title: Histone demethylase RBP2 promotes malignant progression of gastric cancer through TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit.
abstract: Some feedback pathways are critical in the process of tumor development or malignant progression. However the mechanisms through which these pathways are epigenetically regulated have not been fully elucidated. Here, we demonstrated that the histone demethylase RBP2 was crucial for TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit that was implicated in malignant progression of tumors and its knockdown significantly inhibited gastric cancer (GC) metastasis both in vitro and in vivo. Mechanistically, RBP2 can directly bind to E-cadherin promoter and suppress its expression, facilitating EMT and distant metastasis of GC. RBP2 can also be induced by TGF-β1, a key inducer of EMT, through phosphorylated Smad3 (p-Smad3) pathway in GC. The upregulated RBP2 can be recruited by p-smad3 to E-cadherin promoter and enhance its suppression, contributing to the promotion of metastasis of GC. In addition, the suppression of E-cadherin by RBP2 attenuated inhibition of Smad3 phosphorylation (exerted by E-cadherin), resulting further induction of RBP2 expression, and thus constituting positive feedback regulation during GC malignant progression. This TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit may be a novel mechanism for GC malignant progression and suppression of RBP2 expression may serve as a new strategy for the prevention of tumor distant metastasis.
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Xiuming
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Biochemistry, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Ci
authors.affiliation: Department of Nursing, Ningxia Peoples Hospital, Yinchuan, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Mutian
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Gastrointestinal Surgery, Jinan Central Hospital, Shandong University, Jinan, Shandong, PR China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Yundong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biochemistry, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Shili
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Jia
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D054840:Retinol-Binding Proteins, Cellular / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D015820:Cadherins; C518459:RBP2 protein, human; D054840:Retinol-Binding Proteins, Cellular; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1
keywords: RBP2; TGF-β1; feedback circuit; metastasis