Colorectal cancer (CRC) is the most common cancer and a leading cause of death worldwide. Extracellular matrix (ECM) proteins regulate tumor growth and development in CRC. Elastin (ELN) is a component of ECM proteins involved in the tumor microenvironment. However, the role of ELN in CRC remains unclear. In this study, we analyzed ELN gene expression in tumors from CRC patients and adjacent non-tumor colon tissues and healthy controls from two existing microarray datasets. ELN protein was measured in human normal colon cells and colon cancer epithelial cells and tumor development was assessed in colon epithelial cells cultured in medium with or without ELN peptide on plates coated with ELN recombinant protein. Control plates were coated with PBS only. We found ELN gene expression was increased in tumors from CRC patients compared to adjacent non-tumor tissues and healthy controls. ELN protein was increased in cancer cells compared to normal colon epithelial cells. Transforming growth factor beta (TGF-β) was a key cytokine to induce production of ECM proteins, but it did not induce ELN expression in colon cancer cells. Matrix metalloproteinase 9 (MMP9) gene expression was increased, but that of MMP12 (elastase) did not change between CRC patients and control. Tissue inhibitor of metalloproteinases 3 (TIMP3) gene expression was decreased in colon tissues from CRC patients compared to healthy controls. However, MMP9, MMP12 and TIMP3 proteins were increased in colon cancer cells. ELN recombinant protein increased proliferation and wound healing in colon cancer epithelial cells. This had further increased in cancer cells incubated in plates coated with recombinant ELN coated plate and in culture media containing ELN peptide. A potential mechanism was that ELN induced epithelial mesenchymal transition with increased alpha-smooth muscle actin and vimentin proteins but decreased E-cadherin protein. Tumor necrosis factor alpha (TNF) mRNA was also increased in CRC patients compared to controls. ELN recombinant protein induced further increases in TNF protein in mouse bone marrow derived macrophages after lipopolysaccharide stimulation. These data suggest ELN regulates tumor development and the microenvironment in CRC.

中文翻译：

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弹性蛋白是大肠癌肿瘤发展的关键因素

大肠癌（CRC）是世界上最常见的癌症和主要死因。细胞外基质（ECM）蛋白调节CRC中的肿瘤生长和发育。弹性蛋白（ELN）是参与肿瘤微环境的ECM蛋白的组成部分。但是，ELN在CRC中的作用仍不清楚。在这项研究中，我们分析了来自两个现有微阵列数据集的CRC患者和邻近的非肿瘤结肠组织的肿瘤以及健康对照中的ELN基因表达。在人正常结肠细胞和结肠癌上皮细胞中测量ELN蛋白，并在用ELN重组蛋白包被的板上在含有或不含ELN肽的培养基中培养的结肠上皮细胞中评估肿瘤的发展。对照板仅用PBS包被。我们发现，与邻近的非肿瘤组织和健康对照组相比，CRC患者的肿瘤中ELN基因表达增加。与正常结肠上皮细胞相比，癌细胞中的ELN蛋白增加。转化生长因子β（TGF-β）是诱导ECM蛋白产生的关键细胞因子，但它并未诱导结肠癌细胞中的ELN表达。CRC患者和对照组的基质金属蛋白酶9（MMP9）基因表达增加，但MMP12（弹性蛋白酶）基因表达不变。与健康对照组相比，CRC患者结肠组织中金属蛋白酶3（TIMP3）基因的组织表达降低。但是，结肠癌细胞中的MMP9，MMP12和TIMP3蛋白增加。ELN重组蛋白可增强结肠癌上皮细胞的增殖和伤口愈合。在用重组ELN包被的板包被的板和含有ELN肽的培养基中孵育的癌细胞中，这进一步增加。潜在的机制是ELN诱导上皮间质转化，其中α-平滑肌肌动蛋白和波形蛋白增加，而E-钙粘蛋白减少。与对照组相比，CRC患者的肿瘤坏死因子α（TNF）mRNA也增加。脂多糖刺激后，ELN重组蛋白诱导小鼠骨髓衍生的巨噬细胞中TNF蛋白进一步增加。这些数据表明ELN调节CRC中的肿瘤发展和微环境。潜在的机制是ELN诱导上皮间质转化，其中α-平滑肌肌动蛋白和波形蛋白增加，而E-钙粘蛋白减少。与对照组相比，CRC患者的肿瘤坏死因子α（TNF）mRNA也增加。脂多糖刺激后，ELN重组蛋白诱导小鼠骨髓衍生的巨噬细胞中TNF蛋白进一步增加。这些数据表明ELN调节CRC中的肿瘤发展和微环境。潜在的机制是ELN诱导上皮间质转化，其中α-平滑肌肌动蛋白和波形蛋白增加，而E-钙粘蛋白减少。与对照组相比，CRC患者的肿瘤坏死因子α（TNF）mRNA也增加。脂多糖刺激后，ELN重组蛋白诱导小鼠骨髓衍生的巨噬细胞中TNF蛋白进一步增加。这些数据表明ELN调节CRC中的肿瘤发展和微环境。