ABSTRACT
Objective To investigate the radiosensitization effect of stattic on the xenograft of esophageal squamous cell carcinoma ( ESCC ) ECA109 cells in nude mouse and explore the underlying mechanisms. Methods Male nude mice inoculated subcutaneously with ECA109 cells were used to examine the radiosensitization effect of stattic in vivo. When average volume of tumors was about 150 mm3 , mice were randomly divided into 4 groups:control group, 25 mg/kg stattic alone group, ionizing radiation (IR) (6 Gy) alone group, and 25 mg/kg stattic plus IR group. During the term of treatment, the volume of tumors was measured every 2 days. On 25 days after treatment, the mice were killed and the expressions of pSTAT3, STAT3, HIF-1α and VEGF in ECA109 xenografts were assessed by Western blot and immunohistochemistry analysis. Results The volume of tumor in nude mice was (705. 1 ± 75. 5) mm3 in stattic plus IR group, which was significantly smaller than that in IR group (113. 5 ± 101. 4) mm3 and stattic alone group(1696.5 ±100.6)mm3(t=4.35, 14.14,P<0.0). The inhibition rate was (66.1 ± 3. 2)％ in stattic plus IR group. The expression levels of pSTAT3, HIF-1α and VEGF were obviously decreased in the stattic plus IR group compared with other groups (t=17. 07, 5. 05, 3. 54, P<0. 05). Conclusions Stattic play a radiosensitization role in the xenograft of esophageal carcinoma in nude mice probably by inhibiting the signaling pathways of pSTAT3, HIF-1α and VEGF.
ABSTRACT
Objective To investigate the radiosensitivity of ESCC by signal transducer and activator of transcription 3 (STAT3) inhibitor Stattic,since the radioresistance of esophageal squamous cell carcinoma(ESCC) remains an obstacle for the effective radiotherapy of ESCC.Methods ECA109 cell line was exposed to hypoxia and treated with Stattic or radiation,alone or in combination.Cell proliferation,colony formation,apoptosis,and double-stranded DNA breaks (DSBs) were examined.The levels of STAT3,pSTAT3,hypoxiainduciblefactor1α (HIF-1α),and vascular endothelial growthfactor (VEGF) in ESCC cells were detected by Western blot.Results Stattic efficiently inhibited the proliferation of ECA109 cells in time-dependent and dose-dependent fashions with an IC50 of 5.499 μmol/ L.Clonogenic survival assay showed that stattic (1.0 μmol/L) sensitized ECA109 cells to ionizing radiation and its SERDo was 1.20 (in normoxia) or 1.28 (in hypoxia).Under hypoxic condition,stattic combined with IR disrupted the repair of DSBs and increased the apoptosis(t =7.33,P ＜ 0.05) in ESCC cells compared to that of radiation treatment alone.Moreover,Western blot assay showed that stattic inhibited STAT3 activation and downregulated the expression level of pSTAT3 and HIF-1α and VEGF.Conclusions Stattic confers radiosensitivity in ESCC cells in vitro and is a potential adjuvant for the radiotherapy of ESCC in the clinical setting.