title: Downregulation of tumor suppressing STF cDNA 3 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by the Wnt/GSK-3β/β-catenin/Snail signaling pathway.
abstract: Epithelial to mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining the invasive and metastatic behavior of cells during cancer progression. Our previous study showed that loss of expression of TSSC3 is positively associated with osteosarcoma malignancy and progression. However, whether TSSC3 mediates EMT in osteosarcoma is poorly understood. In the present study, we determined that TSSC3 downregulation induced cell migration and invasion ability and promoted mesenchymal transition of osteosarcoma cells by upregulating mesenchymal markers and inhibiting the epithelial markers. Furthermore, TSSC3 downregulation elicited a signaling cascade that included increased levels of Wnt3a and LRP5, inactivation of GSK-3β, accumulation of nuclear β-catenin and Snail, the augmented binding of β-catenin to TCF-4, and accordingly increased the expression of Wnt target genes (CD44, MMP7). The gene knockdown of these signaling proteins could inhibit TSSC3 downregulation-promoted EMT, migration, and invasion in osteosarcoma. Finally, TSSC3 overexpression obviously inhibited cell migration, invasion, and repressed mesenchymal phenotypes, reducing lung metastasis through GSK-3β activation. Collectively, TSSC3 downregulation promotes the EMT of osteosarcoma cells by regulating EMT markers via a signal transduction pathway that involves Snail, Wnt-β-catenin/TCF, and GSK-3β.
authors: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China.
authors: Yang-fan
authors: YF
authors: Lv
authors: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China; Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
authors: Huanzi
authors: H
authors: Dai
authors: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China.
authors: Guang-ning
authors: GN
authors: Yan
authors: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China; Department of Pathology, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
authors: Gang
authors: G
authors: Meng
authors: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China; Department of Pathology, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
authors: Xi
authors: X
authors: Zhang
authors: Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China. Electronic address: qiaonan85@263.com.
authors: Qiao-nan
authors: QN
authors: Guo
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000502:physiology*; D012516:Osteosarcoma / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C109277:TSSC3 protein; D014157:Transcription Factors; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: EMT; Osteosarcoma; TSSC3; metastasis