6772

STAT1

signal transducer and activator of transcription 1, 91kDa;STAT1;signal transducer and activator of transcription 1, 91kDa

signal transducer and activator of transcription 1, 91kD|signal transducer and activator of transcription 1-alpha/beta|signal transducer and activator of transcription-1|transcription factor ISGF-3 components p91/p84

2q32.2

protein-coding

Triple-negative breast cancer is difficult to treat because of the lack of rationale-based therapies. There are no established markers and targets that can be used for stratification of patients and targeted therapy. Here we report the identification of novel molecular features, which appear to augment metastasis of triple negative breast tumors. We found that triple-negative breast tumors can be segregated into 2 phenotypes based on their genome-wide protein abundance profiles. The first is characterized by high expression of Stat1, Mx1, and CD74. Seven out of 9 tumors from this group had invaded at least 2 lymph nodes while only 1 out of 10 tumors in group 2 was lymph node positive. In vitro experiments showed that the interferon-induced increase in Stat1 abundance correlates with increased migration and invasion in cultured cells. When CD74 was overexpressed, it increased cell adhesion on matrigel. This effect was accompanied with a marked increase in the membrane expression of beta-catenin, MUC18, plexins, integrins, and other proteins involved in cell adhesion and cancer metastasis. Taken together, our results show that Stat1/CD74 positive triple-negative tumors are more aggressive and suggest an approach for development of better diagnostics and more targeted therapies for triple negative breast cancer. This article is part of a Special Issue entitled: Proteomics: The clinical link.

cancer upregulated gene (CUG) 2, as a novel oncogene, has been predominantly detected in various cancer tissues, such as ovary, liver, lung and colon. We recently showed that CUG2 elevates STAT1 activity, leading to resistance to infection by oncolytic vesicular stomatitis virus. To investigate a possible role for CUG2-induced activation of STAT1 in oncogenesis, we first established a colon cancer cell line stably expressing CUG2 (Colon26L5-CUG2). Colon26L5-CUG2 exhibited higher levels not only in phosphorylation of STAT1, but also phosphorylation of Jak1/Tyk2 compared to that of the control (Colon26L5-Vec) cell line. Inhibition of Akt or ERK activity reduced phosphorylation of STAT1 in Colon26L5-CUG2 cells whereas inhibition of p38 MAPK did not significantly decrease levels of STAT1 phosphorylation, indicating that cell proliferation signals may be involved in CUG2-mediated activation of STAT1. Suppression of STAT1 expression diminished cell migration and wound healing compared to the control cells. In addition, since CUG2 expression conferred resistance to DNA damage caused by doxorubicin treatment, we investigated whether STAT1 is involved in resistance to doxorubicin-induced cell death. We found that STAT1 was not activated in Colon26L5-Vec cells while phosphorylated STAT1 was maintained in Colon26L5-CUG2 cells during doxorubicin treatment. Furthermore, suppression of STAT1 expression sensitized Colon26L5-CUG2 cells to doxorubicin-induced apoptosis whereas the control cells exhibited resistance to doxorubicin. Taken together, our results suggest that CUG2 enhances metastasis and drug resistance through STAT1 activation, which eventually contributes to tumor progression.

OBJECTIVE: The transcription factor Stat1 is a member of the family of signal transducers and transcription activators and responds to interferon-gamma stimulation. p21 is a p53-responsive gene for cell cycle regulation and mediates Stat1 antitumor activity. The aim of this study was to analyze their expression for prediction of pancreatic cancer progression and prognosis. METHODS: A total of 100 pancreatic adenocarcinoma tissue specimens were used for construction of a pancreatic cancer tissue microarray for immunohistochemical staining of Stat1 and p21 expression. RESULTS: Stat1 and p21 proteins were expressed in 88% (88/100) and 82% (82/100) of pancreatic adenocarcinoma tissue specimens, and the expression was inversely associated with tumor differentiation, clinical stages, and lymph node metastasis of pancreatic cancer. There was no association with age, tumor size, or invasion. Moreover, the Kaplan-Meier curve analysis showed that patients with higher Stat1 and p21 expression had better overall survival rates than those with low expression of Stat1 and p21 proteins. CONCLUSIONS: The loss of expression of Stat1 and p21 proteins corresponded to lymph node metastasis, advanced stage, tumor dedifferentiation, and poor prognosis in patients with pancreatic cancer.