| Over the past several decades, Western populations have seen a shift in both the location and lethality of gastric cancers. The distal gastric cancers (DGC) have become rare, while the incidence of adenocarcinoma of the proximal stomach and distal esophagus has risen. Esophageal adenocarcinoma has increased significantly. Interest in adenocarcinomas of the esophagogastric junction (AEG) has recently increased, especially in the West. The epidemiology, risk factors, classification, diagnosis and treatment of AEG were widely studied. As we know that the incidence of Barrett's Esophaghus and esophageal adenocarcinoma was very lower in China. All the adenocarcinomas in the vicinity of esophagogastric junction were categorized as gastric cardia carcinoma. Few studies about adenocarcinoma of the esophagogastric junction in China have been seen. And cardia carcinoma was not listed as distict entity independent of gastric cancer in the cancer registry forms in our country. Some basic problems of AEG in Chinese people, such as the epidemiology, incidence and clinical pathological features were still not clear.Gene regulation at transcription level is an interesting subject in the study of carcinogenesis and progression of malignant tumors. KLF4,SP1 and Cyclin D1 are all important factors involving in the proliferation and malignant transformation of cells.Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that binds to a consensus sequence 5'-(G/A)(G/A)GG(C/T)G(C/T)-3'. It is a member of the KLF family and is highly expressed in the gastrointestinal tract and other epithelial tissues. KLF4 can either activate or repress the transcription of several genes, and its alterations lead to aberrant proliferation and differentiation in gastric and colonic epithelium. Additionally, accumulating clinical evidence shows that KLF4 is a potential tumor suppressor. Reduced KLF4 expression has been reported in various tumors including esophagus, stomach, colon, bladder, lung, and adult T cell leukemia cells. And Restored KLF4 expression induces growth arrest in several tumor cells. Sp1 is also a zinc finger transcription factor that is important to the transcription of many cellular and viral genes that contain GC boxes in their promoter. Although Sp1 has been perceived as a basal transcription factor since its discovery, increasing evidence suggests that it regulates a variety of biological functions, including cell survival, growth and differentiation, and tumor development and progression. Sp1 overexpression is directly correlated with the angiogenic potential and poor prognosis of human gastric cancer.Recently, though studies on the expression and significance of KLF4, SP1 and cyclin D1 in gastric carcinoma could be seen in the literatures, but none of them involved in the cardia carcinoma. And the putative differences in the expression of KLF4, SP1 and cyclin D1 between AEG and distal gastric carcinoma are still unknown.Based on the afore-mentioned reasons, we conducted the following study. The study included the following two parts. Part I Changes of the proportion of cardia and distal gastric carcinoma in Cixian and Zanhuang County, Hebei province ObjectiveTo explore the trend of changes in the location of gastric carcinoma in the past decades and to determine the proportion of AEG in our country, we retrospectively analyzed the percentages of gastric cancers arised from different location of stomach, eg, cardia, body and distal gastric part in the residents of Cixian and Zanhuang County, which is respectively high incidence area of esophageal carcinoma and gastric carcinoma in Hebei province, from 1993 to 2006.MethodAll the gastric cancer cases (n=4334) of the local residents in Cixian county and Zanhuang county initially diagnosed from 1993 to 2006 were included. The clinical data and pathological materials were retrospectively analysed. The percentages of gastric cancers arised from different location of stomach, eg, cardia, body and distal gastric part was calculated. And the changes in the recidence of gastric carcinoma from different locations in that peroid were evaluated.ResultsOver the peroid from 1993 to 2006, among the 4334 gastric carcinoma cases, cardia adenocarcinoma account for 68.0%, which was significantly