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

ABSTRACT: The interferon-inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated sex-specific STAT1 functions in colitis and colitis-associated colorectal cancer (CRC) using mice with specific STAT1 deletion in intestinal epithelial cells (STAT1?IEC ). Male but not female STAT1?IEC mice were more resistant to DSS-induced colitis than sex-matched STAT1flox/flox controls and displayed reduced intraepithelial infiltration of CD8+ TCR??+ granzyme B+ T cells. Moreover, DSS treatment failed to induce expression of T-cell-attracting chemokines in intestinal epithelial cells of male but not of female STAT1?IEC mice. Application of the AOM-DSS protocol for induction of colitis-associated CRC resulted in increased intestinal tumor load in male but not in female STAT1?IEC mice. A sex-specific stratification of human CRC patients corroborated the data obtained in mice and revealed that reduced tumor cell-intrinsic nuclear STAT1 protein expression is a poor prognostic factor in men but not in women. These data demonstrate that epithelial STAT1 is a male-specific tumor suppressor in CRC of mice and humans.

SUBMITTER: Crncec I

PROVIDER: S-EPMC5891040 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Crnčec Ilija I Modak Madhura M Gordziel Claire C Svinka Jasmin J Scharf Irene I Moritsch Stefan S Pathria Paulina P Schlederer Michaela M Kenner Lukas L Timelthaler Gerald G Müller Mathias M Strobl Birgit B Casanova Emilio E Bayer Editha E Mohr Thomas T Stöckl Johannes J Friedrich Karlheinz K Eferl Robert R

Molecular oncology 20180220 4

The interferon-inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated sex-specific STAT1 functions in colitis and colitis-associated colorectal cancer (CRC) using mice with specific STAT1 deletion in intestinal epithelial cells (STAT1∆IEC ). Male but not female STAT1∆IEC mice were more resistant to DSS-induced colitis than sex-matched STAT1flox/flox controls and displayed reduced intraepithelial infiltration of CD8<sup ...[more]

PMID: 29419930

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Project description:BackgroundColorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer.MethodsSRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo.ResultsFerrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway.ConclusionsFerrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.

Dataset Information

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

Publications

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

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