Somatostatin receptor (SSTR) is a glycoprotein with 7 transmembrane segments, which mainly exists in the central system and secretory organs and is mostly related to neuroendocrine neoplasms. Currently, the recognized molecular subtype is SSTR1-5. Since SSTRs is widely used in neuroendocrine tumors, antitumor therapy is commonly used. It was found that SSTR2 was the most commonly express subtype, followed by SSTR5 [8,9]. However, there are few studies on SSTR2 and SSTR5 in gastric neuroendocrine neoplasms (G-NENs). Currently, there are no major case studies on the expression of SSTR2 and SSTR5 in gastric neuroendocrine neoplasms, and the prognostic value of SSTR2 and SSTR5 in patients with gastric neuroendocrine neoplasms has not been clearly reported. Therefore, in this study, the expression levels of SSTR2 and SSTR5 proteins were detected by immunohistochemical S-P method in the tissue samples of 66 patients with gastric neuroendocrine neoplasms and 12 samples of paracancer normal tissues. Then, correlation analysis and survival analysis were conducted based on the clinicopathological data and follow-up data of the patients.
The results of this study showed that the positive expression rate of SSTR2 in gastric neuroendocrine neoplasms tissue specimens and paracancer normal tissue specimens was 48.5% and 25.0%, respectively, with statistically significant differences. That is, the positive expression rate of SSTR2 protein in gastric neuroendocrine neoplasms tissues is higher than that in normal tissues, which is consistent with other common neuroendocrine neoplasms tissues reported in the literature. The positive expression rates of SSTR5 in gastric neuroendocrine neoplasms and paracancer normal tissues were 65.2% and 25.0%, respectively. That is, the positive expression rate of SSTR5 protein in gastric neuroendocrine neoplasms tissues is higher than that in normal tissues.
Cytokeratin (CK) is the main skeletal protein of cells. Studies have shown that CK-8, a member of the cytokeratin (CK) family, is a receptor of plasminogen, which can activate plasminogen and has the effect of reducing the extracellular matrix and basement membrane of tumor. CK-8 is closely related to the metastasis and invasion of tumor. As a member of the superimmune protein family, CD-56 molecule is an isomer of the adhesion molecules of nerve cells and a marker of natural killer lymphocytes (NK). It mediates the interaction between cells and cells, and is mostly associated with acute myeloid leukemia.Studies have also shown that CD-56 has different prognostic significance in AML of different subtypes. CgA is an acidic protein composed of 439 amino acids, which is mostly located in the dense core granules of neuroendocrine cells and is often used for the detection of neuroendocrine cells . Syn is a membrane protein closely related to the function of cell transmission synapses, which is mostly located in nerve tissues . Ki-67 is a nuclear antigen related to cell proliferation, which is mainly used to evaluate the proliferation activity of various tumor cells. It is currently recognized as the most optimal and convenient biological marker for tumor cell proliferation [12,13]. Ki-67 protein is highly correlated with the development, metastasis and prognosis of malignant tumors, which is an indicator closely related to cell proliferation. In addition, high tumor proliferation is usually associated with tumor invasion and metastasis. So high expression of Ki-67 often indicates poor prognosis of patients with tumor.
In this study, the expression rates of CK-8 and CD-56 were both over 60%, suggesting that gastric neuroendocrine neoplasms have the possibility of highly malignant transformation.The expression rates of CgA and Syn were 65.9% and 97.0%, respectively, which also confirmed the high specificity of CgA and Syn in the detection of gastric neuroendocrine neoplasms. Ki-67 is expressed to different degrees in gastric neuroendocrine neoplasms, which indicates that different G-NENs have different proliferation activities and prognosis. The higher the expression of Ki-67, the worse the prognosis.In order to analyze the clinical significance and prognostic value of SSTR2 and SSTR5 on gastric neuroendocrine neoplasms, this study was divided into SSTR2, SSTR5 positive group and SSTR5 negative group. Immunohistochemical results showed that SSTR2 expression was not significantly correlated with age, gender, tumor site, tumor size, invasion depth, lymph node metastasis, vessel and nerve invasion in G-NENs patients, which was consistent with relevant literature reports. SSTR2 expression was closely related to tumor grade, SSTR5 and ki-67 in G-NENs patients, and the difference was statistically significant. Moreover, SSTR2 was negatively associated with the increase of tumor grade and ki-67 while it was positively correlated with the expression of SSTR5. SSTR5 expression was closely related to tumor grade, CD-56, Ki-67 and SSTR2 in G-NENs patients, and the difference was statistically significant. Moreover, SSTR5 is negatively associated with the increase of tumor grade and ki-67 while it was positively correlated with the expression of SSTR2.
