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| Home > Publications database > SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis. |
| Home > Publications database > SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis. |
| Journal Article | DKFZ-2023-00560 |
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2023
Biomed Central
London
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Please use a persistent id in citations: doi: DOI: 10.1186/s12943-023-01734-w doi:10.1186/s12943-023-01734-w doi:DOI: 10.1186/s12943-023-01734-w
Abstract: Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and the consequences on disease aggressiveness are insufficiently understood.Data of 27 tumor entities (about 5000 samples) were downloaded from the TCGA and GEO databases. Multi-omic analyses were performed on these and in-house data to investigate molecular determinants of tumor aggressiveness. Using molecular loss-of-function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness were addressed. Patient specimens and in vivo disease models were subsequently used to validate findings.There was significant association between somatic copy number alterations (sCNAs) and tumor aggressiveness. SOX2 amplification was the most important feature among novel and known aggressiveness-associated alterations. Mechanistically, SOX2 regulates a group of genes, in particular the AP1 transcription factor FOSL2, to sustain pro-inflammatory signaling pathways, such as IL6-JAK-STAT3, TNFA and IL17. FOSL2 was found overexpressed in tumor sections of specifically aggressive cancers. In consequence, prolonged inflammation induces immunosuppression and activates cytidine deamination and thus DNA damage as evidenced by related mutational signatures in aggressive tumors. The DNA damage affects tumor suppressor genes such as TP53, which is the most mutated gene in aggressive tumors compared to less aggressive ones (38% vs 14%), thereby releasing cell cycle control. These results were confirmed by analyzing tissues from various tumor types and in vivo studies.Our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.
Keyword(s): FOSL2 ; Gene expression ; IL6 ; Inflammation ; Mutational signatures ; SOX2 ; Somatic copy number alterations ; Tumor aggressiveness
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