Correlation Of STAT3 Expression To Cisplatin Resistance In Head And Neck Squamous Cell Carcinoma

ObjectiveSignal transducers and activators of transcription 3(STAT3) is an important member of family of signal transducers and activators of transcription.Many tumor-derived cell lines as well as samples from human cancer have been reported to express high levels of constitutively active Stat3 protein,for example head and neck squamous cell carcinoma(HNSCC),breast cancer,prostate cancer,multiple myeloma and so on.Constitutively active Stat3 has important roles in several biological responses such as tumor prolifertion,differentiation,apoptosis and migration.Besides its classic functions,STAT3 oncogenic pathway may be involved in drug resistance. However,its role in cisplatin resistance of HNSCC is unclear.This study is to explicit the expression levels of STAT3 in HNSCC,and explore the correlation of the STAT3 oncogenic pathway to cisplatin resistance.Methods1.Twenty-eight cases of HNSCC pathologically confirmed after resection were obtained as surgical samples from patients treated at the head and neck neoplasms department of Tian jin cancer hospital,including 8 cases of laryngeal carcinoma,7 cases nasopharyngeal cancer,5 cases tongue carcinoma,5 cases gingival carcinoma,1 case carcinoma of the floor of mouth,1 case carcinoma of upper esophagus,1 case maxillary sinus carcinoma.All the specimens were divided into two portion,the sensitivity to cisplatin of one portion was detected by collagen gel droplet embedded culture-drug sensitivity test(CD-DST),another was embedded by paraffin and tested the expression levels of STAT3 by immunohistochemistry. Besides,17 cases of normal squamous epithelium were collected for the control.Cell line of tongue squamous cell carcinoma was recoveried,and creep plates of induction culture cell were collected for immunocytochemistry.2.The sensitivity to cisplatin of 28 cases of HNSCC was detected by CD-DST. 3.Labelled streptavidin biotin method was used to detect the expression levels of STAT3 protein in the cisplatin resistant group,cisplatin sensitive group,normal squamous epitheliums and Tb3.1 cells.4.After Tb3.1 cells were treated by AG490 which was one inhibitor of the STAT3 oncogenic pathway for 24 hours,the sensitivity to cisplatin of the AG490 treatment group and the control group were detected by CD-DST.5.SPSS13.0 statistical software was used for the data analysis.The expression levels of STAT3 in HNSCC and its correlation to cisplatin resistance were analysed by x~2 test.The difference of cisplatin sensitivity between the AG490 treatment group and the control group was analysed by t test.Results1.The chemosensitivity was successfully evaluated by CD-DST for 25 of 28 patients.The efficacy rate was 89.3%(25/28).Eight cases were assessed as sensitive,and sevevteen as resistant.The response rate was 32.0%.2.The expression levels of STAT3 protein were elevated in HNSCC tumor samples as compared with levels in normal squamous epithelium(x~2=13.137, P＜0.005).In the cisplatin resistant group,4 cases have higher expression of STAT3,12 cases have moderate expression of STAT3,1 case has weak expression.While in cisplatin sensitive group,1 case has higher expression of STAT3,2 cases have moderate expression of STAT3,5 cases have weak expression(x~2=9.616,P=0.008).3.STAT3 protein is positively expressed in the cytoplasm of Tb3.1 cetls,with brown granulations.4.The cell survial rate of Tb3.1 cells was(96.59±10.01)%after treated by DMSO,and(95.22±7.16)%by AG490 respectively.There was no statistical difference as compared with the blank control group.The Tb3.1 cells were sensitive to cisplatin,and the cell survial rate was(22.69±2.79)%.There was significantly different cisplatin sensitivity between the AG490 treatment group(8.94±1.06)%and the DMSO treatment group(21.19±2.74)% (P=0.000). Conclusions1.STAT3 protein was positively expressed in HNSCC.The expression levels of STAT3 were elevated in HNSCC tumor samples as compared with levels in normal squamous epithelium.2.There was a positive correlation between the expression levels of STAT3 protein and cisplatin resistance in HNSCC.3.STAT3 protein was positively expressed in Tb3.1 cells.4.The sensitivity to cispaltin of Tb3.1 cell could be improved after the STAT3 oncogenic pathway was blocked by AG490.