Longmate Whitney M, Miskin Rakshitha Pandulal, Van De Water Livingston, DiPersio C Michael
Department of Surgery, Albany Medical College, Albany, New York, USA.
The Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, New York, USA.
JID Innov. 2021 Apr 30;1(2):100017. doi: 10.1016/j.xjidi.2021.100017. eCollection 2021 Jun.
As the major cell surface receptors for the extracellular matrix, integrins regulate adhesion and migration and have been shown to drive tumor growth and progression. Previous studies showed that mice lacking integrin α3β1 in the epidermis fail to form skin tumors during two-step chemical tumorigenesis, indicating a protumorigenic role for α3β1. Furthermore, genetic ablation of α3β1 in established skin tumors caused their rapid regression, indicating an essential role in the maintenance of tumor growth. In this study, analysis of immortalized keratinocyte lines and their conditioned media support a role for α3β1 in regulating the expression of several extracellular proteases of the keratinocyte secretome, namely BMP-1, matrix metalloprotease (MMP)-9, and MMP-3. Moreover, immunofluorescence revealed reduced levels of each protease in α3β1-deficient tumors, and RNA in situ hybridization showed that their expression was correspondingly reduced in α3β1-deficient tumor cells in vivo. Bioinformatic analysis confirmed that the expression of , , and genes correlate with the expression of (gene encoding the integrin α3 subunit) in human squamous cell carcinoma and that high and associate with poor survival outcome in these patients. Overall, our findings identify α3β1 as a regulator of several proteases within the secretome of epidermal tumors and as a potential therapeutic target.
作为细胞外基质的主要细胞表面受体，整合素调节细胞黏附和迁移，并已被证明可驱动肿瘤生长和进展。先前的研究表明，表皮中缺乏整合素α3β1的小鼠在两步化学致癌过程中无法形成皮肤肿瘤，这表明α3β1具有促肿瘤作用。此外，在已形成的皮肤肿瘤中对α3β1进行基因敲除会导致肿瘤迅速消退，这表明其在维持肿瘤生长中起着至关重要的作用。在本研究中，对永生化角质形成细胞系及其条件培养基的分析支持α3β1在调节角质形成细胞分泌组中几种细胞外蛋白酶（即骨形态发生蛋白-1（BMP-1）、基质金属蛋白酶（MMP）-9和MMP-3）的表达方面发挥作用。此外，免疫荧光显示α3β1缺陷型肿瘤中每种蛋白酶的水平降低，RNA原位杂交表明它们在体内α3β1缺陷型肿瘤细胞中的表达相应降低。生物信息学分析证实，在人类鳞状细胞癌中，BMP-1、MMP-9和MMP-3基因的表达与整合素α3亚基编码基因（ITGA3）的表达相关，并且在这些患者中，高BMP-1和MMP-9与不良生存结果相关。总体而言，我们的研究结果确定α3β1是表皮肿瘤分泌组中几种蛋白酶的调节因子，也是一个潜在的治疗靶点。
