The relationship between the expression of VEGF, EGFR, and HER-2 mRNA in esophageal squamous cell carcinoma (ESCC) and clinicopathological features of different ethnic groups in Xinjiang

Esophageal cancer is a multifactorial, a multi-stage, and multi-gene participating diseases. The amplifications and deletions of some important genes within the mucosal cells undoubtedly play a very important role in this process. The regions with a high prevalence of esophageal cancer cover the Central Asia from the former Soviet to northeastern Iran and Turkmen. Based on the studies of the population in these areas, it was found that ESCC is related with genetic factors: genetic polymorphisms can increase an individual’s susceptibility to cancer [5]. China is a high-incidence area of esophageal cancer. Among the esophageal cancer at diagnosis, there is approximately 90 % of esophageal squamous cell carcinoma [6], as a result, there may be some difference in the mechanism of the development of ESCC of our country and that of adenocarcinoma of the esophagus of Western countries [7]. Based on the results of clinical efficacy and preliminary of experimental studies, and at the same time when we retrospectively analyzed 170 cases of ESCC patients from different ethnic groups and compared the efficacy and side effects of different ethnic groups during the clinical observation, we found that the short-term efficacy of esophageal cancer chemotherapy of Han, Uyghur, and Kazakh patients in Xinjiang were similar, but the long-term survivals were different: the Han patients were better than Uyghur and Kazakh. However, Uyghur and Kazakh patients’ side effects were relatively lighter, and they were better tolerated [8]. And we simultaneously applied ELISA and immunohistochemistry to detect the expression levels of VEGF, EGFR, ES, and HER-2 and the NF-kBp in serum and tissue of Han, Kazakh, and Uyghur ESCC patients, the results indicated that there were ethnic differences in serum tumor marker levels of Han, Uyghur, and Kazakh ESCC patients in Xinjiang [9]. We believed that the fundamental reason that causes different tolerance and efficacy of the ethnic groups in Xinjiang is the polymorphism of the gene. At present, genomics technologies can help find some kind of biological markers to predict the efficacy of cancer patients, so that individualized treatment could be in the true sense.

VEGF is a specific endothelial cell-stimulating factor, and it can specifically act on endothelial cells and induce angiogenesis, increase permeability of small venules and veins, promote endothelial cell division and proliferation, and induce angiogenesis VEGF which is its major role playing in the process of tumor formation.

In this research, we found that in the adjacent tissues to esophageal carcinoma, VEGF mRNA expression levels of the Han, Uyghur, and Kazakh indicated that there was no significant statistical difference, which means that there were no ethnic characteristics in EGFR expression in the adjacent tissues to esophageal carcinoma. While the expression level of VEGF mRNA of 60 cases of ESCC patients is higher than that of the adjacent esophageal tissue, which was consistent with results of Kitadai’s [10] study: the VEGF expression levels are also different with different populations. We found that most studies indicated that the expression level of VEGF, either in protein or in serum, was closely related with clinicopathological factors. Ling Danxia et al. [11] found that the high expression of VEGF of esophageal cancer patients was related with the degree of tumor invasion and lymph node metastasis. In this study, the expression level of VEGF mRNA was closely related with ethnic and lymph node metastasis, but it was independent of gender, age, clinical stage, and degrees of pathological differentiation. This result was basically the same with Christian et al. [12] results, while the expressions of VEGF mRNA of different ethnic groups in Xinjiang were different: the expression levels of the Han ESCC patients were significantly higher than those of Uyghur and Kazakh patients. If such ethnic difference in expression levels of different ethnic groups in Xinjiang could provide the basis for clinical screening, the specificity of esophageal cancer still needs further study.

EGFR is epidermal growth factor (EGF) and proliferation signaling receptors. EGFR receptor tyrosine kinase inhibitors gefitinib and erlotinib have caused widespread concern in the clinic, and they have been applied in non-small cell lung cancer, which they inhibited EGFR autophosphorylation, thereby inhibited the signaling pathway. It has been confirmed [13] in ESCC that LRIG1 as a candidate tumor suppressor gene could feedback the high expression of inhibition of EGFR, and by increasing the high expression level of LRIG1, EGFR pathway for therapeutic intervention, therefore effectively reduces the EGFR expression levels, which provide new ideas for the clinical treatment of esophageal cancer.

Currently, the researches, from home and abroad, on the relationship between the EGFR expression levels and clinicopathological features show that abnormal expression of epidermal growth factor are closely related with the degree of tumor differentiation, sensitivity of radiotherapy and chemotherapy, tumor resistance and prognostic factors, etc. Wang [14] found in the study of esophageal adenocarcinoma that the protein expression of EGFR receptor was linked with the late clinical stage, the depth of tumor invasion, lymph node metastasis, and pathological staging; and also found that patient has a poor prognosis with positive protein expression, which can be used as a monitoring indicator of esophageal cancer prognosis. The results of this study showed that the expression levels of EGFR mRNA in ESCC was higher than that of adjacent tissues to esophageal carcinoma, and in the clinical and pathological features, the EGFR expression level was independent of gender, ethnicity, age, tumor differentiation, and clinical staging of patients with ESCC patients, but it was related with lymph node metastasis (P < 0.05). And some scholars believe that the length of the survival of esophageal cancer patients was independent of EGFR overexpression, or at least it could not be an independent prognostic factor [15]. As there are few relevant literature on the level of EGFR gene expression in ESCC, EGFR mRNA still cannot be an indicator of prognosis of esophageal cancer.

HER-2/neu, also known as C-erbB-2, is a member of the human epidermal growth factor receptor. There were some studies showing that HER-2 gene plays an important role in tumor carcinogenic process. HER-2/neu gene in esophageal cancer research, such as Sato-Kuwabara [16], the latest research report shows a state of HER-2 overexpression in 30.3 % of ESCC patients. In the present study, we also got the same result, the HER-2 mRNA expression levels of 60 cases of ESCC patients (0.97 ± 0.04) were higher than those of the adjacent tissues to esophageal carcinoma (0.93 ± 0.06); such difference was statistically significant.

Deilich et al. [17] found that the overexpression of HER-2 gene in ESCC was related with prognosis. And another study of ESCC of HER-2 found that the amplification of HER-2 gene in ESCC was related with the degree of tumor differentiation and staging. That means the amplification or overexpression of HER-2 gene in ESCC can be used as an independent prognostic factor. And the positive HER-2 gene expression was also considered for the purposes of neoadjuvant therapy [18]; HER-2 may be as a prognosis indicator of ESCC patients. The results of this study indicate that the expressions of HER-2 of ESCC patients were independent of gender and age, but closely related to ethnic groups, pathological grading, and lymph node metastasis of the patients. The ESCC HER-2 expression levels of Han ESCC patients were significantly higher than those of Uyghur and Kazakh patients. Differentiation and metastasis is the main factor affecting the prognosis of esophageal cancer. Therefore, the detection of expression of HER-2 in esophageal cancer in Xinjiang may have important prognostic and therapeutic significance. This also indirectly reflects that HER-2 may be one of the indicators of esophageal cancer metastasis and progression.

Currently, the targeted therapy of esophageal cancer has entered a stage of rapid development. Multi-target combination, target drugs, especially monoclonal antibody drugs combined novel cytotoxic agents, and radiotherapy are the focus of research. Although recently there are many projects of targeted therapy research, the problem is that almost all of the papers focus on the discovery of molecular markers, and few researchers further study the discovered molecular markers and apply them to clinical practice. This is the weakness of esophageal basic research, but we can enhance this point in the future. And we believe that with further research, there will be new discoveries of treatment and prevention of esophageal cancer.