Meier Katharina, Drexler Stefan K, Eberle Franziska C, Lefort Karine, Yazdi Amir S
Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
PLoS One. 2016 Oct 21;11(10):e0164742. doi: 10.1371/journal.pone.0164742. eCollection 2016.
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important adaptor protein for inflammasome activation, mediating the secretion of protumorigenic innate cytokines. However, ASC is also known to trigger apoptosis in tumor cells, acting as a tumor-suppressor gene, which is lost in several human cancers. The aim of this study was to evaluate the clinical significance of ASC in human cutaneous squamous cell carcinoma (SCC). Initially, ASC expression was immunohistochemically evaluated in non-metastic and metastatic SCC. While ASC expression does not correlate with metastatic potential, it correlates with the degree of dedifferentiation. Using methylation specific PCR we were able to demonstrate ASC silencing by promotor specific methylation and impaired inflammasome function in methylated cell lines, linking epigenetic modifications to innate immune activation in keratinocytes. Interestingly, upon ASC restoration by treatment with demethylating agents, we were able to restore AIM2 and NLRP3 activation. In summary, loss of ASC driven tumor development is counterbalanced in the identical cell by the inhibition of pro-tumorigenic inflammation in the tumor cell itself.
含半胱天冬酶募集结构域的凋亡相关斑点样蛋白（ASC）是炎性小体激活的重要衔接蛋白，介导促肿瘤固有细胞因子的分泌。然而，ASC也已知可在肿瘤细胞中触发凋亡，作为一种肿瘤抑制基因，在几种人类癌症中缺失。本研究的目的是评估ASC在人类皮肤鳞状细胞癌（SCC）中的临床意义。最初，通过免疫组织化学评估非转移性和转移性SCC中ASC的表达。虽然ASC表达与转移潜能无关，但与去分化程度相关。使用甲基化特异性PCR，我们能够证明启动子特异性甲基化导致ASC沉默，以及甲基化细胞系中炎性小体功能受损，将表观遗传修饰与角质形成细胞中的固有免疫激活联系起来。有趣的是，在用去甲基化剂处理使ASC恢复后，我们能够恢复AIM2和NLRP3的激活。总之，ASC缺失驱动的肿瘤发展在同一细胞中通过抑制肿瘤细胞自身的促肿瘤炎症而得到平衡。
