Division of Internal Medicine and Chronobiology Unit, IRCCS Casa Sollievo della Sofferenza, Research Hospital, San Giovanni Rotondo, FG, Italy.
J Cancer Res Clin Oncol. 2012 Mar;138(3):501-11. doi: 10.1007/s00432-011-1126-6. Epub 2011 Dec 24.
Cathepsin and plasmin may favor cancer cell invasion degrading extracellular matrix. Plasmin formation from plasminogen is regulated by plasminogen activator inhibitor type-1 (PAI-1). ARNTL2 activates the promoters of the PAI-1 gene, officially called SERPINE1, driving the circadian variation in circulating PAI-1 levels.
We evaluated ARNTL2 and SERPINE1 expression in 50 colorectal cancer specimens and adjacent normal tissue and in colon cancer cell lines.
We found up-regulation of ARNTL2 (P = 0.004) and SERPINE1 (P = 0.002) in tumor tissue. A statistically significant association was found between high ARNTL2 mRNA levels and vascular invasion (P < 0.0001), and between high SERPINE1 mRNA levels and microsatellite instability (MSI-H and MSI-L, P = 0.025). Sorting the subjects into quartile groups, a statistically significant association was found between high ARNTL2 expression and lymph node involvement (P < 0.001), between high SERPINE1 expression and grading (P < 0.001) and between high SERPINE1 expression and MSI H-L (P < 0.0001). In SW480 cells, a more proliferative model compared to CaCo2 cells, there were higher mRNA levels of ARNTL2 (P < 0.001) and SERPINE1 (P = 0.001).
ARNTL2 and SERPINE1 expression is increased in colorectal cancer and in a highly proliferative colon cancer cell line and is related to tumor invasiveness and aggressiveness.
组织蛋白酶和纤溶酶可能有利于降解细胞外基质的癌细胞侵袭。纤溶酶原向纤溶酶的转化受纤溶酶原激活物抑制剂-1（PAI-1）调节。ARNTL2 激活 PAI-1 基因的启动子，正式称为 SERPINE1，驱动循环 PAI-1 水平的昼夜节律变化。
我们评估了 50 例结直肠癌标本及其相邻正常组织和结肠癌细胞系中 ARNTL2 和 SERPINE1 的表达。
我们发现肿瘤组织中 ARNTL2（P=0.004）和 SERPINE1（P=0.002）的上调。高 ARNTL2 mRNA 水平与血管侵犯之间存在统计学显著相关性（P<0.0001），高 SERPINE1 mRNA 水平与微卫星不稳定性（MSI-H 和 MSI-L，P=0.025）之间存在统计学显著相关性。将受试者分为四分位组，高 ARNTL2 表达与淋巴结受累之间存在统计学显著相关性（P<0.001），高 SERPINE1 表达与分级之间存在统计学显著相关性（P<0.001），高 SERPINE1 表达与 MSI H-L 之间存在统计学显著相关性（P<0.0001）。在 SW480 细胞中，与 CaCo2 细胞相比，该细胞具有更高的增殖能力，ARNTL2（P<0.001）和 SERPINE1（P=0.001）的 mRNA 水平更高。
ARNTL2 和 SERPINE1 的表达在结直肠癌和高增殖性结肠癌细胞系中增加，与肿瘤侵袭性和侵袭性相关。
