STAT1 is a sex-specific tumor suppressor in colitis-associated colorectal cancer.
Ilija CrnčecMadhura ModakClaire GordzielJasmin SvinkaIrene ScharfStefan MoritschPaulina PathriaMichaela SchledererLukas KennerGerald TimelthalerMathias MüllerBirgit StroblEmilio CasanovaEditha BayerThomas MohrJohannes StöcklKarlheinz FriedrichRobert EferlPublished in: Molecular oncology (2018)
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+ TCRαβ+ 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.
Keyphrases
- cell proliferation
- high fat diet induced
- endothelial cells
- randomized controlled trial
- stem cells
- metabolic syndrome
- dendritic cells
- insulin resistance
- ejection fraction
- mesenchymal stem cells
- newly diagnosed
- mass spectrometry
- wild type
- high resolution
- skeletal muscle
- bone marrow
- cell therapy
- dna binding
- big data
- electronic health record
- polycystic ovary syndrome
- binding protein