higher than that from corpus and autrum (24.2% and 7.8% respectively), and an increasing tendency in the proportion of cardia adenocarcinoma as the time progressed was seen.The average age of the patients of cardia carcinoma was higher than that of corpus and autrum (61.60±9.07 vs 59.87±10.20, P<0.01;61.60±9.07 vs 60.18±10.56, P<0.01). The percentages of cardia cancer in the high incidence area of esophageal carcinoma -Cixian county was much higher than that in the high incidence area of gastric cancer-Zanhuang county (71.2% vs 51.2%).The increases in the proportion of cardia cancer in Cixian county was due to the increase of cardia cancer from 1993 to 2006,while the contributing factor for the increase in the proportion of cardia cancer was the results of the decrease in the proportion of antrum cancer in Zanhuang at the same peroid (P<0.05).Part II Comparative study on the expression of KLF4, SP1 and Cyclin D1 between AEG and DGCObjectiveOn the bases of the results in the first part of this study, to explore the biological specificity and to analyze the possible difference in the carcinogenesis, the expression of KLF4, SP1 and cyclin D1 at protein level in AEG and distal gastric carcinoma was comparatively studied with immunohistochemical staining.Method1 Formalin fixed, paraffin embedded tissue blocks of 152 cases of AEG and DGC, archived from 2004 to 2006 in Department of Pathology, the Second Hospital, Hebei Medical University and Department of Pathology, Cixian County Hospital were included in this study. The expression of KLF4, SP1 and Cyclin D1 was studied in 58 cases of Siewert II type AEG, 47 cases of Siewert III type AEG, 47 cases of DGC by SP immunohistochemical staining method. All cases in each group were subgrouped into high-differentiated cases (tubular adenocarcinoma, mpapillary adenocarcinoma, moderately adenocarcinoma) and low-differentiated cases (poorly-differentiated adenocarcinoma, mucoid adenocarcinoma, signet-ring cell carcinoma). The clinical pathological significances of KLF4, SP1 and Cyclin D1 expression were analyzed.2 The experimental data were statistically analyzed with Chi-square test, Fisher's exact test and correlation analysis with statistics software of SPSS13.0 edition.Results1 Expressions of KLF4 in different groups1.1 Expressions of KLF4 in AEG and DGCImmunohistochemical staining results showed that the positive expression of KLF4 in AEG was higher than that in DGC (65.7% vs 43.6%,P<0.05). Among the two different types of AEG, the positive expression of KLF4 in Siewert II type AEG was significantly higher than that in DGC (70.0% vs 43.6%,P<0.05). There was no statistical significance in KLF4 expression between Siewert III type AEG and DGC cases (65.9% vs 43.6%, P>0.05). Further analysis showed that the positive expressions of KLF4 in both the high-differentiated group and low-differentiated group of Siewert II type AEG were all significantly higher that their corresponding cases in DGC (79.2% vs 53.3%, P<0.05; 61.8% vs 23.5%, P<0.05).1.2 The clinical pathological significance of KLF4 expression in AEG and DGCThe positive expression of KLF4 was not significantly related with sex and age of the patients,differatiation, size and infiltrating depth of tumor and lymph node metastasis in Siewert II type AEG(P>0.05). while in DGC, the positive expression of KLF4 was significantly higher in high-differentiated group than that in low-differentiated group(53.3% vs 23.5%, P<0.05). The positive expression of KLF4 was significantly higher in cases without lymph node metastasis than that with lymph node metastasis group(63.2% vs 28.6%, P<0.05). The expression of KLF4 in DGC was not related with sex and age of patient, size of tumor and depth of invasion (P>0.05).2 Expressions of SP1 in different groups2.1 Expressions of SP1 in AEG and DGCImmunohistochemical staining results showed that the positive expression of SP1 in AEG was lower than that in DGC (43.8% vs 68.1%, P<0.05). The positive expression of SP1 in Siewert II type AEG was lower than that in DGC (40.0% vs 68.1%, P<0.05). There was no statistical significance in the SP1 expression between Siewert III AEG and DGC(48.9% vs 68.1%, P>0.05). In high-differentiated group the positive expression of SP1 in Siewert II type