新型癌睾抗原PRSS56通过激活PI3K/AKT轴促进结直肠癌和胃癌恶性进展

A Novel Oncotestis Antigen PRSS56 Promotes Malignant Progression of Colorectal and Gastric Cancer by Activating the PI3K/AKT Pathway

目的:肿瘤-睾丸(cancer-testis,CT)基因通常在癌症中过度表达,并表现出高免疫原性,使其成为免疫治疗和癌症疫苗的潜在靶点。丝氨酸蛋白酶PRSS56在癌症中的作用迄今仍不清楚。方法:RNA测序(RNA sequencing,RNA-seq)研究筛选暴露于DNA甲基转移酶(DNA methyltransferase,DNMT)抑制剂5-AZA-CdR的胃癌(gastric cancer,GC)和结直肠癌(colorectal cancer,CRC)细胞的CT基因。通过功能实验探讨PRSS56在胃癌和结直肠癌中的生物学功能。结果:睾丸特异性丝氨酸蛋白酶PRSS56被证实是一种新的CT抗原。PRSS56在多种癌症中过表达,尤其是胃肠道癌。PRSS56的表达与启动子DNA甲基化水平呈负相关,与基因体甲基化水平呈正相关。暴露于DNMT抑制剂的结直肠癌和胃癌细胞中PRSS56的表达显著激活。此外,我们的发现强调了PRSS56启动子区CpG位点cg10242318甲基化水平的降低导致其在GC和CRC中过表达。功能分析证实PRSS56过表达激活了GC和CRC中的PI3K/AKT信号通路。结论:丝氨酸蛋白酶PRSS56是一种新型的CT抗原,在胃肠癌中被DNA低甲基化再激活。PRSS56过表达通过激活PI3K/AKT轴在GC和CRC中发挥致癌作用。值得一提的是,此项研究首次报道了丝氨酸蛋白酶PRSS56在胃肠肿瘤中的促癌作用。

Objective Cancer-testis(CT)genes are often overexpressed in cancer and exhibit high immunogenicity,making them potential targets for immunotherapy and cancer vaccines.The role of the serine protease PRSS56 in cancer has so far remained unclear.Methods RNA sequencing(RNA seq)study screened CT genes in gastric cancer(GC)and colorectal cancer(CRC)cells exposed to DNA methyltransferase(DNMT)inhibitor 5-AZA-CdR.The biological function of PRSS56 in gastric and colorectal cancer was explored through functional experiments.Results The testis-specific serine protease PRSS56 was confirmed as a novel CT antigen.PRSS56 is overexpressed in various cancers,especially gastrointestinal cancers.The expression of PRSS56 was negatively correlated with promoter DNA methylation level and positively correlated with gene body methylation level.Expression of PRSS56 was significantly activated in colorectal and gastric cancer cells exposed to DNMT inhibitors.Furthermore,our findings highlighted that the reduced methylation level of cg10242318 at the CpG site in the PRSS56 promoter region led to its overexpression in GC and CRC.Functional analysis confirmed that PRSS56 overexpression activated the PI3K/AKT signaling pathway in GC and CRC.Conclusion The serine protease PRSS56 is a novel CT antigen that is reactivated by DNA hypomethylation in gastrointestinal cancer.PRSS56 overexpression plays an oncogenic role in GC and CRC through activation of PI3K/AKT axis.It is worth mentioning that this study is the first to report the tumor-promoting effect of serine protease PRSS56 in gastrointestinal tumors.