Casein kinase 2 interacting protein 1 positively regulates caudal-related homeobox 1 in intestinal-type gastric cancer

Background:Gastric cancer(GC)is one of the most common malignancies,and intestinal-type GC is the main histopathologic type of GC in China.We previously reported that casein kinase 2 interacting protein 1(CKIP-1)acts as a candidate tumor suppressor in intestinal-type GC.CKIP-1 participates in the regulation of multiple signaling pathways,including the Wnt/b-catenin pathway,of which caudal-related homeobox 1(CDX1)may be a downstream target gene.The purpose of this study was to investigate the relationship between CKIP-1 and CDX1 in intestinal-type GC.Methods:Sixty-seven gastroscopy biopsy specimens and surgically resected gastric specimens were divided into four groups:gastric mucosa group,intestinal metaplasia(IM)group,dysplasia group,and intestinal-type GC group.The expression levels of CKIP-1 and CDX1 were detected in these groups and GC cell lines,and the correlations between these expression levels were analyzed.SGC7901 and BGC823 cells were divided into CKIP-1 shRNA groups and CKIP-1 over-expression groups,and CDX1 expression was detected.b-Catenin expression was detected in intestinal-type GC tissue samples and CKIP-1 shRNA and CKIP-1 overexpression SGC7901 cells,and its correlation with CKIP-1 expression in intestinal-type GC tissue was analyzed.The Wnt/b-catenin pathway inhibitor DKK-1 and activator LiCl were incubated with SGC7901 cells,BGC823 cells,and CKIP-1 shRNA and CKIP-1 over-expression SGC7901 and BGC823 cells,following which CDX1 and Ki-67 expression were detected.Results:The expression levels of CKIP-1 and CDX1 were lower in patients with intestinal-type GC than in patients with IM and dysplasia(both P<0.05).CKIP-1 and CDX1 expression levels were positively correlated in IM,dysplasia,and intestinal-type GC tissue and cell lines(r=0.771,P<0.01;r=0.597,P<0.01;r=0.654,P<0.01;r=0.811,P<0.01,respectively).CDX1 expression was decreased in the CKIP-1 shRNA groups and increased in the CKIP-1 over-expression groups of SGC7901 and BGC823 cells compared to that in the corresponding control groups(both P<0.05).CKIP-1 expression was negatively correlated with b-catenin expression in intestinal-typeGCpatients(r=0.458,P<0.01).Compared to the control group,b-catenin expression was increased in the CKIP-1 shRNA SGC7901 cell group and decreased in the CKIP-1 over-expression SGC7901 cell group(P<0.05).CDX1 expression was increased inSGC7901 andBGC823 cells treatedwithDKK-1,DKK-1 increasedCDX1 expression and decreased Ki-67 expression in the CKIP-1 shRNA group;the opposite result was observed in SGC7901 and BGC823 cells treated with LiCl,and LiCl decreased CDX1 expression and increased Ki-67 expression in the CKIP-1 over-expression group(both P<0.05).Conclusions:Through the Wnt/b-catenin signaling pathway,CKIP-1 may positively regulate CDX1 in intestinal-type GC.

New insights into the functions and localization of the homeotic gene CDX2 in gastric cancer

Gastric cancer is one of the most frequent cancers,and it ranks the third most common cancer in China.The most recently caudal-related homeobox transcription factor 2(CDX2)is expressed in a large number of human gastrointestinal cancers.In addition,gastric epithelial cell mutations in CDX2 result in tumor promotion,which is characterized by cellular drug resistance and a high proclivity for developing cancer.A series of publications over the past years suggests a mechanism by which CDX2 overexpression results in multidrug resistance.CDX2 appears to forward control regenerating Ⅳand the multidrug resistance 1 expression signaling pathway for regulation of cell drug resistance.

Relationships of CDXs and apical sodium-dependent bile acid transporter in Barrett's esophagus

Barrett's esophagus (BE) is characterized by intestinal metaplasia with the differentiated epithelium replaced by another type of epithelium morphologically similar to normal intestinal epithelium. The metaplasia is preceded by bile and acid reflux into the esophagus. BE is a premalignant condition associated with increased risk of esophageal cancer, especially esophageal adenocarcinoma. The Caudal-related homeodomain transcription factors Caudal-related homeodomain transcription factor CDX1 and CDX2 are expressed exclusively in the small and large intestine, playing important roles in proliferation and differentiation of intestinal epithelial cells. Ectopic expression of CDX1 and CDX2 occurs in BE. The apical sodium-dependent bile acid transporter (ASBT) is expressed primarily in terminal ileum where it is a key factor for intestinal reabsorption of bile salts. In addition to upregulation of CDX1 and CDX2, ASBT expression is up-regulated in BE. Furthermore, both CDX1/CDX2 and ASBT expressions are down-regulated in high-grade esophageal dysplasia. The alteration of the above-mentioned factors calls for attention: what is the relationship between CDXs and ASBT aberrant expression in BE? In this commentary, we discuss this issue on basis of the recent study done by Ma et al .