AEG was lower than that in DGC(25.0% vs 80.0%, P<0.05). While in low-differentiated group the positive expression rate of SP1 in Siewert II type AEG was lower than that in DGC, but it was not statistically significant(25.9% vs 47.1%, P=0.05).2.2 The clinical pathological significance of SP1 ExpressionThe expression of SP1 was not related with sex and age of the patients,differatiation and size of tumor , depth of invation and lymph node metastasis in Siewert II type AEG(P>0.05). But the expression of SP1 in DGC was closely related with differentiation and metastasis of tumor. The positive expression of SP1 was significantly lower in high-differentiated group than that in low-differentiated group (60.0% vs 82.3%, P<0.05). The positive expression of SP1 was lower in cases without lymph node metastasis than that in cases with lymph node metastasis group (47.4% vs 82.1%, P<0.05). The same as in AEG, the expression of SP1 in DGC was not related with sex, and age of patients, size of tumor and depth of invasion (P>0.05).3 Expressions of Cyclin D1 in different groups3.1 Expressions of Cyclin D1 in AEG and DGC Immunohistochemical staining results showed that the expression of Cyclin D1 was not statistically significant between groups (P>0.05).3.2 The clinical pathological significance of Cyclin D1 ExpressionAmong the Siewert II type AEG, the positive expression of Cyclin D1 was lower in high-differentiated group than that in low-differentiated group (25.0% vs 58.8%, P<0.05). The positive expression of Cyclin D1 was lower in cases without lymph node metastasis than that in case with lymph node metastasis(22.7% vs 58.3%, P<0.05). The expression of Cyclin D1 in Siewert II type AEG was not related with sex and age of patients,size of tumor and depth of invasion (P>0.05). In cases of DGC, the positive expression of Cyclin D1 was lower in high-differentiated group than that in low-differentiated group(30.0% vs 70.6%, P<0.05). The positive expression of Cyclin D1 was lower in cases without lymph node metastasis than that in cases with lymph node metastasis (26.3% vs 57.1%, P<0.05). The expression of Cyclin D1 in DGC was not related with sex and age of patient, size of tumor and depth of invasion (P>0.05).4 Relationship between the expression of KLF4,SP1 and Cyclin D1 in Siewert II type AEG and DGCPositive expression of KLF4 and SP1 was reversely related in Siewert II type AEG,inverse correlation could be found between the positive expression of KLF4 and SP1 (r_s=-0.294, P=0.025). There was no correlation between positive expression of KLF4 and Cyclin D1 (r_s =-0.145, P=0.278) in Siewert II type AEG.Inver_se correlation could be found between the positive expression of KLF4 and SP1(r_s =-0.294, P=0.025),KLF4 and Cyclin D1(r_s =-0.341, P=0.019) in DGC.ConclusionsPART I1 The major site of gastric carcinoma has been cardia in high incidence area of esophageal and gastric carcinoma, Hebei province for the past decades. Cardia adenocarcinoma acounts for more than half of all gastric carcinoma cases, and the average age of the patients of cardia adenocarcinoma was higher than that of adenocarcinoma in corpus and autrum.2 Over the peroid from 1993 to 2006, an increasing tendency in the proportion of cardia adenocarcinoma was seen. The increases in the proportion of cardia adenocarcinoma in Cixian County was mainly due to the increase of cardia adenocarcinoma, while the contributing factor for the increase in the constituent ratio of cardia adenocarcinoma was the results of the decrease in the proportion of adenocarcinoma in antrum in Zanhuang County.PART II1 Significant differences could be found in the expression of KLF4 and SP1 between Siewert II type AEG and DGC. The expression of KLF4 and SP1 in Siewert II type AEG was respectively higher and lower than that in DGC. No significant difference was seen in the expression of Cyclin D1 between Siewert II AEG and DGC.2 In Siewert II type AEG, the expression of Cyclin D1 was closely related with differentiation and metastasis, but no clinical pathological significance for the expression of KLF4 and SP1 was found. While in DGC, the expression of KLF4, SP1 and Cyclin D1 were all closely related with differatiation and metastasis.
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