Center for Functional Nanostructures, Karlsruher Institut für Technologie (KIT), Wolfgang-Gaede-Strasse 1a, 76131, Karlsruhe, Germany.
Center for Functional Nanostructures, Karlsruher Institut für Technologie (KIT), Wolfgang-Gaede-Strasse 1a, 76131, Karlsruhe, Germany; WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Micron. 2021 Sep;148:103106. doi: 10.1016/j.micron.2021.103106. Epub 2021 Jun 19.
Integrin αβ is a widely expressed collagen I receptor which also mediates laminin-111 binding in some cell types, but the functional relevance of collagen versus laminin binding for different cell types is poorly understood. Here we use AFM-based singe-cell force spectroscopy (SCFS) to compare αβ-mediated adhesion strength to collagen and laminin in different cell types. Chinese Hamster Ovary (CHO) cells stably expressing integrin αβ (CHO-A2) displayed enhanced adhesion to collagen, but weak adhesion to laminin, consistent with a role of αβ as a receptor only for collagen in these cells. Inversely, the αβ-deficient CHO wildtype cells (CHO-WT) showed weak adhesion to collagen, but strong adhesion to laminin-111, in turn suggesting that integrin αβ expression suppresses laminin binding. Analogous results were obtained in a pair of SAOS-2 human osteosarcoma cell lines. Again, wildtype cells (SAOS-WT) adhered strongly to laminin and poorly to collagen, while expression of integrin αβ (SAOS-A2) induced strong adhesion to collagen, but reduced adhesion to laminin. Expression of αβ also shifted cell spreading preference from laminin to collagen and suppressed laminin-dependent transmigration. In agreement with reduced laminin adhesion, αβ expression downregulated transcription and expression of integrin subunits α and β, components of the main laminin-111 binding receptors integrin αβ and αβ in these cells. Integrin α and β expression was also reduced when α expression was chemically induced using tetradecanoyl-phorbol-acetate (TPA). Our results thus show that integrin αβ expression negatively regulates integrin αβ and αβ-mediated adhesion, spreading and invasion on laminin in different cancer cell types. In contrast to SAOS-WT, but similar to SAOS-A2 osteosarcoma cells, primary Human osteoblasts (HOB) cells express α but only low levels of β integrin, preferentially adhere to and spread on collagen over laminin and show suppressed laminin-dependent transmigration. By enhancing collagen binding directly and suppressing laminin binding indirectly through laminin receptor downregulation, αβ expression may thus re-direct migrating cancer cells from laminin-rich to collagenous tissues and partially revert osteosarcoma cells towards an untransformed phenotype.
整合素 αβ 是一种广泛表达的 I 型胶原受体，在某些细胞类型中也介导层粘连蛋白-111 的结合，但不同细胞类型对胶原与层粘连蛋白结合的功能相关性知之甚少。在这里，我们使用基于原子力显微镜的单细胞力谱学（SCFS）比较不同细胞类型中整合素 αβ 介导的对胶原和层粘连蛋白的粘附强度。稳定表达整合素 αβ 的中国仓鼠卵巢（CHO）细胞（CHO-A2）对胶原的粘附增强，但对层粘连蛋白的粘附较弱，这与 αβ 作为这些细胞中胶原受体的作用一致。相反，整合素 αβ 缺失的 CHO 野生型细胞（CHO-WT）对胶原的粘附较弱，但对层粘连蛋白-111 的粘附较强，这反过来表明整合素 αβ 的表达抑制了层粘连蛋白的结合。在一对 SAOS-2 人骨肉瘤细胞系中也得到了类似的结果。同样，野生型细胞（SAOS-WT）强烈粘附于层粘连蛋白，而对胶原的粘附较弱，而整合素 αβ 的表达（SAOS-A2）诱导对胶原的强烈粘附，但减少了对层粘连蛋白的粘附。αβ 的表达还将细胞铺展偏好从层粘连蛋白转移到胶原，并抑制了层粘连蛋白依赖的迁移。与层粘连蛋白粘附减少一致，αβ 的表达下调了这些细胞中主要的层粘连蛋白-111 结合受体整合素 αβ 和 αβ 的整合素亚基 α 和 β 的转录和表达。使用十四烷酰佛波醇-13-乙酸酯（TPA）化学诱导 α 表达时，α 和 β 表达也减少。因此，我们的结果表明，整合素 αβ 的表达负调节不同癌症细胞类型中整合素 αβ 和 αβ 介导的对层粘连蛋白的粘附、铺展和侵袭。与 SAOS-WT 不同，但与 SAOS-A2 骨肉瘤细胞相似，原代人成骨细胞（HOB）细胞表达 α，但仅表达低水平的 β 整合素，优先粘附于胶原，而非层粘连蛋白，在胶原上的铺展优于层粘连蛋白，并显示抑制层粘连蛋白依赖的迁移。通过直接增强胶原结合并通过下调层粘连蛋白受体间接抑制层粘连蛋白结合，αβ 的表达可能会使迁移的癌细胞从富含层粘连蛋白的组织重新定向到富含胶原的组织，并使骨肉瘤细胞部分恢复到未转化的表型。
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