| BackgroundEsophageal cancer is a common digestive tract malignant tumor,and the incidence of esophageal cancer is in the top ten of malignant tumor in the world. In our country, esophageal cancer belongs to the high incidence of tumor, and epidemiology shows that the morbidity and mortality has obvious regional differences. In histopathological classification, esophageal cancer consists of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). The two types of the esophageal cancer are different in occurrence mechanism, the epidemiology characteristics and prognosis, we should take different prevention and treatment strategies. At present, the incidence of esophageal cancer in China is given priority with ESCC, the proportion is as high as 90% above. The development of esophageal cancer is a multi-factor, multi-step, progressive evolutionary process, and generally through normal esophageal mucosa, basal cell hyperplasia, dysplasia, carcinoma in situ, invasive carcinoma to the final metastases. At present, in terms of treatment, surgical treatment is the main way to the esophageal cancer, however, due to various reasons, patients’5 years survival rate is low, which leads to a poor prognosis. Therefore, the research of how to prevent the happening of esophageal cancer, how to improve the curative effect, how to improve the prognosis of patients, has a great significance.In the process of development of malignant tumor, the key link is the carcinogens or various oxidative stress to the cell, especially in DNA damage, if external stress cannot remove and repair the damage in time, eventually lead to the activation of proto-oncogenes and (or) the inactivation of tumor suppressor genes, thus cause cancerous cells. According to the new studies, Keapl (Kelch-like epichlorohydrin-associated proteinl, Keapl), Nrf2 (nuclear factor-E2-related factor 2, Nrf2)and ARE (antioxidant response element, ARE) three parts make up Keapl-Nrf2-ARE signaling pathway, which is one of the important pathways in cellular response to oxidative stress. It has the effect of preventing tumorigenesis through the startup of phase II metabolic enzymes to remove the reactive oxygen species, (ROS) to protect normal cells. In the malignant tumor, however, the activation of this pathway is not only to protect normal cells, but also can promote tumor growth at the same time, so that the tumor cells resistant for survival advantage. As Keapl-Nrf2-ARE signaling pathway in the tumor has a dual function, makes it become a hot spot in tumor research in recent years. Keap1 protein is a repressor protein in Keap1-Nrf2-ARE signaling pathway, it is an "Molecular Switch" of this signaling pathway. Several studies have shown that Keapl has relationship with many malignant tumors, such as non-small cell lung cancer, colorectal cancer, live cancerr, gallbladder cancer, breast cancer, head and neck squamous cell carcinomas, but there is no report about Keap1 in ESCC now. Clarify the connection between the Keapl protein expression and the prognosis of postoperative ESCC,could offer help for the prevention, treatment and judgment of the prognosis of ESCC.ObjectiveDetect the Keapl protein expression both in ESCC and normal tissue adjacent to carcinoma, and analyze the relationship between the clinical characteristics and the the pathologicalcharacteristics and the prognosis of patients. We expect it can give help to the diagnosis, treatment and prognosis of ESCC. MethodsThis study collected 62 cases with ESCC who underwent surgical treatment in the thoracic surgery surgery in Henan Cancer Hospital from January 2008 to December 2009. All of these cases were confirmed esophageal squamous cell carcinoma by pathological examination and after review, and patients did not receive anticancer treatment,such as adiation and chemotherapy before preoperative. The other 34 cases were randomly selected from normal esophageal tissue as normal tissue sample, which were 5 cm above the edge of the tumor and pathology confirmed no tumor cell invasion. Detecting Keapl expression of esophageal squamous cell carcinoma and adjacent esophageal tissue by immunohistochemistry method, collecting the patients’data of postoperative treatment and survival. In the 62 cases, 26 cases donot received postoperative treatmen and 36 cases received postoperative adjuvant chemotherapy. In patients undergoing postoperative adjuvant chemotherapy, platinum joint plan fluorouracil-based chemotherapy in 32 cases,4 cases were other types of chemotherapy; 13 cases accepted 4 cycles of chemotherapy,8 patients accepted three cycles of chemotherapy,12 cases accepted 2 cycles of chemotherapy,3 cases received 1 cycle of chemotherapy. All 