STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett’s adenocarcinomas

Timme, Sylvia; Ihde, S; Fichter, Christiane D.; Waehle, Verena; Bogatyreva, L; Atanasov, Kostadin E.; Kohler, Ilona; Schöpflin, Anja; Geddert, Helene; Faller, Gerhard; Klimstra, David S.; Tang, Laura H.; Reinheckel, Thomas; Hauschke, Dieter; Busch, Hauke; Boerries, Melanie; Werner, Martin; Laßmann, Silke

doi:10.1038/onc.2013.298

Cited by 47 publications

(61 citation statements)

References 48 publications

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“…[73][74][75] Cell lines were verified by DNA fingerprinting/STR analysis for authenticity via the Leibniz-Institute DSMZ (July 2013; data available upon request), except Kyse-270 and Kyse-410. All drugs were purchased from Selleckchem (SAHA #S1047; MS-275 S1053; FK228 #S3020; AZA #S1782; DAC #S1200) and dissolved in DMSO.…”

Section: Cell Culture and Inhibitor Treatmentmentioning

confidence: 99%

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Ahrens¹,

Timme

Hoeppner³

et al. 2015

Epigenetics

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Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.

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Section: Cell Culture and Inhibitor Treatmentmentioning

confidence: 99%

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Ahrens¹,

Timme

Hoeppner³

et al. 2015

Epigenetics

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“…Aberrant activation of STAT3 has been shown to promote tumorigenesis in this type of cancer (25)(26)(27)(28). Using ESCC as a study model, we examined the interaction between STAT3a and STAT3b in details, with the hope that the generated data can provide insights into the tumor suppressor role of STAT3b and the molecular mechanism underlying the dual role of STAT3 in cancers.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Chen

et al. 2016

Clinical Cancer Research

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Purpose: STAT3 is known to have both oncogenic and tumor suppressive effects, but the regulation of these opposing effects is elusive. We hypothesized that STAT3b, one of the two STAT3 isoforms, is the key determinant in this context.Experimental Design: The prognostic significance of STAT3b and phospho-STAT3a Y705 (pSTAT3a Y705 ) was evaluated in 286 cases of patients with esophageal squamous cell carcinoma (ESCC). STAT3b-induced changes in the chemosensitivity to cisplatin and 5-fluorouracil were assessed both in vitro and in vivo. STAT3b-induced changes in the frequency of cancer stem cells were evaluated using Hoechst and CD44 staining. How STAT3b regulates STAT3a was determined using immunoprecipitation, confocal microscopy, DNA-binding, and chromatin immunoprecipitation-PCR.Results: STAT3b expression is an independent protective prognostic marker in patients with ESCC, which strongly correlated with longer overall survival (P ¼ 0.0009) and recurrence-free survival (P ¼ 0.0001). STAT3b significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5-fluorouracil in tumor xenografts. Mechanistically, STAT3b markedly attenuated the transcription activity of STAT3a via inducing STAT3a:STAT3b heterodimers. However, the heterodimer formation decreased the binding between STAT3a and PTPN9 (better known as PTP-MEG2), a protein tyrosine phosphatase, thereby promoting the phosphorylation of STAT3a Y705 and enhancing its nuclear translocation and DNA binding. Correlating with this, high STAT3b expression converts the prognostic value of pSTAT3a Y705 from unfavorable to favorable in patients with ESCC.Conclusions: STAT3b suppresses chemoresistance and cancer stemness by blocking the transcriptional activity of STAT3a. The paradoxical increase in pSTAT3a Y705 induced by STAT3b carries important implications as to how the biologic and prognostic significance of STAT3 in cancers should be interpreted. Clin Cancer Res; 22(3); 691-703. Ó2015 AACR.

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“…Multiple studies have highlighted STAT3 overexpression in ESCC. Timme et al 92 reported abundant expression of cytoplasmic STAT3 and nuclear phospho-STAT3 in ESCC tissue sections, and siRNA knockdown of STAT3 leads to reduced proliferation of ESCC cells. The increased expression of STAT3 may also result from activation of the Wnt/β-catenin signaling pathway as STAT3 harbors transcription factor (TCF)-binding element within its promoter.…”

Section: Stat3mentioning

confidence: 99%

“…94,95 STAT3 can also be activated by EGF, a growth factor signaling often amplified or overexpressed in ESCC. 92 The importance of STAT3 signaling in ESCC is exemplified by its known targets which affects multiple facets of cancer progression, such as, cell proliferation and anti-apoptosis (Oct-1, c-myc, Bcl-2, and Bcl-XL), angiogenesis (VEGF), immune evasion (CXCL10 inhibition), and invasion (MMP-2). 96,97 STAT3 inhibitors, either in the form of JAK1/2 inhibitors or STAT3 dimerization blockers, are currently undergoing clinical trials for cancer.…”

Section: Stat3mentioning

confidence: 99%

Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma

Sundaram

Bramhachari

2017

Tumour Biol.

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Esophageal squamous cell carcinoma is the sixth most common cancer in the developing world. The aggressive nature of esophageal squamous cell carcinoma, its tendency for relapse, and the poor survival prospects of patients diagnosed at advanced stages, represent a pressing need for the development of new therapies for this disease. Chronic inflammation is known to have a causal link to cancer pre-disposition. Nuclear factor kappa B and signal transducer and activator of transcription 3 are transcription factors which regulate immunity and inflammation and are emerging as key regulators of tumor initiation, progression, and metastasis. Although these pro-inflammatory factors in esophageal squamous cell carcinoma have been well-characterized with reference to protein-coding targets, their functional interactions with noncoding RNAs have only recently been gaining attention. Non-coding RNAs, especially microRNAs and long non-coding RNAs demonstrate potential as biomarkers and alternative therapeutic targets. In this review, we summarize the recent literature and concepts on non-coding RNAs that are regulated by/regulate nuclear factor kappa B and signal transducer and activator of transcription 3 in esophageal cancer progression. We also discuss how these recent discoveries can pave way for future therapeutic options to treat esophageal squamous cell carcinoma.

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STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett’s adenocarcinomas

Cited by 47 publications

References 48 publications

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

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

Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma

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