Overproduction of Gastrointestinal 5-HT Promotes Colitis-Associated Colorectal Cancer Progression via Enhancing NLRP3 Inflammasome Activation

Li, Tao; Fu, Bin; Zhang, Xin; Zhou, Yunjiang; Yang, Mei; Cao, Mingtao; Chen, Yaxin; Tan, Yingying; Hu, Rong

doi:10.1158/2326-6066.cir-20-1043

Cited by 53 publications

(38 citation statements)

References 48 publications

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“…In this study, we finally confirmed the oncogenetic role of TPH1 in OV cancer. TPH1 catalyzed the reaction of enhanced degradation of tryptophan to serotonin, and its oncogenetic has been discovered in breast cancer, bladder cell carcinoma, and colon cancer [31][32][33]. Similarly, we found that the knockdown of TPH1 inhibited OV cancer - clone formation and migration ability, which is consistent with previous findings.…”

Section: Discussionsupporting

confidence: 91%

Identification of an Amino Acid Metabolism Signature Participating in Immunosuppression in Ovarian Cancer

Yang

2022

Evidence-Based Complementary and Alternative Medicine

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Ovarian cancer is one of the most fatal gynecologic cancer types, and its heterogeneity in the microenvironment limited the efficacy of the current treatment. In this study, we aimed at building a risk score to predict patient survival based on the amino acid metabolic genes and TCGA RNA-seq dataset (n = 376). We first used univariate analysis and PCA to select and test the survival-related genes, and the LASSO regression was applied to build the risk score signature with prediction accuracy estimation by survival analysis and ROC. We then conducted GSEA and GSVA to investigate the biological roles of the signature and run ESTIMATE and 4 different immunocyte infiltration algorithms to investigate the immunological diversity between the risk groups. Furthermore, the immune checkpoint expression was compared. We finally explored the cMap and PRISM database to screen out sensitive drugs for high-risk patients and analyzed the oncogenic role of TPH1 by clone formation and transwell migration assays. As a result, the risk score predicted patients’ survival and stage with high accuracy. We found that the signature mainly affected the extracellular activities and cancer immunity by functional enrichment. We further discovered that the high-risk OV harbored a high level of stromal cell infiltration and was associated with highly infiltrated fibroblasts and decreased CD8+ T cells. The immune checkpoint analyses showed that TGFB1 and CD276 were upregulated. Finally, we screened out 4 PRISM drugs with lower IC50 in the high-risk group and validated the oncogenic role of TPH1 in OV cancers. We believe this research offered a novel understanding of the interplay between amino acid metabolism and immunity in OV and will benefit patients with better prognostic management and therapeutic strategy development.

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Section: Discussionsupporting

confidence: 91%

Identification of an Amino Acid Metabolism Signature Participating in Immunosuppression in Ovarian Cancer

Yang

2022

Evidence-Based Complementary and Alternative Medicine

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“…The latter finding sheds light on the link between pyroptosis and IBD-related CRC development ( Tan et al, 2020 ). Further, the overproduction of 5-HT in the gastrointestinal tract promotes IBD-related CRC progression by enhancing NLRP3 inflammasome activation ( Li et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A mendelian randomization study with populations of European ancestry rules out a causal relationship between inflammatory bowel disease and colorectal cancer

Liu²,

Wang³

et al. 2022

Front. Genet.

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Background: Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), has been found to be associated with colorectal cancer (CRC) in observational studies, but there is no evidence to support a causal relationship or reverse causality between the two diseases.Methods: We employed two-sample bidirectional Mendelian randomization to estimate an unconfounded bidirectional causal relationship between IBD (including UC and Crohn’s disease (CD)) and colorectal cancer. After searching IEU GWAS database and filtering SNPs, we applied a variety of MR methods including IVW method using qualified instrumental variables, and conducted sensitivity analysis to detect the heterogeneity and pleiotropy of instrumental variables.Results: After using three groups of SNPs (CD: 106, UC: 113, IBD: 70), the IVW method MR analysis showed that the results were not significant (result for UC: odds ratio (OR) [95% Confidence Interval (CI)]: 0.9998 [0.9991–1.0005], p value: 0.58; result for CD: OR [95%CI]: 0.99962 [0.99912–1.00012], p value: 0.14; results for IBD: OR [95%CI]: 0.99959 [0.99869–1.00048], p value: 0.36). MR-Egger regression, WM method and MR-RAPS method reached the same conclusion. Sensitivity analysis did not reveal heterogeneity and pleiotropy. Bidirectional MR analysis was performed using the same procedure, and the results of IVW MR analysis were also not significant (result for CD: OR [95%CI]: 1.07985 [0.00049–2372.38304], p value 0.98; result for UC: OR [95%CI]: 0.27117 [0.00014–528.3707], p value: 0.74; result for IBD: OR [95%CI]: 0.47101 [0.0001–2242.94159], p value: 0.86). MR-Egger regression, WM method and MR-RAPS method also reached the same conclusion. Sensitivity analysis did not find any evidence of heterogeneity and pleiotropy.Conclusion: Contrary to the conclusions of previous observational studies, a two-sample MR analysis did not find a causal relationship or reverse causal relationship between IBD and CRC. Sporadic CRC (sCRC) may differ in pathogenesis from IBD-related CRC.

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“…The protein concentration was quantified by BCA assay (P0010S, Beyotime, Shanghai, China). Western blots were performed as previously described [ 43 , 44 ].…”

Section: Methodsmentioning

confidence: 99%

Acquired temozolomide resistance in MGMTlow gliomas is associated with regulation of homologous recombination repair by ROCK2

Zhang

Yang

et al. 2022

Cell Death Dis

Self Cite

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It was reported that MGMTlow gliomas may still be resistant to TMZ, while the mechanisms remain poorly understood. In this study, we demonstrated that rho-associated kinase 2 (ROCK2), a cytoskeleton regulator, was highly expressed in MGMTlow recurrent gliomas, and its expression strongly correlated with poor overall survival (OS) time in a subset of MGMTlow recurrent gliomas patients with TMZ therapy. And we also found that overactive ROCK2 enhanced homologous recombination repair (HR) in TMZ-resistant (TMZ-R) glioma cell lines with low MGMT expression. Silencing ROCK2 impaired HR repair, and induced double-strand break (DSB) and eradicated TMZ-R glioma cells in culture. Notably, in MGMTlow TMZ-R models, as a key factor of HR, ataxia telangiectasia-mutated (ATM) expression was upregulated directly by hyper-activation of ROCK2 to improve HR efficiency. ROCK2 enhanced the binding of transcription factor zinc finger E-box binding homeobox 1 (ZEB1) to ATM promoter for increasing ATM expression. Moreover, ROCK2 transformed ZEB1 into a gene activator via Yes-associated protein 1 (YAP1). These results provide evidence for the use of ROCK inhibitors in the clinical therapy for MGMTlow TMZ-resistant glioma. Our study also offered novel insights for improving therapeutic management of MGMTlow gliomas.

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Overproduction of Gastrointestinal 5-HT Promotes Colitis-Associated Colorectal Cancer Progression via Enhancing NLRP3 Inflammasome Activation

Cited by 53 publications

References 48 publications

Identification of an Amino Acid Metabolism Signature Participating in Immunosuppression in Ovarian Cancer

Identification of an Amino Acid Metabolism Signature Participating in Immunosuppression in Ovarian Cancer

A mendelian randomization study with populations of European ancestry rules out a causal relationship between inflammatory bowel disease and colorectal cancer

Acquired temozolomide resistance in MGMTlow gliomas is associated with regulation of homologous recombination repair by ROCK2

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