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      Activated STAT3 Could Reduce Survival in Patients with Esophageal Squamous Cell Carcinoma by Up-regulating VEGF and Cyclin D1 Expression

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          Abstract

          Signal transduction and activators of transcription factor (STAT) 3 is associated with a poor prognosis in certain types of cancer. The purpose of the present study was to investigate the clinical and prognostic significance of STAT3/p-STAT3 expression in esophageal squamous cell cancer (ESCC) patients. A total of 71 patients were enrolled in the study. STAT3 and p-STAT3 expression were detected by Western Blot and immunohistochemistry assays. Stattic, the STAT3 inhibitor, was used to block the activation of STAT3 in ESCC cell lines Eca-109 and Kyse-30, and the CCK8 assay was performed to detect the effect of Stattic on the viability of ESCC cells. The expression of associated genes was assessed by RT-PCR and Western blot at RNA and protein levels, respectively. STAT3 expression was correlated with infiltration degree (pT) and pTNM. And p-STAT3 expression was correlated with pT, lymphatic metastasis (pN) and pTNM. The expression of VEGF, Bcl-xl and Cyclin D1 was up-regulated in ESCC tissues and positively correlated with p-STAT3 level, besides Bcl-xl. In vitro, Stattic inhibited the viability of Eca-109 and Kyse-30 cells in a dose- and time- dependent manner, and significantly inhibited the expression of VEGF, Bcl-xl and CyclinD1 at mRNA and protein level. The 5-year survival rate of the 71 patients was significantly associated with pT, pN, pTNM stage, p-STAT3 level, VEGF expression and Cyclin D1 expression. pN and p-STAT3 expression were independent relevant factors. Our results showed that p-STAT3 might serve as an essential biomarker for tumor invasion and metastasis in ESCC.

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          Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways.

          Vascular endothelial growth factor (VEGF) upregulation is induced by many receptor and intracellular oncogenic proteins commonly activated in cancer, rendering molecular targeting of VEGF expression a complex challenge. While VEGF inducers abound, only two major transcription activators have been identified for its promoter: hypoxia inducible factor-1 (HIF-1) and signal transducer and activator of transcription (Stat3). Both HIF-1 expression and Stat3 activity are upregulated in diverse cancers. Here, we provide evidence that Stat3 is required for both basal and growth signal-induced expression of HIF-1. Moreover, induction of VEGF by diverse oncogenic growth stimuli, including IL-6R, c-Src, Her2/Neu, is attenuated in cells without Stat3 signaling. We further demonstrate that Stat3 regulates expression of Akt, which is required for growth signal-induced HIF-1 upregulation. Targeting Stat3 with a small-molecule inhibitor blocks HIF-1 and VEGF expression in vitro and inhibits tumor growth and angiogenesis in vivo. Furthermore, tumor cells' in vivo angiogenic capacity induced by IL-6R, which simultaneously activates Jak/STAT and PI3K/Akt pathways, is abrogated when Stat3 is inhibited. Activation of Stat3 signaling by various growth signaling is prevalent in diverse cancers. Results presented here demonstrate that Stat3 is an effective target for inhibiting tumor VEGF expression and angiogenesis.
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            The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations.

            Proteins of the signal transducer and activator of transcription (STAT) family mediate cellular responses to cytokines and growth factors. Aberrant regulation of the STAT3 oncogene contributes to tumor formation and progression in many cancers, including head and neck squamous cell carcinoma (HNSCC), where hyperactivation of STAT3 is implicated in both treatment resistance and immune escape. There are no oncogenic gain-of-function mutations in HNSCC. Rather, aberrant STAT3 signaling is primarily driven by upstream growth factor receptors, such as Janus kinase (JAK) and epidermal growth factor receptor (EGFR). Moreover, genomic silencing of select protein tyrosine phosphatase receptors (PTPRs), tumor suppressors that dephosphorylate STAT3, may lead to prolonged phosphorylation and activation of STAT3. This review will summarize current knowledge of the STAT3 pathway and its contribution to HNSCC growth, survival, and resistance to standard therapies, and discuss STAT3-targeting agents in various phases of clinical development.
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              Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis

              Accumulated studies have provided controversial evidences of the association between signal transducer and activator of transcription proteins 3 (STAT3) expression and survival of human solid tumors. To address this inconsistency, we performed a meta-analysis with 63 studies identified from PubMed, Medline and EBSCO. We found STAT3 overexpression was significantly associated with worse 3-year overall survival (OS) (OR = 2.06, 95% CI = 1.57 to 2.71, P < 0.00001) and 5-year OS (OR = 2.00, 95% CI = 1.53 to 2.63, P < 0.00001) of human solid tumors. Similar results were observed when disease free survival (DFS) were analyzed. Subgroup analysis showed that elevated STAT3 expression was associated with poor prognosis of gastric cancer, lung cancer, gliomas, hepatic cancer, osteosarcoma, prostate cancer, pancreatic cancer but better prognosis of breast cancer. The correlation between STAT3 and survival of solid tumors was related to its phosphorylated state. High expression level of STAT3 was also associated with advanced tumor stage. In conclusion, elevated STAT3 expression is associated with poor survival in most solid tumors. STAT3 is a valuable biomarker for prognosis prediction and a promising therapeutic target in human solid tumors.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2020
                20 January 2020
                : 11
                : 7
                : 1859-1868
                Affiliations
                [1 ]Department of Oncology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University; Jinan 250013, P.R. China.
                [2 ]Department of Dermatology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University; Jinan 250013, P.R. China.
                [3 ]Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China.
                [4 ]Department of Pathology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University; Jinan 250013, P.R. China.
                [5 ]Department of Thoracic Surgery, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University; Jinan 250013, P.R. China.
                Author notes
                ✉ Corresponding author: Zhi-Gang Sun, Department of Thoracic Surgery, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University; Jinan 250013, P.R. China. Phone: +8613370582825. E-mail: szg@ 123456zxyy.cn .

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav11p1859
                10.7150/jca.38798
                7052867
                32194797
                b9ed5772-08a9-4f59-a9ea-b613d97adfa2
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 28 July 2019
                : 1 December 2019
                Categories
                Research Paper

                Oncology & Radiotherapy
                stat3,p-stat3,esophageal squamous cell cancer,western blot,immunohistochemistry.

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