| Objective:Esophageal cancer is one of the most common malignant tumors of digestive tract in the world.Esophageal cancer has two main pathological types: Esophageal squamous cell carcinoma(Esophageal squamous cell carcinoma,ESCC)and Esophageal adenocarcinoma(Esophageal adenocarcinoma,EAC);The ESCC accounted for 80% of the cases in the world,is Asia's main subtypes of early esophageal cancer symptom is not obvious,when the majority of patients see a doctor is in stage ?,or later;So the main research focus in locally advanced esophageal cancer treatment(?-?).Definitive chemoradiation(d CRT)is the standard treatment for locally advanced esophageal cancer,but local recurrence after treatment is a major cause of this model's failure.Apoptosis and autophagy play a very important role in the growth and development of cells,and are even closely related to the occurrence and development of malignant tumors.After radical chemoradiotherapy,whether there is a clear relationship between the causes of local recurrence and cell apoptosis and autophagy has not been confirmed by relevant studies.Therefore,this study further explored the relationship between local recurrence of esophageal squamous cell carcinoma after radical chemoradiotherapy and apoptosis and autophagy dysfunction by detecting the genes associated with apoptosis and autophagy in the paired samples of primary and locally recurrent tumors in patients with esophageal squamous cell carcinoma after radical chemoradiotherapy.Methods:The clinical data of patients with locally advanced esophageal squamous cell carcinoma who underwent radical chemoradiotherapy from March 2002 to September2012 were retrospectively analyzed.During the follow-up,patients with local recurrence confirmed by computed tomography,endoscopy of the digestive tract and pathological biopsy were included in the study,and paraffin-embedded tissues of primary esophageal squamous cell carcinoma before radical chemoradiotherapy and tumor tissues after local recurrence were detected and analyzed.Results:Part one: a total of 126 patients were included in the final study,stage ?patients with 60 cases(47.6%),stage ? patients 66 cases(52.4%).1-year,3-years and5-years local relapse-free survival(local recurrence-free survival,LRFS)were54.8%,19.8% and 14.3%,the median LRFS is 13 months.patients with clinical T2 stage showed significantly longer median LRFS than those with clinical T3-4 stage(15.5 vs.10.1 months,P = 0.007.Patients with stage II disease had a median LRFS of19.0 months,which was much longer than those with stage III disease of which LRFS was 10.6 months,P = 0.001.Gender,age,tumor location,tumor differentiationand lymph node status had no significant correlation with LRFS.Part two:Comparison between the pairs of primary and recurrent tumor samples,it was found that the expression profile of the key genes of apoptosis mechanism had5 up-regulated and 7 down-regulated apoptotic genes in locally recurrent tumor,among which the up-regulated CD40,TRAF4 and BCL2A1 were associated with the down-regulated CARD6 and TNFRSF21 and the increased risk of early local recurrence.Patients with CD40 expression ?2-fold had a shorter median LRFS than those with CD40 expression <2-fold(11.0 months vs.16.5 months,P = 0.050,).Of the 42 patients with TRAF4 expression ?2-fold,32(76.2 %)had local tumor recurrence within 24 months after CCRT.14 out of 28(50.0 %)patients of which TRAF4 expressed < 2-fold developed local recurrence during the same period and the median LRFS in two groups was 10.6 months,19.0 months respectively,P = 0.018.Compared to those with BCL2A1 expression ?2-fold,patients with BCL2A1 expression <2-fold showed a significantly longer median LRFS,and the median LRFS in two groups was 9.0 months,16.5 months respectively,P = 0.035.Oppositely,up-regulations of CARD6 and TNFRSF21 in tumor samples were associated with lower risk of early local recurrence after CCRT.Patients with CARD6 expression?2-fold showed a significantly longer median LRFS compared to those with CARD6 expression <2-fold,and the median LRFS was 15.5 months,11.0 months respectively,P = 0.038.Of the 37 patients with TNFRSF21 expression ?2-fold,20(54.1%)had local tumor recurrence,while26 of 32(81.3%)patients of which TNFRSF21 expressed< 2-fold developed local recurrence within 24 months after CCRT,and the median LRFS in the two groups was 21.0 months,9.0 months respectively,P = 0.001.The correlations between the expression level of BCL10,BIRC3,TNFRSF10 A,AKT1,BAG4,BFAR,CASP8 and LRFS were not discovered in this study.Part three: compared with paired primary tumor tissues,more autophagy lysosomal structure formation can be observed in locally recurrent tumor tissues,while autophagy lysosomes can only be observed occasionally in primary tumor tissues.Protein by immunohistochemistry and western blot method to detect LC3-?expressed in pairs in the tumor samples,the results found that local recurrence pairing LC3-? protein expression in tumor tissues is higher than the primary tumor tissue.Compared with LC3-? express positive patients,LC3-? express negative patients LRFS extended obviously,the median LRFS was 13.7 months(P =0.002).The LRFS rates for each stage in LC3-II protein were calculated in ESCC patients following CCRT,the findings showed that stage II patients with negative LC3-II showed a median LRFS of 25.0 months,which was statistically longer than those with positive LC3-II expression with the median LRFS of 13.5 months,P =0.004.The 2-,3-LRFS rate in stage III patients with negative LC3-II was also better than that with positive LC3-II expression,though the difference was not significant.Conclusion:After radical radiotherapy and chemotherapy,early local recurrence in patients with locally advanced esophageal squamous cell carcinoma is associated with apoptosis and autophagy dysfunction,which provides new ideas for the treatment and research of esophageal squamous cell carcinoma in the future,but more studies are needed to understand the biological mechanism of esophageal cancer recurrence. |
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