title: Novel signaling collaboration between TGF-β and adaptor protein Crk facilitates EMT in human lung cancer.
abstract: The signaling adaptor protein Crk has been shown to play an important role in various human cancers. However, its regulatory machinery is not clear. Here, we demonstrated that Crk induced EMT in A549 human lung adenocarcinoma cells through differential regulation of Rac1/Snail and RhoA/Slug, leading to decreased expression of E-cadherin and increased N-cadherin, fibronectin, and MMP2 expression. Cancer cells with mesenchymal features produced TGF-β and also increased the levels of TGF-β receptor. TGF-β increased the endogenous levels of Crk and also augmented Crk-dependent expression of Snail and Slug, and conversely TGF-β receptor inhibitor suppressed the levels of Snail and Slug. Overexpression of Crk was observed at the invasive front of human lung cancer tissues and was significantly associated with poor prognosis. Thus, TGF-β and Crk collaborate to form a positive feedback loop to facilitate EMT, which may lead to the malignancy of human cancers possibly being affected by their microenvironment.
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Aiman Z
authors.initials: AZ
authors.lastname: Elmansuri
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Mishie A
authors.initials: MA
authors.lastname: Tanino
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Roshan
authors.initials: R
authors.lastname: Mahabir
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kinoshita
authors.affiliation: Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Dosaka-Akita
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.|Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000072283:A549 Cells; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: C485285:CRK protein, human; D050737:Proto-Oncogene Proteins c-crk; D016212:Transforming Growth Factor beta
keywords: Crk; EMT; TGF-β; lung cancer; small G protein