title: Targeting of the β6 gene to suppress degradation of ECM via inactivation of the MAPK pathway in breast adenocarcinoma cells.
abstract: Integrin ανβ6 has emerged as a potential novel target for anticancer and plays a major role in promoting malignant tumor progression. Recent studies indicate that integrin ανβ6 occurs in many cancers. However, whether and how ανβ6 is regulated by genetic and epigenetic mechanisms in breast cancer remain unknown. In the present study, two different short hairpin RNAs (shRNAs) targeting the β6 gene were designed and constructed into pSUPER, respectively, which were transfected into the MCF-7 human breast adenocarcinoma cell line. The β6-shRNA stably transfected cells were successfully established, and significant lower levels of ανβ6 mRNA and protein expression were confirmed. Furthermore, inhibition of integrin ανβ6 markedly downregulated the expression of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-3 (MMP-3) and urokinase plasminogen activator (uPA) in tumor conditioned medium. Furthermore, β6-shRNA-mediated silencing of the ανβ6 gene obviously decreased the expression of ERK1/2. In particular, supression of integrin ανβ6 caused significant downregulation of the degradation of basement membrane type IV collagen secretion via modulation of the plasminogen activation cascade. Our results thus indicate that ανβ6 plays a fundamental role in promoting invasion and growth of breast adenocarcinoma cells. Taken together, this study revealed that targeting of the β6 gene by RNA interference (RNAi) could efficiently downregulate ανβ6 expression and suppress the ERK1/2-dependent extracellular matrix degradation in vitro, which is dependent upon inactivation of the mitogen-activated protein kinase (MAPK) pathway. These findings may offer a useful therapeutic approach to block invasion and migration of breast cancer cells.
authors.affiliation: Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Urology, Shandong Provincial Hospital, Jinan, Shandong 250021, P.R. China.
authors.forename: Lijing
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Guang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Xiuru
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Anliu
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics* / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D039641:Integrin beta Chains; D016023:Integrins; D034741:RNA, Small Interfering; C073878:integrin alphavbeta6; C072170:integrin beta6; D014568:Urokinase-Type Plasminogen Activator; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9