RESUMEN
High fat diet is implicated in the elevated deoxycholic acid (DCA) in the intestine and correlated with increased colon cancer risk. However, the potential mechanisms of intestinal carcinogenesis by DCA remain unclarified. Here, we investigated the carcinogenic effects and mechanisms of DCA using the intestinal tumour cells and Apcmin/+ mice model. We found that DCA could activate epidermal growth factor receptor (EGFR) and promote the release of EGFR ligand amphiregulin (AREG), but not HB-EGF or TGF-α in intestinal tumour cells. Moreover, ADAM-17 was required in DCA-induced promotion of shedding of AREG and activation of EGFR/Akt signalling pathway. DCA significantly increased the multiplicity of intestinal tumours and accelerated adenoma-carcinoma sequence in Apcmin/+ mice. ADAM-17/EGFR signalling axis was also activated in intestinal tumours of DCA-treated Apcmin/+ mice, whereas no significant change occurred in tumour adjacent tissues after DCA exposure. Conclusively, DCA activated EGFR and promoted intestinal carcinogenesis by ADAM17-dependent ligand release.
Asunto(s)
Proteína ADAM17/genética , Adenoma/genética , Anfirregulina/genética , Ácido Desoxicólico/administración & dosificación , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Intestinales/genética , Proteína ADAM17/metabolismo , Adenoma/inducido químicamente , Adenoma/metabolismo , Adenoma/patología , Proteína de la Poliposis Adenomatosa del Colon/deficiencia , Proteína de la Poliposis Adenomatosa del Colon/genética , Anfirregulina/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Células Epiteliales/metabolismo , Células Epiteliales/patología , Receptores ErbB/metabolismo , Células HCT116 , Humanos , Neoplasias Intestinales/inducido químicamente , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
The gut microbiota plays an important role in maintaining intestinal homeostasis. Dysbiosis is associated with intestinal tumorigenesis. Deoxycholic acid (DCA), a secondary bile acid increased by a western diet, correlates with intestinal carcinogenesis. However, evidence relating bile acids, intestinal microbiota and tumorigenesis are limited. In our study, we investigated the effect of DCA on induction of intestinal dysbiosis and its roles in intestinal carcinogenesis. Alteration of the composition of the intestinal microbiota was induced in DCA-treated APCmin/+ mice, which was accompanied by impaired intestinal barrier, gut low grade inflammation and tumor progression. The transfer of fecal microbiota from DCA-treated mice to another group of Apcmin/+ mice increased tumor multiplicity, induced inflammation and recruited M2 phenotype tumor-associated macrophages. Importantly, the fecal microbiota transplantation activated the tumor-associated Wnt/ß-catenin signaling pathway. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block DCA-induced intestinal carcinogenesis, further suggesting the role of dysbiosis in tumor development. Our study demonstrated that alteration of the microbial community induced by DCA promoted intestinal carcinogenesis.
Asunto(s)
Ácidos y Sales Biliares/efectos adversos , Carcinogénesis/inducido químicamente , Disbiosis/inducido químicamente , Intestinos/patología , Animales , Carcinogénesis/patología , Ácido Desoxicólico/efectos adversos , Disbiosis/microbiología , Disbiosis/patología , Heces/microbiología , Inflamación/microbiología , Inflamación/patología , Intestinos/microbiología , Ratones , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismoRESUMEN
Autoimmune liver diseases (AILDs) often coexist with other extrahepatic autoimmune diseases (EHAIDs). The spectrum of EHAIDs in patients with AILDs is similar, whereas the incidence is different. Notably, autoimmune thyroid disease and Sjogren's syndrome are the most common EHAIDs. Associated extrahepatic diseases may predate the appearance of AILDs or coincide with their onset. More frequently, they may appear during the course and even occur years after the diagnosis of AILDs. Importantly, associated EHAIDs may influence the natural course and prognosis of AILDs. To date, a definite pathophysiological pathway which contributes to the coexistence of AILDs and EHAIDs is still lacking. The current view of autoimmunity clustering involves a common susceptibility genetic background which applies to related pathologies. Herein, we review the current published researches regarding EHAIDs in patients with AILDs, particularly in relation to their clinical impact and pathophysiology. In managing patients with AILDs, gastroenterologists should be aware of the possibly associated EHAIDs to ensure a prompt diagnosis and better outcome.