Zevian Shannin C, Johnson Jessica L, Winterwood Nicole E, Walters Katherine S, Herndon Mary E, Henry Michael D, Stipp Christopher S
a Department of Biology ; University of Iowa ; Iowa City , IA USA.
b Central Microscopy Research Facility, University of Iowa ; Iowa City , IA USA.
Cancer Biol Ther. 2015;16(11):1626-40. doi: 10.1080/15384047.2015.1095396. Epub 2015 Sep 29.
Integrins function in collective migration both as major receptors for extracellular matrix and by crosstalk to adherens junctions. Despite extensive research, important questions remain about how integrin signaling mechanisms are integrated into collective migration programs. Tetraspanins form cell surface complexes with a subset of integrins and thus are good candidates for regulating the balance of integrin functional inputs into cell-matrix and cell-cell interactions. For example, tetraspanin CD151 directly associates with α3β1 integrin in carcinoma cells and promotes rapid α3β1-dependent single cell motility, but CD151 also promotes organized adherens junctions and restrains collective carcinoma cell migration on 2D substrates. However, the individual roles of CD151s integrin partners in CD151s pro-junction activity in carcinoma cells were not well understood. Here we find that CD151 promotes organized carcinoma cell junctions via α3β1 integrin, by a mechanism that requires the a3b1 ligand, laminin-332. Loss of CD151 promotes collective 3D invasion and growth in vitro and in vivo, and the enhanced invasion of CD151-silenced cells is α3 integrin dependent, suggesting that CD151 can regulate the balance between α3β1s pro-junction and pro-migratory activities in collective invasion. An analysis of human cancer cases revealed that changes in CD151 expression can be linked to either better or worse clinical outcomes depending on context, including potentially divergent roles for CD151 in different subsets of breast cancer cases. Thus, the role of the CD151-α3β1 complex in carcinoma progression is context dependent, and may depend on the mode of tumor cell invasion.
整合素在集体迁移中发挥作用，既是细胞外基质的主要受体，又通过与黏附连接的相互作用来实现。尽管进行了广泛的研究，但关于整合素信号传导机制如何整合到集体迁移程序中仍存在重要问题。四跨膜蛋白与一部分整合素形成细胞表面复合物，因此是调节整合素功能输入到细胞 - 基质和细胞 - 细胞相互作用平衡的良好候选者。例如，四跨膜蛋白CD151在癌细胞中直接与α3β1整合素结合，并促进快速的α3β1依赖性单细胞运动，但CD151也促进有组织的黏附连接，并抑制癌细胞在二维基质上的集体迁移。然而，CD151的整合素伙伴在癌细胞中CD151的促连接活性中的个体作用尚未得到很好的理解。在这里，我们发现CD151通过α3β1整合素促进有组织的癌细胞连接，其机制需要α3β1配体层粘连蛋白 - 332。CD151的缺失促进体外和体内的集体三维侵袭和生长，并且CD151沉默细胞侵袭增强是α3整合素依赖性的，这表明CD151可以调节集体侵袭中α3β1的促连接和促迁移活性之间的平衡。对人类癌症病例的分析表明，CD151表达的变化根据具体情况可能与更好或更差的临床结果相关，包括CD151在不同乳腺癌病例亚组中可能存在不同作用。因此，CD151 - α3β1复合物在癌进展中的作用取决于具体情况，并且可能取决于肿瘤细胞侵袭的模式。
