The focal adhesion protein, Hic-5 plays a key role in promoting extracellular matrix deposition and remodeling by cancer associated fibroblasts within the tumor stroma to promote breast tumor cell invasion. However, whether stromal matrix gene expression is regulated by Hic-5 is still unknown. Utilizing a constitutive Hic-5 knockout, Mouse Mammary Tumor Virus-Polyoma Middle T-Antigen spontaneous breast tumor mouse model, bulk RNAseq analysis was performed on cancer associated fibroblasts isolated from Hic-5 knockout mammary tumors. Functional network analysis highlighted a key role for Hic-5 in extracellular matrix organization, with both structural matrix genes, as well as matrix remodeling genes being differentially expressed in relation to Hic-5 expression. The subcellular distribution of the MRTF-A transcription factor and expression of a subset of MRTF-A responsive genes was also impacted by Hic-5 expression. Additionally, cytokine array analysis of conditioned media from the Hic-5 and Hic-5 knockout cancer associated fibroblasts revealed that Hic-5 is important for the secretion of several key factors that are associated with matrix remodeling, angiogenesis and immune evasion. Together, these data provide further evidence of a central role for Hic-5 expression in cancer associated fibroblasts in regulating the composition and organization of the tumor stroma microenvironment to promote breast tumor progression.

粘着斑蛋白 Hic-5 在促进肿瘤基质内癌症相关成纤维细胞的细胞外基质沉积和重塑以促进乳腺肿瘤细胞侵袭方面发挥着关键作用。然而，基质基质基因表达是否受Hic-5调控仍不清楚。利用组成型 Hic-5 敲除小鼠乳腺肿瘤病毒多瘤中 T 抗原自发性乳腺肿瘤小鼠模型，对从 Hic-5 敲除型乳腺肿瘤中分离出的癌症相关成纤维细胞进行批量RNAseq分析。功能网络分析强调了 Hic-5 在细胞外基质组织中的关键作用，结构基质基因以及基质重塑基因的表达与 Hic-5 表达相关。MRTF-A 转录因子的亚细胞分布和 MRTF-A 响应基因子集的表达也受到 Hic-5 表达的影响。此外，对来自 Hic-5 和 Hic-5 敲除癌症相关成纤维细胞的条件培养基进行细胞因子阵列分析表明，Hic-5 对于与基质重塑、血管生成和免疫逃避相关的几个关键因子的分泌非常重要。总之，这些数据进一步证明了癌症相关成纤维细胞中 Hic-5 表达在调节肿瘤基质微环境的组成和组织以促进乳腺肿瘤进展中的核心作用。