Clinical Significance And Correlationship Of The Expression Between HMGA2 And Its Downstream Regulation Factor HDAC6 In Gastric Carcinoma

BACKGROUND AND OBJECTIVES: Gastric cancer is one of the most common malignant tumor of digestive tract, and its morbidity and mortality are located in the forefront, the 5-year survival rate is about 5% ~15%. Gastric cancer is the third most common cause of cancer-related mortality in the world. In Chinese, more than 400 thousand new cases of gastric cancer occur each year, accounting for about 42% of the world,more than 300 thousand deaths per year, has becoming the third largest cause of cancer death in China. Gastric cancer is an obvious regional difference, the incidence of gastric cancer in the eastern coastal area and northwest of China is significantly higher than the south. Gastric cancer occurs more among people who aged 50 or older, male and female incidence ratio is about 2:1, the prognosis ralates to the pathological staging of gastric cancer, location, historical type, biological behavior and treatment measures.High-mobility-group A2(HMGA2) is a small nonhistonechromosomal protein that binds through its three AT-hook DNA-binding motifs to AT-rich sequences in the minor groove of DNA strands. Although HMGA2 has no intrinsic transcriptional activity,it modulates transcription by combining with chromatin to alter the architecture of chromatin or interacting with related-chromatin proteins directly and By participating in enhancing body formation to influence the formation of embryo,organization development and tumorigenesis.Since HMGA2 is highly expressed during embryogenesis and in many malignant tumors such as breast cancer, lung cancer, ovarian cancer, oral squamous cell carcinoma,and pancreatic cancer,but is absent or present only at low levels in normal adult tissues, and its expression relate to the prognosis, classification and metastasis in tumor patients,it seems to play a critical role in cell proliferation and differentiation during tumor development.according to several studies,HMGA2 is also expressed in the development of malignancy and, through its relationship to EMT, participates in tumor metastasis.In addition, the HMGA2 influences the tumor angiogenesis,interferes with the cell cycle,promote tumor cells to acquire stem cell characteristics and EMT to maintain the growth of tumor cells,differentiation, self-renewal ability and so on. Yet, while a correlation between HMGA2 overexpression and malignancy has been reported, the exact mechanism is not fully explained. In gastric cancer, for example,there are few studies on the consequences of HMAG2 overexpression inthese tumors. The aim of the present study was to use surgical gastric cancer specimens and patient clinicopathological data to investigate the clinical significance of HMGA2 overexpression in gastric cancer.At present,HDAC6 is one member of the 18 HDACs family which have been found in the human body. HDACs are divided into four categories: Ⅰ(HDAC1, 2, 3 and 8), Ⅱ(HDAC4, 5,6,7,9 and 10),Ⅲ,3,4,5,6(SIRT1, 2 and 7) and Ⅳ(HDAC11 only). Ⅰ, Ⅱ, Ⅳ were called classic HDACs. knocking down specific HDACs can cause death in mice with no defects, inhibition of HDAC6 gene expression can increase the acetylation of non-histone, thus inhibiting tumor occurrence and reduce cell migration.In our previous study, we used chromatin immunoprecipitation and promoter microarray(Ch IP-on-chip), then analysed the results through the KEGG-PATHWAY. it showed that HDAC6 might be a target gene of HMGA2 in the process of EMT in gastric cancer cells by Wnt/β-catenin pathway. This research aims to test the expression of the protein and m RNA between HMGA2 and HDAC6, secondly, the expression of HMGA2 and its downstream regulation target HDAC6 were analyzed. with gastric cancer and its correlation with clinical pathological data. IHC SP method,Western blot and Real-time PCR were used to detect the expressions of HMGA2 and its downstream regulation target HDAC6 in 82 gastric cancer specimens, corresponding peritumor specimens and normalones, relationships between expression levels of HMGA2 and HDAc6 were analyzed,associations between, and both expressions’ influences on the prognosis of patients Application of statistical methods were used to analyze the relationship between HMGA2 and HDAC6 immunohistochemical staining and corresponding clinicopathologic parameters and the effect of the expression of the two genes on the prognosis of gastric cancer patients.METHODS: IHC SP method, Western blot and Real-time PCR were used to detect the expressions of HMGA2 and its downstream signaling targets HDAC6 in 82 gastric cancer specimens, paired paracancerous specimens and normal ones. and both expressions’ influences on the prognosis of patients were analyzed. Statistical methods were used to analyze both the relationship between the expression levels of HMGA2 and HDAc6 immunohistochemical staining and clinical pathological parameters and the expression of two both on the prognosis of patients with gastric carcinoma.RESULTS : Among 82 gastric cancer specimens, respectively,the positive expression of HMGA2 and HDAC6 were 69.51%(57/82) and65.58%(54/82) in GC,, while peritumor tissues and normal gastric tissues were 14.63%(12/82),12.19%(10/82) and 9.76%(8/82),7.32%(6/82),P <0.05;The m RNA and protein levels of HMGA2 and HDAC6 in GC tissues were higher than those in the paired peritumor tissues and normaltissues,P < 0.05. Furthermore,the expression was obviously correlated to clinical stage of GC and lymph node metastases(P < 0.05),but no significant differences in sex, age, tumor size, degree of differentiation and tumor invasion in the serous membrane. The expression of HDAC6 protein was significantly associated with lymph node metastasis(P=0.009).Pearson rank correlation analysis show a positive correlation between the expression of HMGA2 and HDAC6 in GC tissues(r=0.56,P<0.05).CONCLUSIONS: The high expression of HMGA2 and HDAC6 coexist in GC tissues, It may be related to malignant transformation of tumor.