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Prolyl 4-hydroxylase alpha subunit is the enzymic active site of prolyl 4-hydroxylase, which is a critical enzyme to maintain the stability of newly synthesized collagens. The expression profile and functional role of P4HA3 in gastric cancer have not been explored. In the Cancer Genome Atlas-Stomach Cancer, P4HA3 RNA is significantly upregulated in gastric cancer than in normal stomach tissues. In the Human Protein Atlas, Prolyl 4-hydroxylase alpha subunit is not detectable by immunohistochemistry staining in normal stomach tissues, but it has weak staining in 7 of 12 gastric cancer tissues. Further study showed that SNAI2 (encoding Slug) is highly coexpressed with P4HA3 (Pearson r = 0.70) in Cancer Genome Atlas-Stomach Cancer. In vitro cell assay showed that Slug could efficiently bind to the P4HA3 promoter and increase its transcription. P4HA3 exon array data in Cancer Genome Atlas-Stomach Cancer revealed that 2 exons are significantly upregulated in M1 (N = 27) cases than in M0 (N = 367) cases. In MKN-45 and AGS cells, P4HA3 upregulation could enhance cell motility and invasiveness. In Cancer Genome Atlas-Stomach Cancer, high P4HA3 exon expression is associated with significantly worse 5-year and 10-year overall survival ( P = .007 and .009, respectively). Data mining in Kaplan-Meier plotter also showed that high P4HA3 expression is related to unfavorable overall survival (hazard ratio: 1.54, 95% confidence interval: 1.23-1.93, P < .001) and first progression-free survival (hazard ratio: 1.64, 95% confidence interval: 1.29-2.1, P < .001). Based on findings above, we infer that P4HA3 is epigenetically activated by Slug, and its deregulation is associated with enhanced metastasis and poor survival of gastric cancer.

P4HA3is Epigenetically Activated by Slug in Gastric Cancer and its Deregulation is Associated With Enhanced Metastasis and Poor Survival