Both STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma

Abstract

Background:Aberrant activities of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways have been implicated in the development and spread of various cancer entities, among them colorectal carcinoma (CRC). Transcription factors STAT3 and STAT1, both downstream effectors of interleukin (IL)-6 and its receptor, are involved in growth and developmental control of CRC cells. Constituents of the signalling network around IL-6 and STAT activation are discussed as potential biomarkers and therapeutic targets in CRC.Methods:By immunohistochemical analysis of a tissue microarray covering >400 CRC biopsies, the expression and activity status of STAT1, STAT3 as well as of IL-6 and the IL-6 receptor α-chain was determined. The outcome was correlated with clinical information and patients' survival data. Colorectal carcinoma biopsies were also analysed for specific DNA-binding activity of STATs.Results:Statistical analysis showed tendential associations between individual STATs, IL-6/IL-6 receptor-α and clinicopathological parameters. The study revealed a significant correlation of high STAT1 activity with longer patient overall survival. Surprisingly, strong STAT3 expression in surgical specimens was correlated with an increase in median overall survival by about 30 months. Statistical analysis revealed that high expression levels of STAT1 and STAT3 were associated. This finding was backed up by biochemical data that showed simultaneous STAT1 and STAT3 DNA-binding activity in randomly selected CRC biopsies.Conclusion:By multivariate data analysis, we could show that STAT3 expression and activity constitutes an independent favourable prognostic marker for CRC.

The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

“…6E). Importantly, our findings may explain the accumulating controversies regarding the tumor suppressor function of STAT3 in various cancer types (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, there are many publications in which the immune-detection of pSTAT3 Y705 or nuclear STAT3 was found to significantly correlate with a better outcome (9)(10)(11)(12)(13)(14).…”

“…The oncogenic potential of STAT3 has been well documented; specifically, the constitutively activated STAT3 mutant (commonly labeled STAT3C) can effectively induce malignant transformation (4), and many human cancers harbor constitutively active STAT3 (1)(2)(3). Nevertheless, accumulating evidence from both experimental and clinical studies has suggested that STAT3 may also carry a tumor suppressor role in specific contexts (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, in a mouse model of intestine adenoma, tissue-specific STAT3 gene knockout was found to enhance tumor invasion and promote tumor progression (5,6).…”

“…STAT3 expression was found to be reduced in the majority of skin squamous cell carcinomas compared with adjacent nonmalignant tissues (8). Moreover, nuclear-STAT3 or pSTAT3 Y705 was shown to correlate with a better prognosis in multiple cancers, such as head and neck squamous cell carcinoma, salivary gland cancer, low-grade or node-negative breast cancer, colorectal cancer, and nasopharyngeal carcinoma (9)(10)(11)(12)(13)(14). In a recent review article, we have speculated that the molecular basis of how STAT3 can function as a tumor suppressor and oncoprotein may be related to the existence of two STAT3 isoforms, STAT3a and STAT3b (3).…”

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

“…Several studies reported oncogenic effects of elevated STAT3 signalling (30)(31)(32)(33)(34)(35)(36). In contrast, others reported on STAT3 as a determinant of positive outcome in intestinal tumour progression (37,38). Moreover, we could show recently that absence of STAT1 and/ or STAT3 proteins is correlated with shorter survival of CRC patients (37,39).…”

“…In contrast, others reported on STAT3 as a determinant of positive outcome in intestinal tumour progression (37,38). Moreover, we could show recently that absence of STAT1 and/ or STAT3 proteins is correlated with shorter survival of CRC patients (37,39). We performed a systematic study to shed light on the functional interplay and the tumour growth-associated roles of STAT1/3 in CRC progression.…”