Aberrant expression of AID and AID activators of NF-κB and PAX5 is irrelevant to EBV-associated gastric cancers, but is associated with carcinogenesis in certain EBV-non-associated gastric cancers

Abstract

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric cancer characterized by clinicopathological features including lymphoepithelioma-like histology. Aberrant expression of activation-induced cytidine deaminase (AID) as a genomic modulator was demonstrated through pathogen-related nuclear factor κB (NF-κB) signaling in Helicobacter pylori-associated gastric cancer. To elucidate whether or not AID expression is relevant to carcinogenesis in EBVaGC, immunohistochemical expression of AID and AID-regulatory factors between EBVaGC and EBV-non-associated gastric carcinoma (GC) were evaluated, each using 15 cases of GC with lymphoid stroma (GCLS) and other types of GC. Aberrant expression of AID, NF-κB and paired box 5 (PAX5) were significantly decreased in EBVaGC (0/11, 1/11 and 1/11) compared with in EBV-non-associated GC (7/19, 12/19 and 11/19) (P=0.025, 0.005 and 0.01, respectively); however, no significant difference in c-Myb proto-oncogene expression was identified. AID expression was also decreased in EBV-associated GCLS (0/10) compared with in EBV-non-associated GCLS (3/5). Unexpectedly, decreased expression of NF-κB and PAX5 was observed in GCLS (1/15 and 2/15) compared with in GC without LS (12/15 and 10/15) (P<0.001 and P=0.003, respectively). Decreased AID expression observed in EBVaGC is consistent with the reported molecular characterization of hypermethylation and rare somatic gene mutation in EBVaGC. Only PAX5 was identified to be significantly associated with venous invasion (P=0.022). The results of the present study suggest that pathogen-induced AID expression may be irrelevant to carcinogenesis of EBVaGC, whereas it contributes to carcinogenesis in certain types of EBV-non-associated GC.

The off-target effects of AID in carcinogenesis

“…Chronic inflammation is a well-known risk factor for cancer, with the continual production of pro-inflammatory cytokines being thought to contribute to the development of tumors (46). Recent studies have shown that tumor necrosis factor a (TNFa) triggers abnormal AID expression via nuclear factor-kB (NF-kB) in certain inflammation-related cancers such as helicobacter pylori-associated gastric cancer and colitis-associated colon cancers (34,47,48). Human cancers have been found with ectopic AID expression, and mutations in exons of genes related to tumors, such as TP53, have been observed in such cases (49).…”

Unifying Different Cancer Theories in a Unique Tumour Model: Chronic Inflammation and Deaminases as Meeting Points

“…In fact, it has been noted that both the TNFα pro-inflammatory factor and NFKβ pro-inflammatory signalling promoted AID upregulation [ 11 ]. Moreover, the dysregulation of AID has been documented to play a relevant role in the progression of lymphoid carcinomas, such as Burkitt’s B-cell lymphoma [ 6 ], and non-lymphoid malignancies, such as gastric cancer [ 21 ], colorectal cancer [ 22 ], and cholangiocarcinoma [ 11 ]. In the same regard, a close relationship between inflammatory-related cytokines, such as IFN, TNFα, IL1, and IL6, and APOBEC3s subfamily member expressions have been shown [ 12 ].…”

Evolutionary Comparative Analyses of DNA-Editing Enzymes of the Immune System: From 5-Dimensional Description of Protein Structures to Immunological Insights and Applications to Protein Engineering

“…AID-induced hypermutations have also been observed in chronic lymphoid leukemia (CLL) (92). There has also been evidence of AIDmediated carcinogenesis in germinal center (GC) B cells as the result of Epstein-Barr virus (EBV)-induced AID expression (93). Interestingly, under strong inflammatory stimuli, the premature expression of AID during B cell development creates an opportunity for cooperation between RAG and AID to drive the clonal evolution of childhood B cell acute lymphoblastic leukemia (B-ALL) (94).…”