School of Nursing, Bengbu Medical College, Bengbu, Anhui, China.
Faculty of Health, University of Technology Sydney, Ultimo, New South Wales, Australia.
BMC Cancer. 2020 Mar 14;20(1):217. doi: 10.1186/s12885-020-6686-x.
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.
结直肠癌（CRC）是最常见的癌症，也是全球范围内主要的死亡原因。细胞外基质（ECM）蛋白调节 CRC 中的肿瘤生长和发展。弹性蛋白（ELN）是 ECM 蛋白的组成部分，参与肿瘤微环境。然而，ELN 在 CRC 中的作用尚不清楚。
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 患者肿瘤和相邻非肿瘤结肠组织以及健康对照者的 ELN 基因表达。在人正常结肠细胞和结肠癌细胞中测量了 ELN 蛋白，并在涂有 ELN 重组蛋白的平板上用或不用 ELN 肽的培养基培养结肠上皮细胞，评估肿瘤的发展。对照平板仅涂有 PBS。
我们发现 CRC 患者的肿瘤中 ELN 基因表达高于相邻非肿瘤组织和健康对照者。与正常结肠上皮细胞相比，癌症细胞中 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，但它不会诱导结肠癌细胞中 ELN 的表达。基质金属蛋白酶 9（MMP9）基因表达增加，但 MMP12（弹性蛋白酶）在 CRC 患者和对照者之间没有变化。与健康对照者相比，CRC 患者结肠组织中的组织金属蛋白酶抑制剂 3（TIMP3）基因表达降低。然而，MMP9、MMP12 和 TIMP3 蛋白在结肠癌细胞中增加。ELN 重组蛋白增加了结肠癌细胞的增殖和伤口愈合。在涂有重组 ELN 涂层平板的平板和含有 ELN 肽的培养基中孵育的癌细胞中，这一作用进一步增强。一种潜在的机制是 ELN 通过增加α-平滑肌肌动蛋白和波形蛋白蛋白但减少 E-钙粘蛋白蛋白诱导上皮间质转化。与对照组相比，肿瘤坏死因子-α（TNF）mRNA 在 CRC 患者中也增加。ELN 重组蛋白在脂多糖刺激后进一步增加了来自小鼠骨髓来源的巨噬细胞中的 TNF 蛋白。
这些数据表明，ELN 调节 CRC 中的肿瘤发展和微环境。
