Journal
MOLECULAR ONCOLOGY
Volume 12, Issue 4, Pages 514-528Publisher
WILEY
DOI: 10.1002/1878-0261.12178
Keywords
CD8(+) T cells; colitis; colorectal cancer; gender; sex; STAT1
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Funding
- Austrian Science Fund (FWF) Doktoratskolleg-plus grant 'Inflammation and Immunity' [W1212]
- FWF [P25925-B20, P26908-B20, P29222-B28, SFB F6101, F6106]
- Austrian Science Fund (FWF) [W1212] Funding Source: Austrian Science Fund (FWF)
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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(Delta IEC)). Male but not female STAT1(Delta IEC) mice were more resistant to DSS-induced colitis than sex-matched STAT1(flox/flox) controls and displayed reduced intraepithelial infiltration of CD8(+) TCR alpha beta(+) 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(Delta 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(Delta 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.
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