These results indicate that during the whole development process of gastric neuroendocrine neoplasms, the expression levels of SSTR2 and SSTR5 gradually decrease and the inhibitory effect on tumor proliferation is reduced, which is in favor of the growth of gastric neuroendocrine neoplasms. Moreover, the expressions of SSTR2 and SSTR5 complement each other, which are positively correlated. However, in the SSTR5-positive group, the positive rate of CD-56 increased significantly, suggesting that patients with SSTR5-positive expression of gastric neuroendocrine neoplasms have a poor prognosis. It seems to contradict the tumor grade and the expression of Ki-67 in the SSTR5-positive group. But the carcinogenesis of gastric neuroendocrine neoplasms is a complex and dynamic process with the participation of many molecules, which mutual coordinated and restrained each other. Moreover, it is important to note that in this study, tumor grade is divided into four grades (G1, G2, G3 NEN, and G3), which some scholars believe that the G3 neuroendocrine neoplasms is not a simple neuroendocrine carcinoma, but high proliferation activity of the neuroendocrine tumor and G3 neuroendocrine carcinoma . The research also proved the importance of tumor grade in gastric neuroendocrine neoplasms and rationality.
Vesterinen T et al used immunohistochemistry to detect the expression of SSTR1-5 in lung neuroendocrine tumor specimens and found that the expressions of SSTR2 and SSTR5 highly expressed in lung neuroendocrine tumor, and SSTR2 expression was higher than SSTR5 expression. Survival analysis showed that SSTR2 and SSTR5 were related to their prognosis and SSTR2 was an independent prognostic factor in patients with pulmonary neuroendocrine tumor and improved the prognosis . Lodewijk L et al showed that SSTR2 was related to the prognosis of patients with medullary thyroid cancer . Orlova KV et al revealed that the expression of SSTR2 in merkel cell carcinoma was associated with prognosis . Kiviniemi A showed that SSTR2 is associated with oligodendroglioma in glioma cells and has A good prognosis . Wang Y's study showed that SSTR2 and SSTR5 are the most common SSTR2 and SSTR5 positive expressions in gastrointestinal pancreatic neuroendocrine tumors while SSTR2 and SSTR5 positive expressions can predict the survival rate of patients with GEP-NENs. Meanwhile, the expression of various SSTRS on tumor cells constitutes the basis for the treatment of patients with neuroendocrine tumors with somatostatin.
Therefore, the authors suggest that the expression of SSTR2 and SSTR5 may be a potential indicator of the prognosis of gastric neuroendocrine neoplasms. According to the above literature, SSTR2 and 5 have higher positive expression rates in various neuroendocrine tumors than those in normal tissues , which mostly believe that the expression of SSTR2 is related to the prognosis of patients and improves the prognosis. However, there are few reports on the correlation between SSTR5 and the prognosis of neuroendocrine tumors. In this study, the 3-year survival rate of positive group of SSTR2 and SSTR 5 were 47% (82% vs. 35%) and 7% (83% vs. 76%) , which were higher than those of negative group, respectively, with statistically significant differences. Single factor analysis showed that in the SSTR2 positive group, SSTR5, CD-56 and Ki-67 were closely related to the prognosis of patients with G-NENs. In the SSTR2 negative group, SSTR5 and CD-56 were closely related to the prognosis of patients with G-NENs. In the SSTR5-positive group, tumor grade, SSTR2, CD-56, Ki-67 were closely related to the prognosis of patients with G-NENs. All of these suggest that SSTR2 and SSTR5 proteins may have a certain influence on the carcinogenesis and prognosis of gastric neuroendocrine neoplasms.
Cox multivariate analysis showed that among all patients with gastric neuroendocrine neoplasms, SSTR2 and SSTR5 were independent prognostic factors for patients with gastric neuroendocrine neoplasms, and their positive expression suggested improved prognosis, which was consistent with the study results of Vesterinen T et al in lung carcinoid. Meanwhile, CD-56 was an independent factor affecting the prognosis of G-NENs patients in the SSTR2 positive group, SSTR2 negative group and SSTR5 positive group, which suggests that SSTR2 and SSTR5 are closely related to the expression of CD-56. Although CD-56 in patients with G-NENs is rarely studied, the expression of CD-56 in acute myeloid leukemia is more studied, which belongs to the member of the super-immune protein family and has a cellular regulatory effect, indicating poor prognosis of AML [19,20]. These also indirectly reflected the positive association between SSTR2, SSTR5 expression and tumor prognosis.