title: Proteomic identification of betaig-h3 as a lysophosphatidic acid-induced secreted protein of human mesenchymal stem cells: paracrine activation of A549 lung adenocarcinoma cells by betaig-h3.
abstract: Lysophosphatidic acid (LPA) is enriched in the serum and malignant effusion of cancer patients and plays a key role in tumorigenesis and metastasis. LPA-activated mesenchymal stem cells promote tumorigenic potentials of cancer cells through a paracrine mechanism. LPA-conditioned medium (LPA CM) from human adipose tissue-derived mesenchymal stem cells (hASCs) elicited adhesion and proliferation of A549 human lung adenocarcinoma cells. To identify proteins involved in the LPA-stimulated paracrine functions of hASCs, we analyzed the LPA CM using liquid-chromatography tandem mass spectrometry-based shotgun proteomics. We identified βig-h3, an extracellular matrix protein that is implicated in tumorigenesis and metastasis, as an LPA-induced secreted protein in hASCs. LPA-induced βig-h3 expression was abrogated by pretreating hASCs with the LPA receptor(1/3) inhibitor Ki16425 or small interfering RNA-mediated silencing of endogenous LPA(1). LPA-induced βig-h3 expression was blocked by treating the cells with the Rho kinase inhibitor Y27632, implying that LPA-induced βig-h3 expression is mediated by the LPA(1)- Rho kinase pathway. Immunodepletion or siRNA-mediated silencing of βig-h3 abrogated LPA CM-stimulated adhesion and proliferation of A549 cells, whereas retroviral overexpression of βig-h3 in hASCs potentiated it. Furthermore, recombinant βig-h3 protein stimulated the proliferation and adhesion of A549 human lung adenocarcinoma cells. These results suggest that hASC-derived βig-h3 plays a key role in tumorigenesis by stimulating the adhesion and proliferation of cancer cells and it can be applicable as a biomarker and therapeutic target for lung cancer.
authors.affiliation: Medical Research Center for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Shin
authors.forename: Jaeyoon
authors.initials: J
authors.lastname: Kim
authors.forename: Soon Chul
authors.initials: SC
authors.lastname: Heo
authors.forename: Yang Woo
authors.initials: YW
authors.lastname: Kwon
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.forename: Taehoon G
authors.initials: TG
authors.lastname: Lee
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D019899:Paracrine Communication; D020543:Proteome / Q000032:analysis; D040901:Proteomics; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases / Q000378:metabolism; D000099222:betaIG-H3 Protein
chemical_list: D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D008246:Lysophospholipids; D020543:Proteome; D049368:Receptors, Lysophosphatidic Acid; D016212:Transforming Growth Factor beta; D054460:rho-Associated Kinases; D000099222:betaIG-H3 Protein; C032881:lysophosphatidic acid