RUNX3 And Pin1 Regulate β-catenin/cyclin D1 in Cancers of Upper Digestive Tract

Abstract

Cancer is one of major health issues Gastric cancer and esophageal squamous cell carcinoma (ESCC) are common and fatal malignancy Despite multi-modality therapies most patients eventually die from the disease or treatment-related complications More comprehensive investigations of carcinogenesis and tumor progression are necessary for developing novel diagnostic and therapeutic strategies for these cancers RUNX3 is recognized as a tumor suppressor The tumor suppressive functions of RUNX3 were first reported in gastric epithelial cells RUNX3 was inactivated by gene silencing or protein mislocalization in more than 80% of gastric cancers Although restoration of RUNX3 in gastric cancer cells could inhibit tumorigenesis through regulating several target genes the mechanisms were not clearly understood The role of RUNX3 in regulating β-catenin and cyclin D1 in gastric cancer was studied in my thesis RUNX3 repressed Akt1 expression through transcriptional inhibition Two RUNX3-binding sites on Akt1 promoter were identified The inhibition of Akt1 facilitated β-catenin degradation followed by cyclin D1 downregulation The data suggested loss of RUNX3 in gastric cancer promoted tumorigenesis through Akt1/β-catenin/cyclin D1 signaling pathway β-catenin and cyclin D1 are well known substrates of Pin1 which is a peptidyl-prolyl isomerase and promotes oncogenesis by regulating multiple oncogenic signaling at various levels Pin1/β-catenin/cyclin D1 signaling pathway in ESCC was investigated The experimental evidences were provided that Pin1 knockdown inhibited expression of β-catenin/cyclin D1 and tumorigenesis of ESCC cells The inhibited tumorigenesis in cells with Pin1 knockdown was partially recovered by cyclin D1 restoration In addition high Pin1 expression was correlated with poor prognosis of ESCC patients The results supported that Pin1 may promote ESCC aggressiveness through β-catenin and cyclin D In summary β-catenin and cyclin D1 are repressed by tumor suppressor RUNX3 but positively regulated by Pin1 in cancers of upper digestive tract The results of my thesis can help people understand carcinogenic mechanisms and provide rationales for developing novel target therapy of cancer in the future

Date of Award	2014 Dec 4
Original language	English
Supervisor	Bor-Shyang Sheu (Supervisor)