Changes Of Cdx2 And Muc2 Expression In Gastric Cardia Adenocarcinoma And Intestinal Metaplasia Adjacent To Gastric Cardia Adenocarcinoma

BackgroundGastric cardia adenocarcinoma (GCA) is one of the most common malignant digestive diseases in northern China, especially Linzhou in Henan Province. GCA has a remarkable epidemiological characteristic, which is very similar geographic distribution with esophageal squamous cell carcinoma (ESCC). In contrast to the strikingly decline of incidence of distal gastric cancer in America and Europe in the past two decades, the incidence of GCA increased dramatically. The incidence of esophageal-gastric-junction cancer has raised to 6-folds with a speed of 20% annually, which is one of the fastest increasing malignant diseases. The reason is not clear yet. There were several differentes between GCA and distal gastric cancer in respect of epidemiology, etiology, pathology and clinical characteristics. Thus GCA should be categorized as a clinically distinct disease. Deficiency of sensitive biomarkers and techniques for early diagnose, as well as the lack of effective treatment and chemo prevention, leads to GCA has high mortality rate and poor prognosis. It has been well known that intestinal metaplasia (IM) is considered as precancerous lesion for distal gastric cancer. Mass survey and follow-up studies by us have showed that IM in gastric cardia tissue, especially in cancer tissues was extreme common at HIA in Henan. However, the research of the relationships between IM and GCA is very limited and the information for molecular basis of GCA is much less. So far, GCA classification based on different IM types has not been reported. CDX2 and MUC2 have been demonstrated to be the intestine specificity genes. CDX2 was an important factor to intestinal metaplasia, which attached to caudal type homeobox gene family. And the high positive expression of MUC2 protein (+++) in goblet cell was one of the features of IM. To further understand significance of IM in carcinogenesis of GCA and related molecular changes, the present study was undertaken to determine the histological chemistry characteristic and the expression of CDX2 and MUC2 in GCA and IM adjacent to GCA from the patients in Linzhou.Materials and MethodsOne hundred and ninety five surgically resected GCA tissues were enrolled from GCA patients in Linzhou Central Hospital in Henan in 2005. Either chemotherapy or radiotherapy had not been treated on all the patients before operation. All the resected tissues were fixed with 85% alcohol, paraffin embedded and serially sectioned for histopathological diagnosis. Histochemical (AB-PAS and HID-AB methods) and immunohistochemical analysis (SP method) were applied to the resected tissues with IM adjacent to GCA and resected tissues with GCA, to determine the type of mucus protein in IM, the expression of CDX2 and MUC2 proteins in IM and GCA tissues and the relationship with lesion progress. The x~2 test and Spearman rank correlation test were used for the statistical analysis (P < 0.05 was considered significant).Results1. Prevalence and histochemistry of IM and the relationship between IM types and pathology①The detection rate of IM adjacent to GCA was 38% (74/195). The differences among the rates of the four IM types were significant (P<0.05). The detection rate of complete colonic type IM was 36% (27/74), which occurred more frequently than other three types (P<0.05). ②The positive expression rate of complete colonic type IM was significantly correlated with lymph nodes metastasis, infiltration and tumor differentiation (P<0.05). The positive expression rate of complete intestinal-type IM was signifcantly correlated with TNM staging and clinical stages (P<0.05).2. Expression of CDX2 and MUC2 in GCA and IM adjacent to GCA①The positive expression of CDX2 protein (+～+++) in GCA tissues was significantly lower than that in IM adjacent to GCA (P<0.05).②The positive expression of MUC2 protein (+～+++) in GCA tissues was significantly lower than that in IM adjacent to GCA(P<0.05).3. Expression of CDX2 and MUC2 in the four IM types①The positive expression of CDX2 protein (+～+++) in incomplete intestinal-type IM was significantly lower than that in the other types (P<0.05).②The positive expression of MUC2 protein (+～+++) in incomplete intestinal-type IM was significantly lower than that in the other types (P<0.05).4. Correlation of CDX2 and MUC2 in GCA and IM adjacent to GCA Expression of CDX2 and MUC2 in GCA was positively correlated (P<0.05) andthat in IM adjacent to GCA was not correlated (P>0.05) .Conclusions1. IM adjacent to GCA was very common at HIA in Henan, and its detection rate was apparently high, indicating that IM may be related to GCA; Most of them belong to complete type, which was different from Barrett's esophagus and IM in gastric antrum, indicating that IM adjacent to GCA has special mucin protein.2. The positive expression rate of complete colonic type IM was significantly different among lymph nodes metastasis, infiltration and tumor differentiation, which showed that complete colonic type IM may be relevant to the development, infiltration and transfer of GCA; the positive expression rate of complete intestinal-type IM was significantly correlated with TNM staging and clinical stages, which indicated that complete intestinal-type IM may be relevant to the canceration of GCA. 3. The positive expression of CDX2 and MUC2 in GCA tissues were significantly lower than that in IM adjacent to GCA, indicating that expression of CDX2 and MUC2 was reduction in the progression of IM and GCA.4. The positive expression of CDX2 and MUC2 in incomplete intestinal-type IM were significantly lower than that in the other types, suggesting that incomplete intestinal-type IM may be precancerous lesions of GCA, as well as the other types had the lower risk of canceration.5. Expression of CDX2 and MUC2 in GCA was positively correlated, indicating that higher CDX2 expression, MUC2 expression also increased; expression of CDX2 and MUC2 in IM adjacent to GCA was not correlated, suggesting that expression of them do not have synergistic action in IM.