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Patients with ulcerative colitis are at a very high risk of developing colorectal cancer. Corticotrophin-releasing hormone (CRH) family peptides and their receptors (CRHRs) are found to modulate inflammation and tumor cell growth. However, the role of CRH family peptides and their receptors in the inflammation-related colon cancer is still unknown. The aim of this study was to investigate the functions of CRHR1 signaling on the development of colitis-associated cancer (CAC). Crhr1-deficient (Crhr1 K/K ) mice were used to explore the role of CRHR1 in the development of azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced CAC. WT (Crhr1 C/C ) littermates were set as control. We found that the expression of CRHR1 and its endogenous ligands: urocortin and CRH were enhanced in the colon of Crhr1 C/C mice during treatment with AOM and DSS. Tumorigenesis was significantly reduced in Crhr1 K/K mice, determined by analysis of survival rate (increased by 20%), weight loss (decreased by 10%), tumor formation (decreased by 60% in tumor number), histological scores (decreased by 58%), and cytokine production. During early CAC tumorigenesis, Crhr1 K/K mice exhibited much less tumorigenesis, accompanied by lower inflammatory response, including decreased IL1b, IL6 and TNFa expression and macrophage infiltration and increased IL10 expression. Moreover, Crhr1 K/K mice displayed a reduced activation of NFkB and STAT3 phosphorylation with decreased proliferating and enhanced apoptotic cells in the colon. In conclusion, CRHR1 has a proinflammatory and therefore a protumorigenesis effect in terms of CAC, which may be helpful to develop new therapeutic approaches for inflammation and cancer prevention and treatment.

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Objectives This study was aimed to explore whether and how berberine suppresses colon cancer cell metastasis via lipid modulation. Methods Lipid accumulation was measured by an oil red O staining kit. The expression of proteins and message RNA was detected by Western blot and quantitative real-time PCR. The interaction of sterol-regulatory element-binding proteins cleavage-activating protein (SCAP) with promyelocytic leukaemia zinc finger (PLZF) was confirmed by co-immunoprecipitation assay. Expressions of fatty acid synthase (FASN) and PLZF were knocked down by specific small interfering RNA. Key findings Berberine inhibited the migration and invasion of HCT-8, HCT-116 and HT-29 cells. Moreover, it was observed that berberine decreased lipid droplet accumulation. FASN knockdown abolished the inhibitory effects of berberine on cell migration and invasion. Further investigation revealed that berberine induced the ubiquitination degradation of SCAP. And PLZF interacted with SCAP and promoted its ubiquitination, which was inhibited by berberine treatment. Silence of PLZF impaired the effects of berberine on SCAP ubiquitination and lipogenesis. Conclusions Berberine suppressed lipogenesis via promotion of PLZF-mediated SCAP ubiquitination, thereby inhibiting colon cancer cell metastasis.