Anti-STAT4 monoclonal antibody, clone T2

Background. Signal transducer and activator of transcription proteins (STATs) are crucial regulators of cell growth and differentiation; however, their specific prognostic impact in human colon cancer has only been studied to limited extent. We aimed to assess the prognostic significance of specific STAT expression patterns in colon carcinoma. Methods. Protein expression patterns of activated STAT1, STAT3, STAT4, and STAT5 in human colon carcinoma tissue and corresponding healthy mucosa (n = 104) were assessed using multiplex bead-based immunoassay technologies. Expression patterns were correlated with clinical and survival data. Immunohistochemistry was performed to assess spatial expression of STAT3 and STAT5. Results. STAT3 was underexpressed whereas STAT4 and STAT5 were overexpressed in colon carcinoma tissue. Primary tumors from patients with distant metastases (M1) displayed significantly increased expression of STAT1 and STAT3 but decreased expression of STAT4 and STAT5. Increased tumor expression of STAT1 or STAT3 was associated with impaired patient survival, whereas increased expression of STAT4 or STAT5 correlated with improved survival. Multivariate analysis identified an increased STAT3/'STAT5 expressional ratio as an adverse prognostic marker in colon cancer patients. Conclusions. The tumor progression-associated transcription factors STAT3, STAT4, and STAT5 are differently expressed in colon carcinoma tissue and colon mucosa. Moreover, the STAT3/'STAT5 expression ratio is an independent prognostic marker in colon cancer patients.

Genome-wide association studies as well as murine models have shown that the interleukin 23 receptor (IL23R) pathway plays a pivotal role in chronic inflammatory diseases such as Crohn disease (CD), ulcerative colitis, psoriasis, and type 1 diabetes. Genome-wide association studies and targeted re-sequencing studies have revealed the presence of multiple potentially causal variants of the IL23R. Specifically the G149R, V362I, and R381Q IL23R chain variants are linked to protection against the development of Crohn disease and ulcerative colitis in humans. Moreover, the exact mechanism of action of these receptor variants has not been elucidated. We show that all three of these IL23R variants cause a reduction in IL23 receptor activation-mediated phosphorylation of the signal-transducing activator of transcription 3 (STAT3) and phosphorylation of signal transducing activator of transcription 4 (STAT4). The reduction in signaling is due to lower levels of cell surface receptor expression. For G149R, the receptor retention in the endoplasmic reticulum is due to an impairment of receptor maturation, whereas the R381Q and V362I variants have reduced protein stability. Finally, we demonstrate that the endogenous expression of IL23R protein from V362I and R381Q variants in human lymphoblastoid cell lines exhibited lower expression levels relative to susceptibility alleles. Our results suggest a convergent cause of IL23R variant protection against chronic inflammatory disease.