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STAT1? enhances STAT1 function by protecting STAT1? from degradation in esophageal squamous cell carcinoma.

ABSTRACT: STAT1, which carries tumor suppressor functions in several models, consists of two isoforms, namely STAT1? and STAT1?. The biological function and significance of STAT1? has never been examined in human cancer. We examined STAT1? function in esophageal squamous cell carcinoma (ESCC) by transfecting a STAT1? gene into various ESCC cell lines. The interaction between STAT1? and STAT1? was examined by using co-immunoprecipitation and confocal microscopy. The prognostic significance of STAT1? expression, detectable by immunohistochemistry and western blot, was evaluated in a large cohort of ESCC patients. Enforced expression of STAT1? induced and prolonged the expression and phosphorylation of STAT1? in ESCC cells, and these effects were amplified by gamma-interferon (IFN-?). We also found that STAT1? interacts with STAT1? and decreases STAT1? degradation by the proteasome. Moreover, STAT1? substantially increased the DNA binding and transcription activity of STAT1. STAT1? also sensitized ESCC cells to chemotherapeutic agents, including cisplatin and 5-flurouracil. Using western blot and immunohistochemistry, we found that STAT1? was frequently decreased in esophageal cancer, as compared to their adjacent benign esophageal epithelial tissue. Loss of STAT1? significantly correlated with lymph node metastasis, invasion and shorter overall survival in ESCC patients. Therefore, STAT1? plays a key role in enhancing the tumor suppressor function of STAT1?, in ESCC, in a manner that can be amplified by IFN-?.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5682650 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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STAT1β enhances STAT1 function by protecting STAT1α from degradation in esophageal squamous cell carcinoma.

Zhang Ying Y Chen Yelong Y Yun Hailong H Liu Zhaoyong Z Su Min M Lai Raymond R

Cell death & disease 20171005 10

STAT1, which carries tumor suppressor functions in several models, consists of two isoforms, namely STAT1α and STAT1β. The biological function and significance of STAT1β has never been examined in human cancer. We examined STAT1β function in esophageal squamous cell carcinoma (ESCC) by transfecting a STAT1β gene into various ESCC cell lines. The interaction between STAT1α and STAT1β was examined by using co-immunoprecipitation and confocal microscopy. The prognostic significance of STAT1β expres ...[more]

PMID: 28981100

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Project description:ObjectiveMiR-21 is an oncomir expressed by malignant cells and/or tumor microenvironment components. In this study we focused on understanding the effects of stromal miR-21 on esophageal malignant cells.DesignMiR-21 expression was evaluated in formalin-fixed paraffin-embedded samples from patients with esophageal squamous-cell carcinoma (SCC) by quantitative RT-PCR. MiR-21 tissue distribution was visualized with in situ hybridization. A co-culture system of normal fibroblasts and esophageal cancer cells was used to determine the effects of fibroblasts on miR-21 expression levels, and on SCC cell migration and invasion.ResultsMiR-21 was overexpressed in SCCs, when compared to the adjacent non-tumor tissues (P?=?0.0007), and was mainly localized in the cytoplasm of stromal cells adjacent to malignant cells. Accordingly, miR-21 expression was increased in tumors with high versus low stromal content (P?=?0.04). When co-cultured with normal fibroblasts, miR-21 expression was elevated in SCC cells (KYSE-30), while its expression was restricted to fibroblasts when co-cultured with adenocarcinoma cells (OE-33 and FLO-1). MiR-21 was detected in conditioned media of cancer cell lines, illustrating the release of this miRNA into the environment. Co-culturing with normal fibroblasts or addition of fibroblast conditioned media caused a significant increase in cell migration and invasion potency of KYSE-30 cells (P<0.0001). In addition, co-culturing cancer cells with fibroblasts and expression of miR-21 induced the expression of the cancer associated fibroblast (CAF) marker S100A4.ConclusionsMiR-21 expression is mostly confined to the SCC stroma and its release from fibroblasts influences the migration and invasion capacity of SCC cells. Moreover, miR-21 may be an important factor in "activating" fibroblasts to CAFs. These findings provide new insights into the role of CAFs and the extracellular matrix in tumor microenvironment formation and in tumor cell maintenance, and suggest miR-21 may contribute to cellular crosstalk in the tumor microenvironment.

Dataset Information

STAT1? enhances STAT1 function by protecting STAT1? from degradation in esophageal squamous cell carcinoma.

Publications

STAT1β enhances STAT1 function by protecting STAT1α from degradation in esophageal squamous cell carcinoma.

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