Abstract 4735: Oncogenic involvement of NF-kB signaling pathway in glioma

Abstract

Abstract Introduction: Aberrant activity of NF-kB has been observed across several cancer types. The current understanding is that the constitutive activation of NF-kB enhances the expression of genes that promote cell proliferation as well as prevent cells from apoptosis. Previous studies have shown that, compared with other cancer types, glioma appears with much significant over-expression of NF-kB. This implies that glioma may be a better subject to elucidate the activity of NF-kB during tumorigenesis. Here we present an analysis aiming to characterize the oncogenic involvement of NF-kB in glioma. Method: We retrieved RNA-Seq expression data of glioblastoma (GBM), low-grade glioma (LGG) as well as other seven major cancer types from TCGA repository. In addition, we collected a total number of 120 tumor samples comprising of 80 GBM and 40 LGG. RNA-Seq experiment was carried out according to standard protocol. Data quality was assessed at multiple steps. In correlation analysis, a number of oncogenic and immune genes / pathways were empirically pre-defined. Pearson coefficient was measured. Expression enrichment analysis was performed using either GSEA or ssGSEA. Immune cell infiltration was assessed using ESTIMATE. Results and conclusion: Pan-cancer analysis shown that, compared with peripheral non-tumor tissue, all five NF-kB member genes, NFKB1, NFKB2, REL, RELA and RELB, are significantly up-regulated in tumor tissue of GBM and LGG, but not in other cancer types. Except previously reported association with EGFR mutation, we also observed that TP53 mutation significantly correlates with over-expression of NF-kB in LGG. CDKN2A and CDKN2B deletion moderately correlate with over-expression of NFKB1,RELB and REL. In addition, RAS and ERBB signaling pathway positively correlates with NF-kB pathway in both GBM and LGG. This is consistent with established cross-talk between these genes. WNT signaling pathway positively correlates with NF-kB in GBM while negatively correlates with NF-kB in LGG. NF-kB regulates WNT signaling through LZTS2 under specific physiological conditions. Our results shown that LZTS2 is up-regulated in LGG while down-regulated in GBM suggesting that NF-kB regulates WNT through LZTS2 in a bidirectional manner. In regulating immune environment, NF-kB expression positively correlates with major immune infiltrates as well as cytokines responsible for modulating the penetrance of blood-brain barrier (BBB), indicating that NF-kB recruit immune cells in response to stimuli in brain despite the existence of BBB. In sum, NF-kB seems to impose rather similar impact on glioma as on other non-CNS solid tumor, i.e. recruitment of immune infiltrates. On the other hand, NF-kB behaves differently in regulating WNT signaling pathway in GBM and LGG. How differential activation of WNT signaling eventually contributes to phenotypical difference between GBM and LGG is to be investigated in further studies Citation Format: Cheng Yan, Lan Su, Xin Qi, Yufei Yang, Jun Wu. Oncogenic involvement of NF-kB signaling pathway in glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4735.