Human EVI2B acts as a Janus-faced oncogene/antioncogene by differently affecting as per cancer type neoplastic cells growth and immune infiltration
Human EVI2B acts as a Janus-faced oncogene/antioncogene by differently affecting as per cancer type neoplastic cells growth and immune infiltration
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DOI：
10.1515/oncologie-2022-1002
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发表时间：
2023-03
期刊：
影响因子：
0.9
通讯作者：
F. Zhang;Xinning Wang;Xiao-qi Zhang;Saquib Waheed;R. Zhong;U. Armato;Jun Wu;A. Chiarini;I. D. Prà;Chao Zhang;Zhibin Li
中科院分区：
文献类型：
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作者：
F. Zhang;Xinning Wang;Xiao-qi Zhang;Saquib Waheed;R. Zhong;U. Armato;Jun Wu;A. Chiarini;I. D. Prà;Chao Zhang;Zhibin Li
摘要目的EVI2B基因编码一种在免疫细胞成熟过程中起关键作用的跨膜糖蛋白。最近的证据表明，EV12B的表达与人类结肠癌的进展有关。然而，EVI2B影响肿瘤生长和肿瘤浸润性细胞的下游途径仍不清楚。方法我们首先利用一系列电子计算机工具和临床标本研究EVI2B在泛癌中的诊断和预后价值。然后，我们鉴定了同一三种肿瘤中EVI2B高表达组的转录调控表达和DNA甲基化。我们通过RT-PCR验证了稳定的EVI2B基因敲除对两种免疫细胞系JAK/STAT相关基因表达的影响，以及对四种肿瘤细胞系增殖的促进作用。最后，用定时器研究了白细胞渗入的调节。结果在SKCM和LUAD中，EVI2B的高表达有助于改善预后。相反，在IGG中，EVI2B的上调与更差的预后一致。EVI2B沉默可促进肿瘤细胞的增殖。高甲基化的基因组增强了EVI2B在高表达SKCM和LUAD肿瘤中的Janus-like效应。而EVI2B高表达LGG的细胞总DNA甲基化水平较低。进一步分析发现，多个EVI2B参与下游的JAK-STAT基因在SKCM、LUAD和LGG进展中也显示出Janus样特征。相应地，抗肿瘤白细胞在EVI2B中高表达SKCM和LUAD，而更多的亲肿瘤白细胞渗入EVI2B则使LGG升高。结论EVI2B通过不同程度地影响肿瘤细胞的增殖率和促癌或抑癌免疫细胞的侵袭，发挥着Janus-Face癌基因/抑癌基因的作用。
Abstract Objectives The EVI2B (Ecotropic Viral Integration Site 2B) gene encodes a transmembrane glycoprotein pivotal in immunocytes maturation. Recent evidence implicated EV12B’s expression with human colon cancer progression. However, EVI2B’s downstream pathways affecting tumor growth and tumor-infiltrating cells remain unclear. Methods We first studied the diagnostic and prognostic value of EVI2B in pan-cancers by utilizing a series of in silico tools and clinical samples. Then we identified the modulated transcriptional expression and DNA methylation in high EVI2B’s expression groups of the same three cancers. We verified via RT-PCR the effect of stable EVI2B knock-down on the expression of JAK/STAT-related genes in two immune cell lines and the acceleration of proliferation in four cancer cell lines. Finally, the regulation of leukocyte infiltration was studied using TIMER. Results In SKCM and LUAD a heightened EVI2B’s expression promoted a better prognosis. Conversely, in LGG EVI2B’s upregulation concurred with a worse prognosis. EVI2B silencing enhanced the proliferation of the tumor cell lines. The hypermethylated genome strengthened EVI2B’s Janus-like effect in high EVI2B expressing SKCM and LUAD tumors. While the total DNA methylation was lower in high EVI2B expressing LGG. Further analysis revealed that multiple EVI2B-involved down-stream JAK-STAT genes also exhibited the Janus-like feature in SKCM, LUAD and LGG progression. Correspondingly, anti-tumor leukocytes infiltrated EVI2B high expressing SKCM and LUAD while more pro-tumor ones penetrated into EVI2B heightened LGG. Conclusions EVI2B acts as a Janus-faced oncogene/antioncogene by differently affecting neoplastic cell proliferation rates and tumor-promoting or tumor-hindering immunocytes’ infiltration.