ABSTRACT
[This corrects the article DOI: 10.18632/oncotarget.9315.].
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+ TCRαß+ 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.
Subject(s)
Colitis/metabolism , Colorectal Neoplasms/metabolism , STAT1 Transcription Factor/metabolism , Sex Characteristics , Tumor Suppressor Proteins/metabolism , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Chemokines/biosynthesis , Colitis/chemically induced , Colitis/pathology , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Dextran Sulfate/toxicity , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mice, Transgenic , Receptors, Antigen, T-Cell, alpha-beta/metabolism , STAT1 Transcription Factor/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
The role of STAT1 and STAT3 for colorectal carcinoma (CRC) development and progression is controversial. We evaluated 414 CRC patient samples on tissue microarrays for differential expression of STAT1 and STAT3 protein levels and correlated ratios with clinical parameters. Concomitant absence of nuclear STAT1 and STAT3 expression was associated with significantly reduced median survival by ≥33 months (p=0.003). To gain insight into underlying mechanisms, we generated four CRC cell lines with STAT3 knockdown. The cell lines harbor different known mutational drivers and were xenografted into SCID mice to analyze the influence of STAT3 on their tumor growth behavior. Experimental downregulation of STAT3 expression had differential, cell-line specific effects on STAT1 expression levels. STAT1 consistently showed nuclear localization irrespective of its tyrosine phosphorylation status. Two characteristic STAT1/3 expression patterns with opposite growth behavior could be distinguished: cell lines with a low STAT1/high STAT3 ratio showed faster tumor growth in xenografts. In contrast, xenografts of cell lines showing high STAT1 and low STAT3 levels grew slower. Importantly, these ratios reflected clinical outcome in CRC patients as well. We conclude that the ratio of STAT1 to STAT3 expression is a key determinant of CRC progression and that STAT1 counteracts pro-tumorigenic STAT3 signaling. Thus, we suggest that the STAT3/STAT1 ratios are better clinical predictors in CRC as compared to STAT3 or STAT1 levels alone.
