Cellura D, Pickard K, Quaratino S, Parker H, Strefford J C, Thomas G J, Mitter R, Mirnezami A H, Peake N J
Molecular mechanisms research unit, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD.
Cancer Genomics, Cancer Sciences, University of Southampton, Southampton, SO16 6YD.
Mol Cancer Res. 2015 Jul;13(7):1095-1105. doi: 10.1158/1541-7786.MCR-14-0466. Epub 2015 May 1.
Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome-13 amplification events, leading to altered invasive behavior in colorectal cancer cells.
Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2.
转谷氨酰胺酶2（TG2）是细胞外基质（ECM）和肿瘤微环境（TME）中的一种关键交联酶。尽管其表达与结直肠癌有关，但其在驱动疾病进程中的功能作用似乎取决于具体情况。现在有大量证据表明，微小RNA（miRNA）在癌症的发生和发展，包括转移过程中发挥作用。使用转移性结肠腺癌的细胞模型来研究miRNA对TG2差异表达的贡献，以及对炎症和侵袭行为的功能影响。在人结直肠肿瘤标本中，并通过对SW480和SW620细胞进行操作，分析了TG2在结直肠癌中的作用。使用Transwell侵袭试验测量对侵袭行为的影响，并通过酶联免疫吸附测定（ELISA）评估细胞因子的产生。通过计算机分析确定TG2为miR-19的靶标，并通过实验得到证实。通过在SW480细胞中过表达pre-miR-19a来评估功能影响。TG2的表达与侵袭行为呈负相关，SW480细胞中的敲低导致侵袭增强，而SW620细胞中的过表达则相反。在结直肠癌原发性肿瘤中观察到TG2表达，但在肝转移中消失。最后，miR-19过表达及随后TG2表达降低与13号染色体扩增事件有关，导致结直肠癌细胞侵袭行为改变。
晚期结直肠癌中的13号染色体扩增通过上调靶向TG2的miR-19促进侵袭和转移。