62 patients received follow-up, the median follow-up time was 56 months, the shortest followed up time wasr 6 months, the longest follow-up time was 76 months.The experimental data was statistical analysed by the software of SPSS 20.0. Count data comparison between groups uesd chi-square test or Fisher’s exact test. Survival analysis used the Kaplan-Meier survival curves, Log-rank test and Cox regression model. P<0.05 was considered statistically significant.Results1. Keapl expression in ESCC and adjacent normal tissuesKeapl protein mainly located in cytoplasm, both expressed in esophageal cancer tissue and tissue adjacent to carcinoma, and expressed mainly located in cytoplasm with a briquette or granular distribution, dyeing for tan to brown. The positive rate of Keapl in esophageal squamous carcinoma tissues was 25.8%(16/62),and the positive rate was 50.00%(17/34) in normal tissue adjacent to carcinoma, the positive rate of Keapl was significantly higher in normal esophageal tissues adjacent than carcinoma of esophagus squamous carcinoma tissues, the difference has statistical significance (P<0.05).2. The didifferent expression of Keapl in patients of esophageal squamous cell carcinoma with different subgroupsKeapl protein expression had relationship with whether the tumor invasive depth (P< 0.05) and local lymph node metastasis (P< 0.05), while the patients’age, sex, tumor location, tumor gross type, depth of invasion and TNM stage did not. Keapl protein expression level was higher in the shallower tumor invasive depth group(T1+T2 group) compared with the deeper tumor invasive depth group(T3+T4 group) (44.1% vs 12.1%, P-0.009).Keap1 protein expression level in lymph node metastasis group was obviously higher than that without local lymph node metastasis group (70.6% vs 8.9%, P< 0.05).3. Keapl protein expression with the relationship between postoperative adjuvant chemotherapyIn patients with Keapl prote in positive group,overall survival (OS) had relationship with whether to accept postoperative adjuvant chemotherapy, which had a statistical difference (P<0.05),the overall survival of patients who accept the postoperative adjuvant chemotherapy was obviously higher than that of patients who did not receive postoperative adjuvant chemotherapy; Keap1 protein in patients with negative groups, overall survival has no relationship with whether to accept postoperative adjuvant chemotherapy (P>0.05).4. The relationship between Keapl expression and the prognosis of patients with esophageal squamous cell carcinomas.Keap1 positive group survival time was 46.9 months on average,and the median survival time was 55.5 months, Keapl negative group average survival time was 46.9 months, the median survival time was 56 months. Kaplan-Meier survival analysis showed that there was no significant differencebetween two groups (P=0.9865). In patients with postoperative adjuvant chemotherapy, the median overall survival (60.5 months) of keapl protein positive group was longger than Keapl protein negative group (52.5 months), but there was no statistically significant difference (P>0.05);In patients who did not receive postoperative adjuvant chemotherapy, Keapl protein expression has no relationship with the patients’overall survival (P> 0.05). Keap1 protein expression cannot be an indicator that estimate the prognosis of ESCC yet.5. The prognosis influence factors of patients with ESCC.Kaplan-Meier survival analysis showed that gender, age, tumor location, gross pathologic morphology, whether to accept the postoperative adjuvant chemotherapy was not the factors that affect the prognosis of patients with ESCC (P>0.05) Different tumor differentiation degree, infiltration depth, presence of regional lymph node metastasis, TNM stage were tatistically different compared with patients’ overall survival time(P<0.05). The result of multivariate survival Cox showed that tumor gross type (HR=1.985, P=0.037) and invasion depth of tumor (HR=3.043,P=0.012) were independent predictive factors of patients’overall survival (OS). The lower the degree of tumor differentiation and the deeper the tumor invasive depth, patients with the shorter overall survival.Conclusions1. Keapl protein expression level in esophageal squamous cell carcinoma tissue was down-regulated compared with normal tissue, and the expression level was closely related to the level of local lymph node metastasis.2. Keapl protein expression can be used as an index of adjuvant chemotherapy in postoperative patients with ESCC3. Keapl protein cannot be as an indicator that estimate the prognosis of esophageal squamous cell carcinomas yet... |
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