The Underlying Mechanism Of OCT1 Involving In The Development And Progression Of Gc And ASAP3 Involving In Gastric Acid Secretion

Section Ⅰ.OCT1 is a determinant of synbindin-related ERK signalling with independent prognostic significance in gastric cancerObjective: Octamer transcription factor 1(OCT1)was found to be expressed in intestinal metaplasia and gastric cancer(GC),but the exact roles of OCT1 in GC remain unclear.The objective of this study was to determine the functional and prognostic implications of OCT1 in GC.Design: Expression of OCT1 was examined in paired normal and cancerous gastric tissues and the prognostic significance of OCT1 was analysed by univariate and multivariate survival analyses.The functions of OCT1 on synbindin expression and extracellular signal-regulated kinase(ERK)phosphorylation were studied in vitro and in xenograft mouse models.Results: The OCT1 gene is recurrently amplified and upregulated in GC.OCT1 overexpression and amplification are associated with poor survival in patients with GC and the prognostic significance was confirmed by independent patient cohorts.Combining OCT1 overexpression with American Joint Committee on Cancer staging improved the prediction of survival in patients with GC.High expression of OCT1 associates with activation of the ERK mitogen-activated protein kinase signalling pathway in GC tissues.OCT1 functions by transactivating synbindin,which binds to ERK DEF domain and facilitates ERK phosphorylation by MEK.OCT1-synbindin signalling results in the activation of ERK substrates ELK1 and RSK,leading to increased cell proliferation and invasion.Immunofluorescent study of human GC tissue samples revealed strong association between OCT1 protein level and synbindin expression/ ERK phosphorylation.Upregulation of OCT1 in mouse xenograft models induced synbindin expression and ERK activation,leading to accelerated tumour growth in vivo.Conclusions: OCT1 is a driver of synbindin-mediated ERK signalling and a promising marker for the prognosis of GC.Section Ⅱ.ASAP3 is essential for gastric acid secretion in miceDeregulated gastric acidity associates with peptic ulcer and other diseases,but commonly used medicines such as proton pump inhibitors(PPIs)have been reported with resistance and side effects,suggesting a need for discovering new therapeutic approaches.Previous in vitro studies suggested potential roles of ASAP3(ARF-GAP containing SH3,ANK repeats and PH domain3)in gastric acid secretion and proton pump translocation.In the present study,we further evaluated the in vivo role of ASAP3 in depth by a conditional knockout mouse model.Targeted ASAP3 gene disruption resulted in impaired gastric acid secretion and gross histopatholoical transformation of gastric epithelium.The ASAP3-/-mice displayed Arf6 hyperactivation and actin rearrangement,as well as defects in H+-K+-ATPase translocation.Consistently,ultrastructure analysis of knockout parietal cells revealed significantly abnormal apical membranes.Our data highlight that ASAP3 is essential for gastric acid secretion in mice,and suggest ASAP3 as a potential therapeutic target for acid control.