STAT1 is a sex‐specific tumor suppressor in colitis‐associated colorectal cancer

Crnčec, Ilija; Modak, Madhura; Gordziel, Claire; Svinka, Jasmin; Scharf, Irene; Moritsch, Stefan; Pathria, Paulina; Schlederer, Michaela; Kenner, Lukas; Timelthaler, Gerald; Müller, Mathias; Strobl, Birgit; Casanova, Emilio; Bayer, Editha; Mohr, Thomas; Stöckl, Johannes; Friedrich, Karlheinz; Eferl, Robert

doi:10.1002/1878-0261.12178

Cited by 32 publications

(30 citation statements)

References 47 publications

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“…Here, this study revealed that CH25H participates in the pathophysiology of colitis in mice through its protective and anti-inflammatory roles. This observation is in contrast with the findings of a recent study that showed no effect in DSS-treated Ch25h −/− mice 36 . We suspect that there are two main explanation for this inconsistency.…”

Section: Discussioncontrasting

confidence: 99%

Cholesterol 25-hydroxylase protects against experimental colitis in mice by modulating epithelial gut barrier function

Sheng

Zhou

et al. 2020

Sci Rep

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Cholesterol 25-hydroxylase (CH25H) encodes the enzyme that converts cholesterol to 25-hydroxycholesterol (25-HC). 25-HC has been demonstrated to be involved in the pathogenesis of inflammatory bowel disease. However, the role of CH25H in experimental colitis remains unknown. Dextran sulfate sodium (DSS)-induced colitis was monitored in wild type and Ch25h −/− mice in 8-weekold male for 7 days by assessment of body weight, histology, inflammatory cellular infiltration, and colon length. The function of CH25H was investigated using loss-of-function and gain-of-function such as Ch25h-deficient mice, supplementation with exogenous 25-HC and treatment of 25-HC into Caco2 and HCT116 colonic epithelial cells. Ch25h −/− mice with DSS-induced colitis exhibited aggravated injury, including higher clinical colitis scores, severe injury of the epithelial barrier, lower tight junction protein levels and higher levels of IL-6. Supplementation with exogenous 25-HC ameliorated disease symptoms and reduced the extent of damage in DSS-induced colitis, which was characterized by lower colon damage, higher tight junction protein expression, significantly decreased local and systemic production of pro-inflammatory cytokines IL-6. In Caco2 and HCT116 cells, 25-HC induced tight junction genes expression in colon cancer epithelial cells. These effects of CH25H were obtained by promoting ATF3 expression. Taken together, our findings reveal a protective role for 25-HC in DSS-induced colitis and the ability of CH25H to maintain epithelial gut barrier function through ATF3 expression. Supplementation with exogenous 25-HC ameliorates disease symptoms, which provides a new therapeutic strategy for ulcerative colitis. Abbreviations 25-HC 25-Hydroxycholesterol IBD Inflammatory bowel disease DSS Dextran sulfate sodium CD Corhn's disease UC Ulcerative colitis WT Wild type CH25H Cholesterol 25-hydroxylase EAE Experimental autoimmune encephalomyelitis HβCD 2-Hydroxypropyl-β-cyclodextrin BMDMs Bone marrow-derived macrophages Inflammatory bowel disease (IBD), which encompasses Corhn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder with increasing incidence and prevalence in many countries 1. Many genetic and

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Section: Discussioncontrasting

confidence: 99%

Cholesterol 25-hydroxylase protects against experimental colitis in mice by modulating epithelial gut barrier function

Sheng

Zhou

et al. 2020

Sci Rep

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“…Moreover, the neoplastic and immunological consequences of epithelial Stat1 deletion in CAC are different from sporadic CRC. We found increased AOM-DSS-induced CAC formation in male Stat1 ΔIEC mice 64 . Stat1 ΔIEC tumors contained reduced numbers of CD8 + T cells 64 , although IDO1 + Paneth cells were absent (unpublished data).…”

Section: Discussionmentioning

confidence: 58%

“…We found increased AOM-DSS-induced CAC formation in male Stat1 ΔIEC mice 64 . Stat1 ΔIEC tumors contained reduced numbers of CD8 + T cells 64 , although IDO1 + Paneth cells were absent (unpublished data). Therefore, Stat1-dependent IDO1 + Paneth cells might be particularly important for the development of sporadic tumors but dispensable for CAC.…”

Section: Discussionmentioning

confidence: 58%

IDO1+ Paneth cells promote immune escape of colorectal cancer

et al. 2020

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Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1) + Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1 + Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1 + Paneth cells as a target for immunotherapy.

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“…Our present study further sheds light on the role of STAT3 signaling in K-ras mutant lung cancer pathogenesis by highlighting stark sex disparity in this process and showing, in contrast, attenuated tumorigenesis in female mice with Stat3 deletion. It is important to note that the report by Crncec and colleagues demonstrated sex-specific tumor suppressor and anti-tumor immune roles for another Stat, Stat1 , in colitis-associated colorectal cancer in male but not female mice 43 . Our findings suggest that, similar to Stat1 43 , epithelial Stat3 may exhibit sex-specific lung tumor suppressor roles in males.…”

Section: Discussionmentioning

confidence: 98%

“…It is important to note that the report by Crncec and colleagues demonstrated sex-specific tumor suppressor and anti-tumor immune roles for another Stat, Stat1 , in colitis-associated colorectal cancer in male but not female mice 43 . Our findings suggest that, similar to Stat1 43 , epithelial Stat3 may exhibit sex-specific lung tumor suppressor roles in males.…”

Section: Discussionmentioning

confidence: 98%

Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer

et al. 2018

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Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3Δ/Δ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.

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STAT1 is a sex‐specific tumor suppressor in colitis‐associated colorectal cancer

Cited by 32 publications

References 47 publications

Cholesterol 25-hydroxylase protects against experimental colitis in mice by modulating epithelial gut barrier function

Cholesterol 25-hydroxylase protects against experimental colitis in mice by modulating epithelial gut barrier function

IDO1+ Paneth cells promote immune escape of colorectal cancer

Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer

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