Expression Of Dopamine Receptor Subtype D₄ And Oncogene C-fos MRNA In Human Gastric Cancer And Their Significance

[Background and Objectives] Gastric cancer is one of the most common malignant tumors in the world, which has a very poor prognosis and impairs people's health fatally. The etiopathogenesis of gastric cancer is a comprehensive process concerned of multifactor, multigene and multistage, but its possible mechanisms are largely unknown. So the pathogenesis, prevention and treatment of gastric cancer have always been our research emphasis.Dopamine (DA) and dopamine receptor (DR), together with the growing recognition of important brain-gut interaction in modulating gastrointestinal physiology and pathology, have been the focus. DA is an important enteric neurotransmitter belonging to catecholamine. DR, the specific receptor of DA, is a G-protein-linked receptor. In the 1980's, DR was divided into two subtypes (DR₁ and DR₂) according to their biochemical, physiological and pharmacological characterization. Nowadays, five subtypes have been cloned. Subtype D₁ and D₅ belong to DR₁, and D₂-D₄ belong to DR2. DA and DR distribute extensively and have a complex effect. It was tested that all five subtypes of DR mRNA existed in the gastrointestinal tract of the rats and human, while subtype D₄ and D₅ expressed higher; Both D₄ and D₅ mRNA expressed in human stomach as well as duodenum, and the value of D₄ expression might be higher than that of D₅. DA has now been implicated in cytoprotection of gastrointestinal epithelium aswell as antidamage and predefense effect, and it can enhance the defensive function of the stomach mucosa. DA involves in the occurrence and development of many gastroenteric diseases, such as diseases concerned of gastrointestinal motility, peptic ulcer, pancreatic diseases and gastrointestinal tumors. Currently, DA has been considered to be a mitotic inhibitor and it has been showed inhibition of tumor cell proliferation as well as active apoptosis and lysis of tumor cells. A recent study found a significant decrease of DR in human malignant stomach tissue, and pharmacological characterization revealed it to be the DR2 type. Subsequent experiment demonstrated a significant decrease of DA content, its receptor expression and its second-messenger cAMP in malignant tissues of human colon.Reports indicated that DR antagonist could produce a inductive expression of oncogene c-fos mRNA and its protein Fos. C-fos belongs to myc oncogene family, and its production Fos is a nuclear protein belonging to transcription factors. Fos can regulate the transcription of many other genes and involves in cell proliferation, differentiation, and signal transduction. Low expression of c-fos has been found in many cells during physiological conditions, but its abnormal high expression can lead to cell malignant transformation and tumorigenesis. Over expression of c-fos has been found in tumor cells of liver cancer, lung cancer, esophageal cancer, gastric cancer, cervical cancer, thyroid cancer, breast cancer, and so on.This study detected the mRNA expression of dopamine receptor subtype D4 and oncogene c-fos in human gastric adenocarcinoma and normal stomach tissue by in situ hybridization, at the same time analyzed their relations with each other and with the clinic-pathological parameters of gastric cancer. This may be of significance in investigating their role in the occurrence and development of gastric cancer, at the same time providing a foundation in understanding the etiopathogenesis, prevention and treatment of gastric cancer at the level of peripheral neurotransmitters.[Materials and Methods] (1) Forty-two stomach cancer patients were selected from the First Affiliated Hospital of Zhengzhou University, who didn't receive prior treatment, including chemotherapy and radiotherapy. Malignant tumor tissue specimenswere taken during surgery. Thirty-five normal gastric tissues of para-carcinoma were obtained from histologically normal portions of surgical specimens not invaded by malignant neoplasms as controls. All the tissues were fixed in 4% PFA/0.1M PBS (contained 1/1000DEPC) and were embedded in paraffin.(2) In situ hybridization was used to detect the mRNA expression of dopamine receptor subtype D4 and c-fos oncogene in human gastric adenocarcinoma and para-carcinoma normal stomach tissue.(3) Results were analyzed by software SPSS 10.0. x 2-test and Spearmancorrelation were used to compare the difference between groups. P0.05).(3) The expression of c-fos mRNA was both associated with the size of tumor (p<0.05) and the differentiation of the adenocarcinoma (P<0.01), but was not associated with the invasive depth (with or without serosa invasion) and lymph node metastasis of gastric cancer (F>0.05).(4) Statistically significant correlation between the expression of D4 and c-fos mRNA in gastric cancer was observed, while the positive rate of c-fos in D4 positive tumors was significantly lower than that in D4 negative tumors (P<0.05); Together with the correlation coefficient (r=-0.439), a significant negative correlation between D4 andc-fos mRNA in human stomach cancer was suggested (JMJ.01).[Conclusions] (1) Decreased expression of D4 mRNA in human gastric cancer and its association with the size of tumor suggest that the lower expression of D4 may be closely related to cell malignant transformation and tumor cell proliferation. Detecting the expression of D4 mRNA may be important to the early diagnosis of gastric cancer. There were no significant differences between D4 and the differentiation of adenocarcinoma, its invasive depth (with or without serosa invasion) and lymph node metastasis, which means that D4 is not fitted for the judgment of gastric cancer patients' prognosis.(2) Over expression of c-fos mRNA in gastric cancer and its association with the differentiation of adenocarcinoma and the size of tumor suggest that c-fos may accelerate gastric tumorigenesis, differentiation and cell proliferation. The better gastric cancer differentiated, the higher c-fos mRNA expressed. This suggests that cancer patients with over expression of c-fos may have a well prognosis. C-fos was not associated with the invasive depth (with or without serosa invasion) and lymph node metastasis of gastric cancer, which indicates that the abnormal expression of c-fos mRNA may be little related to the development of gastric cancer.(3) There existed a close negative correlation between D4 and c-fos mRNA in human gastric cancer, which show that D4 and c-fos may act with each other as a counteractive regulator in gastric tumorigenesis.