| First Author | Rokan A | Year | 2023 |
| Journal | Mol Cancer Res | Volume | 21 |
| Issue | 2 | Pages | 155-169 |
| PubMed ID | 36287175 | Mgi Jnum | J:333992 |
| Mgi Id | MGI:7444761 | Doi | 10.1158/1541-7786.MCR-19-1209 |
| Citation | Rokan A, et al. (2023) Gut-derived Endotoxin-TLR4 Signaling Drives MYC-Ig Translocation to Promote Lymphoproliferation through c-JUN and STAT3 Activation. Mol Cancer Res 21(2):155-169 |
| abstractText | Synergism between obesity and virus infection promotes the development of B-cell lymphoma. In this study, we tested whether obesity-associated endotoxin release induced activation-induced cytidine deaminase (AID). TLR4 activation in turn caused c-JUN-dependent and STAT3-dependent translocations of MYC loci to suppress transactivation of CD95/FAS. We used viral nucleocapside Core transgenic (Tg) mice fed alcohol Western diet to determine whether oncogenesis arising from obesity and chronic virus infection occurred through TLR4-c-JUN-STAT3 pathways. Our results showed B cell-specific, c-Jun and/or Stat3 disruption reduced the incidence of splenomegaly in these mice. AID-dependent t(8;14) translocation was observed between the Ig promoter and MYC loci. Comparison with human B cells showed MYC-immunoglobulin (Ig) translocations after virus infection with lipopolysaccharide stimulation. Accordingly, human patients with lymphoma with virus infections and obesity showed a 40% incidence of MYC-Ig translocations. Thus, obesity and virus infection promote AID-mediated translocation between the Ig promoter and MYC through the TLR4-c-JUN axis, resulting in lymphoproliferation. Taken together, preventative treatment targeting either c-JUN and/or STAT3 may be effective strategies to prevent tumor development. IMPLICATIONS: Obesity increases gut-derived endotoxin which induces Toll-like receptor-mediated MYC-Ig translocation via c-JUN-STAT3, leading to lymphoproliferation. |
