SOCS1 Gene Therapy Improves Radiosensitivity and Enhances Irradiation-Induced DNA Damage in Esophageal Squamous Cell Carcinoma

Abstract

STAT3 has been implicated recently in radioresistance in cancer. In this study, we investigated the association between STAT3 and radioresistance in esophageal squamous cell carcinoma (ESCC). Strong expression of activated phospho-STAT3 (p-STAT3) was observed in 16/22 ESCC patients with preoperative chemoradiotherapy (CRT), compared with 9 of 24 patients with surgery alone, where the prognosis of those with CRT was poor. Expression of p-STAT3 and the antiapoptotic proteins Mcl-1 and survivin was strongly induced in ESCC cells by irradiation. Ectopic STAT3 expression increased radioresistance, whereas expression of the STAT3 negative regulator SOCS1 via an adenoviral vector improved radioresponse. Inhibiting the STAT3-Mcl-1 axis by SOCS1 enhanced DNA damage after irradition and induced apoptosis. Combining SOCS1 with radiotherapy enhanced antitumor responses in a murine xenograft model compared with the individual therapies. Tumor repopulation occurred transiently after treatment by irradiation but not the combination SOCS1/radiotherapy. Tumors subjected to this combination expressed high levels of γH2AX and low levels of Ki-67, which was maintained after cessation of treatment. Overall, we demonstrated that inhibiting the STAT3-Mcl-1 signaling axis by ectopic SOCS1 improved radiosensitivity by inducing apoptosis and enhancing DNA damage after radiotherapy, offering a mechanistic rationale for a new ESCC treatment. .

MicroRNA‐1275 induces radiosensitization in oesophageal cancer by regulating epithelial‐to‐mesenchymal transition via Wnt/β‐catenin pathway

“…Over the past decades, the emerging role of ncRNAs, including miRNAs, have been reported in the development of EC radioresistance. [28][29][30][31] In this study, we proved that miR-1275, which has been revealed to exert paradoxical functions in different cancer types, 12,[32][33][34] was down-regulated in radioresistant EC cells. Meanwhile, we illustrated that miR-1275 could increase the sensitivity of EC cells to radiotherapy both in vitro and in vivo.…”

STAT3 and STAT5 Activation in Solid Cancers

“…Gene therapy strategies are also under development to re-express SOCS1 or SOCS3 in tumors [140][141][142].…”

SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling

“…GIST cells were plated in 96-well plates at a density of 2 × 10 3 cells per well and incubated for 24 h. Cell proliferation was evaluated using the Cell Counting Reagent SF (Nacalai Tesque) at the indicated times, as previously described [14,15]. The following inhibitors were used in this study: Imatinib (Novartis Pharmaceuticals, Basel, Switzerland), JAK inhibitor I (Calbiochem), FAK inhibitor (TAE226, Novartis Pharmaceuticals), and PI3 K inhibitor (LY294002, Cell Signaling Technology, Danvers, MA, USA).…”

“…GIST cell lines were harvested and lysed as previously described, [14,15] and proteins were separated according to standard procedures. The following antibodies were used: anti-phospho (p)-KIT (Tyr703), anti-p-AKT (Thr308), anti-p-AKT (Ser473), anti-AKT, anti-p-p44/42 MAPK, anti-p44/42 MAPK, anti-p-STAT3, and anti-Cleaved-Caspase3 (1:1000 dilution) were from Cell Signaling Technology (Danvers, MA, USA); anti-KIT and anti-STAT3 (1:1000 dilution), and anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH, 1:2000 dilution) were from Santa Cruz Biotechnology (Santa Cruz, CA, USA); anti-SOCS1 (1:2000 dilution) was from IBL (Fujioka, Japan); anti-p-FAK (Tyr397) and anti-FAK (1:1000 dilution) were from BD Transduction Laboratories (San Jose, CA, USA).…”

“…We have previously reported that overexpression of SOCS1 in cells, using adenoviral vectors, has a potent antiproliferative effect obtained through the targeting of several signaling pathways, including the JAK/STAT, MAPK, focal adhesion kinase (FAK), and p53 pathways [10][11][12][13][14]. Since SOCS1 targets multiple signaling pathways, it may be a promising therapeutic approach for the treatment of several tumors, by preventing and/or circumventing drug resistance in tumor cells [15].…”