Expression Of C-fos In Nasopharyngeal Carcinoma And The Relationship With Chemosensitivity And Prognosis

Objective:Nasopharyngeal carcinoma(NPC)is a malignant tumor that occurs on the nasopharyngeal mucosa.It has obvious regional differences.Its prevalent in southern China and Southeast Asia.It is the most common head and neck cancer after thyroid cancer.Through long-term endoscopic biopsy,surgical specimens,cytology and animal studies in vivo,it was confirmed that the carcinogenesis of nasopharyngeal epithelium is a long-term,multi-gene,multi-factor,and multi-stage complex process.The mechanism of carcinogenesis in NPC is closely related to cell proliferation,differentiation,apoptosis,invasion and metastasis.A variety of proto-oncogenes and tumor suppressor genes promote the occurrence and development of NPC.At present,the activation of protooncogenes is receiving more and more attention.C-fos gene is a nuclear oncogene in the proto-oncogene family and is homologous to the retrovirus gene V-fos in murine FBR and FBJ2osteosarcoma Gene,C-fos binds to C-jun proteins to form heterodimeric AP-1complexes,which are involved in the regulation of transcription of downstream target genes.It has been found that C-fos is highly expressed in malignant tumors such as colon cancer and osteosarcoma,and the expression level of its protein product is related to the malignancy of the tumor.It has also been reported in the literature that shRNA interferes with the expression of C-fos protein and can increase the sensitivity of breast cancer to chemotherapy drugs.However,there is still a lack of clear understanding about the expression of C-fos protein in nasopharyngeal carcinoma and its relationship with chemotherapy sensitivity and prognosis.This study examined the expression of C-fos protein in patients with NPC tissue and chronic nasopharyngitis and analyzed its relationship with clinicopathological factors,sensitivity and prognosis of chemotherapy drugs,and explored the role and clinical expression of C-fos in NPC tissue.Methods:(1)To retrospectively select the NPC tissue samples of 75 patients with complete clinical data from March 2014 to August2016 in Department of Otorhinolaryngology Head and Neck Surgery,Affiliated Hospital of Southwest Medical University,and select the same period 30 cases of chronic nasopharyngitis tissue as control group;Immunohistochemistry EnVision two-step method to detect the expression of C-fos protein in the above tissue samples collected under a microscope;using Image-Pro Plus 6.0image analysis software to detect each piece Fos protein expression in NPC tissue,chronic nasopharyngitis tissue characteristics,and combined with the clinical and pathological data of patients further analysis of C-fos protein And the patient's clinicopathological parameters.(2)The above 75 cases of NPC patients were treated with radiotherapy and chemotherapy before the biopsy removed fresh cancer tissue prepared into single cell suspension cultured in vitro;fluorouracil,cisplatin,carboplatin,oxaliplatin,paclitaxel,Docetaxel,gemcitabine and cyclophosphamide were respectively diluted into different drug concentrations(200%,100%,50%,25%,12.5%)according to the plasma peak concentration(PPC),and then added to NPC cells to co-culture with them.The sensitivity of NPC cells to the above eight chemotherapeutic drugs was tested in vitro by ATP biosensitive anti-cancer drug sensitivity assay(ATP-Finally,different chemotherapy drugs for different patients with NPC cell inhibition rate were analyzed.(3)At the end of treatment,75 patients were followed by regular outpatient or telephone follow-up.The follow-up included age,gender,outpatient review,recurrence and metastasis,death and so on.Combined with the expression of C-fos protein in NPC tissues and the detection results of chemosensitivity,the relationship between C-fos protein expression in NPC and chemotherapy sensitivity and prognosis was analyzed.Results:(1)The results of immunohistochemistry showed that C-fos was highly expressed in NPC tissues and mainly expressed in the nucleus,which was brown or tan circular granular,partially expressed in the cytoplasm,showing a light yellow color.The stained MOD values of NPC and chronic inflammatory tissues were0.151±0.037 and 0.079±0.030,respectively.The expression of C-fos protein in NPC was significantly higher than that in chronic nasopharyngitis(P<0.001).However,the expression of C-fos protein was not significantly correlated with gender(P=0.946),age(P=0.953),pathological type(P=0.088),T stage(P=0.558),N stage(P=0.249),M stage(P=0.156)and clinical stage(P=0.939),respectively(all P>0.05).(2)In vitro sensitivity test of NPC cells showed that the sensitivity of NPC to 8 chemotherapeutic agents was different(P<0.001),the sensitivity of fluorouracil was 84.00%,that of cisplatin was 89.33%and that of carboplatin was 92.00%Platinum 88.00%,paclitaxel 76.00%,docetaxel58.67%,gemcitabine 61.33%,cyclophosphamide 76.00%.Carboplatin has the highest sensitivity to chemotherapy and the lowest resistance rate.(3)The follow-up results showed that up to the deadline of November 2017,75 NPC patients were followed up with a follow-up rate of 100%.The follow-up time was 6 to 45 months and the median time was 23 months.During the follow-up period,33 of the 75 NPC patients had recurrence or metastasis,and the total tumor progression rate was 44.00%.Among them,11 cases had recurrence or metastasis in the low expression group of C-fos protein,26 cases did not occur,and the tumor progression rate was 29.73%.22 cases had recurrence or metastasis in the high expression group of C-fos protein,16 cases did not occur,the tumor progression rate was 57.89%.The high-expression group was more likely to have recurrence or metastasis than the patients with low C-fos protein expression group.By truncated time,22 patients in NPC died and both died of the disease.53 patients survived,and the overall survival rate was 70.66%.Further analysis of the relationship between the C-fos protein and chemosensitivity revealed that the NPC drug resistance rate of paclitaxel was34.21%,which was significantly higher than that of low-expression C-fos NPC(13.51%)(P=0.036),The other 7 chemotherapeutic agents were not statistically different.The tumor progression rate in NPC with C-fos overexpression group(57.89%,22/38)was significantly higher than that in low expression group(29.73%,11/37)(?~2=6.035,P=0.014).However,the mortality rate of NPC patients with high expression of C-fos(36.84%,14/38)was not significantly different from that of low expression group(21.62%,8/37)(?~2=2.095,P=0.148).Log-rank analysis showed that the progression-free survival rate of patients with high expression of C-fos was significantly lower than that of patients with low expression(?~2=7.032,P=0.008),while there was no significant difference between patients with high expression and low expression Difference(?~2=3.139,P=0.076).Conclusions:(1)C-fos protein is highly expressed in NPC tissues,suggesting that C-fos protein may be related to the occurrence of NPC.(2)There was no significant correlation between the expression of C-fos protein and the gender,age,pathological type,TNM staging and clinical stage in NPC.(3)NPC tissue cells are generally sensitive to fluorouracil,cisplatin,carboplatin,oxaliplatin,paclitaxel,docetaxel,gemcitabine,and cyclophosphamide,and have different sensitivities.(4)C-fos protein is highly expressed in NPC and is related to tumor progression of NPC.High expression of C-fos protein in NPC may be related to the resistance of paclitaxel.(5)Detecting the expression of C-fos in NPC tissue has the potential of predicting NPC sensitivity to paclitaxel chemotherapy and predicting the progress of NPC tumor.