title: FERMT1 mediates epithelial-mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity.
abstract: We previously demonstrated that fermitin family member 1 (FERMT1) was significantly overexpressed in colon cancer (CC) and associated with poor metastasis-free survival. This study aimed to investigate the precise role of FERMT1 in CC metastasis and the mechanism by which FERMT1 is involved in the epithelial-mesenchymal transition (EMT). Correlations between FERMT1 and EMT markers (E-cadherin, Slug, N-cadherin and β-catenin) were examined via immunohistochemistry in a cohort of CC tissues and adjacent normal colon mucosae. A series of in vitro and in vivo assays were performed to elucidate the function of FERMT1 in CC metastasis and underlying mechanisms. The upregulated expression of FERMT1 in CC tissues correlated positively with that of Slug, N-cadherin and β-catenin, but correlated inversely with E-cadherin expression. Altered FERMT1 expression led to marked changes in the proliferation, migration, invasion and EMT markers of CC cells both in vitro and in vivo. Investigations of underlying mechanisms found that FERMT1 interacted directly with β-catenin and activated the Wnt/β-catenin signaling pathway by decreasing the phosphorylation level of β-catenin, enhancing β-catenin nuclear translocation and increasing the transcriptional activity of β-catenin/TCF/LEF. Activation of the Wnt/β-catenin pathway by CHIR99021 reversed the effect of FERMT1 knockdown, whereas inhibition of the Wnt/β-catenin pathway by XAV939 impaired the effect of FERMT1 overexpression on EMT and cell motility. In conclusion, findings of this study suggest that FERMT1 activates the β-catenin transcriptional activity to promote EMT in CC metastasis.
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: C-C
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Drug allocation center, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: D-L
authors.initials: DL
authors.lastname: Cai
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: F
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Hapatobiliary Surgery, Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Yue
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: S-L
authors.initials: SL
authors.lastname: Zhao
authors.affiliation: Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: X-S
authors.initials: XS
authors.lastname: Wu
authors.affiliation: Department of Pathology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: X-W
authors.initials: XW
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Peng
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: D-W
authors.initials: DW
authors.lastname: Yan
mesh_terms: D015415:Biomarkers; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014158:Transcription, Genetic; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015820:Cadherins; C475301:FERMT1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt