxin 会降低 HN12 对顺铂的耐药性。分析 HN12 细胞在胶原蛋白 I 和层粘连蛋白 I 上的铺展情况表明，减少 p130Cas 或 talin 的表达会抑制在这两种基质上的铺展。有趣的是，减少 zyxin 的表达会增强在层粘连蛋白 I 上的铺展，抑制在胶原蛋白 I 上的铺展。减少 Dek、Src、talin 或 zyxin 的表达会使 HN12 的增殖减少 30%。减少 p130Cas 的表达不会影响细胞的增殖。我们的结论是，p130Cas、Src 和 talin 既参与口腔癌的侵袭，也参与对顺铂的耐药性。
