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AIM: To investigate the effect of pituitary homeobox 1 (PITX1) expression in cases of human gastric cancer on cancer differentiation and progression, and carcinogenesis.METHODS: Using polyclonal PITX1 antibodies, we studied the expression of PITX1 in normal gastric mucosa, atypical hyperplasia, intestinal metaplasia, and cancer tissue samples from 83 gastric cancer patients by immunohistochemistry. Moreover, semi-reverse transcription polymerase chain reaction (semi-RT-PCR)was performed to detect the mRNA level of PITX1 in three gastric cancer cell lines and a normal gastric epithelial cell line. Subsequently, somatic mutations of the PITX1 gene in 71 gastric cancer patients were analyzed by a combination of denaturing high performance liquid chromatography (DHPLC) and DNA sequencing.RESULTS: Immunohistochemistry showed that PITX1 was strongly or moderately expressed in the parietal cells of normal gastric mucosa (100%), while 55 (66.3%)out of 83 samples of gastric cancers showed decreased PITX1 expression. Moreover, PITX1 expression was reduced in 20 out of 28 cases (71.5%) of intestinal metaplasia, but in only I out of 9 cases (11%) of atypical hyperplasia. More importantly, PITX1 expression was significantly associated with the differentiation, position and invasion depth of gastric cancers (r = -0.316,P < 0.01; r = 0.213, P < 0.05; r = -0.259, P < 0.05,respectively). Similarly, levels of PITX1 mRNA were significantly decreased in 2 gastric cancer cell lines,BGC-823 and SGC-7901, compared with the normal gastric epithelial cell line GES-1 (0.306 ± 0.060 vs 0.722 ± 0.102, P < 0.05; 0.356 ± 0.081 vs 0.722 ± 0.102,P < 0.05, respectively). Nevertheless, no somatic mutation of PITX1 gene was found in 71 samples of gastric cancer by DHPLC analysis followed by sequencing.CONCLUSION: Down-regulation of PITX1 may be a frequent molecular event in gastric carcinogenesis.Aberrant levels of PITX1 expression may be closely correlated with the progression and differentiation of gastric cancer.