The tumorigenesis of colorectal cancer (CRC) is a complicated process, involving interactions between cancer cells and the microenvironment. The role of α5 integrin subunit in CRC remains controversial, and previous studies mainly focused on cancer cells. Herein, we report an important role of α5 in stroma fibroblasts in the tumorigenesis of CRC. The expression of α5 was found to be located in colorectal tumor stroma rather than in epithelia cancer cells. Immunofluorescence colocalization and gene correlation analysis confirmed that α5 was mainly expressed in cancer-associated fibroblasts (CAFs). Moreover, experimental evidence showed that α5 expression was required for the tumor-promoting effect of fibroblast cells. In an in vivo xenograft nude mice model, α5 depletion in fibroblasts dramatically suppressed fibroblast-induced tumor growth. In an in vitro cell coculture assay, α5 depletion or knockdown reduced the ability of fibroblasts to promote cancer cell migration and invasion compared with wild-type fibroblasts; moreover, we observed that the expression and assembly of fibronectin were downregulated after α5 depletion or knockdown in fibroblasts. Analysis of the RNA-Seq data of the Cancer Genome Atlas cohort revealed that high expression of ITGA5 (α5 integrin subunit) was correlated with poor overall survival in colorectal adenocarcinoma, which was further confirmed by immunohistochemistry in an independent cohort of 355 patients. Thus, our study identifies α5 integrin subunit as a novel stroma molecular marker for colorectal adenocarcinoma, offers a fresh insight into colorectal adenocarcinoma progression, and shows that α5 expression in stroma fibroblasts underlies its ability to promote the tumorigenesis of colorectal adenocarcinoma.

中文翻译：

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整联蛋白α5亚基是成纤维细胞在结直肠腺癌中的肿瘤支持作用所必需的，并且它是潜在的基质预后标志物。

大肠癌（CRC）的肿瘤发生是一个复杂的过程，涉及癌细胞与微环境之间的相互作用。α5整合素亚基在CRC中的作用仍存在争议，并且以前的研究主要集中在癌细胞上。在本文中，我们报道了α5在间质成纤维细胞中在CRC的肿瘤发生中的重要作用。发现α5的表达位于结肠直肠肿瘤基质中而不是上皮癌细胞中。免疫荧光共定位和基因相关分析证实，α5主要在癌症相关的成纤维细胞（CAFs）中表达。此外，实验证据表明，α5表达对于成纤维细胞的肿瘤促进作用是必需的。在体内异种移植裸鼠模型中，成纤维细胞中的α5耗竭显着抑制了成纤维细胞诱导的肿瘤生长。在体外细胞共培养实验中，与野生型成纤维细胞相比，α5耗竭或敲低降低了成纤维细胞促进癌细胞迁移和侵袭的能力。此外，我们观察到成纤维细胞中α5耗竭或敲低后纤连蛋白的表达和装配被下调。癌症基因组图集队列的RNA-Seq数据分析表明，ITGA5（α5整联蛋白亚基）的高表达与大肠腺癌的整体生存率差有关，这在355名患者的独立队列中通过免疫组织化学进一步证实。因此，我们的研究将α5整联蛋白亚基鉴定为结直肠腺癌的新型基质分子标记，为结直肠腺癌的进展提供了新的见识，