School of Health Science, DHEAR, Translational Medicine, University of Skövde, Skövde, Sweden.
Systems Biology Research Centre, School of Bioscience, University of Skövde, Skövde, Sweden.
J Cancer Res Clin Oncol. 2022 Sep;148(9):2295-2311. doi: 10.1007/s00432-022-04029-7. Epub 2022 May 2.
Loss of expression of DLG2 has been identified in a number of cancers to contribute to the disease by resulting in increased tumor cell proliferation and poor survival. In light of the previous evidence that DLG2 alters the cell cycle and affects proliferation, combined with indications that DLG2 is involved in NLRP3 inflammasome axis we speculated that DLG2 has an immune function. So far, there is no data that clearly elucidates this role, and this study was designed to investigate DLG2 in inflammatory colon disease and in colon cancer as well as its impact on inflammasome induction.
The DLG2 expression levels were established in publicly available inflammation, colon cancer and mouse model datasets. The overexpression and silencing of DLG2 in colon cancer cells were used to determine the effect of DLG2 expression on the activation of the inflammasome and subsequent cytokine release.
The expression of DLG2 is repressed in inflammatory colon diseases IBD and Ulcerative colitis as well as colorectal cancer tissue compared to healthy individuals. We subsequently show that induction with inflammatory agents in cell and animal models results in a biphasic alteration of DLG2 with an initial increase followed by an ensuing decrease. DLG2 overexpression leads to a significant increase in expression of IL1B, IκBζ and BAX, components that result in inflammasome formation. DLG2 silencing in THP1 cells resulted in increased release of IL-6 into the microenvironment which once used to treat bystander COLO205 cells resulted in an increase in STAT3 phosphorylation and an increase proliferating cells and more cells in the G2/M phase. Restoration of DLG2 to the colon resulted in reduced AKT and S6 signaling.
DLG2 expression is altered in response to inflammation in the gut as well as colon cancer, resulting in altered ability to form inflammasomes.
NCT03072641.
在许多癌症中，DLG2 的表达缺失被认为是导致肿瘤细胞增殖增加和生存不良的原因，从而促进了疾病的发生。鉴于先前的证据表明 DLG2 改变细胞周期并影响增殖，并且表明 DLG2 参与 NLRP3 炎性小体轴，我们推测 DLG2 具有免疫功能。到目前为止，尚无明确阐明这一作用的数据，本研究旨在研究 DLG2 在炎症性结肠疾病和结肠癌中的作用及其对炎性小体诱导的影响。
在公开的炎症、结肠癌和小鼠模型数据集中确定了 DLG2 的表达水平。在结肠癌细胞中过表达和沉默 DLG2，以确定 DLG2 表达对炎性小体激活和随后细胞因子释放的影响。
与健康个体相比，DLG2 在炎症性结肠疾病 IBD 和溃疡性结肠炎以及结直肠癌组织中的表达受到抑制。随后我们表明，在细胞和动物模型中用炎症剂诱导会导致 DLG2 发生双相变化，最初增加，随后减少。DLG2 过表达导致 IL1B、IκBζ 和 BAX 的表达显著增加，这些成分导致炎性小体的形成。THP1 细胞中的 DLG2 沉默导致细胞因子 IL-6 释放到微环境中增加，一旦用于治疗旁观者 COLO205 细胞，就会导致 STAT3 磷酸化增加，增殖细胞增加，G2/M 期细胞增加。将 DLG2 恢复到结肠中会降低 AKT 和 S6 信号。
DLG2 的表达在肠道炎症和结肠癌中发生改变，导致形成炎性小体的能力改变。
NCT03072641。
