Transforming growth factor-β1 attenuates junctional adhesion molecule-A and contributes to breast cancer cell invasion.
Transforming growth factor-β1 (TGF-β1) is a potent regulator in promoting the invasion and proliferation of breast cancer cells. Junctional adhesion molecule-A (JAM-A) is a tight junction protein that displays an inverse relationship to cell invasiveness in breast cancer cells. Whether TGF-β1 signaling induces alteration of JAM-A expression leading to cell invasion has not been investigated. In this study, we report that TGF-β1 down-regulated JAM-A expression via its effect on both transcriptional and post-translational regulations of JAM-A, thus inducing cell invasion. On exploring whether TGF-β1 might be the upstream regulator of JAM-A expression, we found that knockdown of TGF-β receptors and canonical Smad signaling could upregulate JAM-A level and inhibit cell invasion in MDA-MB-231 cells. TGF-β1 treatment of MCF-7 cells caused a significant reduction of JAM-A mRNA and protein and induced cell invasion. Delineating the signal mechanisms involved in TGF-β1-mediated JAM-A repression, we found that TGF-β1 significantly inhibited JAM-A gene transcription via the activation of Smads. In addition to Smad activation, we found that involvement of p54 JNK is crucial for post-translational modification of TGF-β1-mediated JAM-A protein degradation. Blockage of JNK pathway by inhibitor could attenuate TGF-β1-induced cell invasion. We provide evidences for the first time that TGF-β1 induces breast cancer cell invasion via TGF-β1-mediated control on JAM-A expression. Identification of JAM-A as a downstream target of TGF-β1 represents a crucial mechanism in cancer progression.
School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
Yang
Y
Wang
Wing-Yee
WY
Lui
D000230:Adenocarcinoma / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002966:Clathrin / Q000037:antagonists & inhibitors / Q000235:genetics; D003094:Collagen; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation; D004338:Drug Combinations; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D007797:Laminin; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011509:Proteoglycans; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D054875:Ubiquitination / Q000187:drug effects
D015815:Cell Adhesion Molecules; D002966:Clathrin; D004338:Drug Combinations; C407243:F11R protein, human; D007797:Laminin; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011509:Proteoglycans; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C059485:matrigel; D003609:Dactinomycin; D003094:Collagen; D048031:JNK Mitogen-Activated Protein Kinases