title: Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways.
abstract: Ovarian cancer has one of the highest mortalities in malignancies in women, but little is known of its tumour progression properties and there is still no effective molecule that can monitor its growth or therapeutic responses. MSLN (mesothelin), a secreted protein that is overexpressed in ovarian cancer tissues with a poor clinical outcome, has been previously identified to activate PI3K (phosphoinositide 3-kinase)/Akt signalling and inhibit paclitaxel-induced apoptosis. The present study investigates the correlation between MSLN and MMP (matrix metalloproteinase)-7 in the progression of ovarian cancer, and the mechanism of MSLN in enhancing ovarian cancer invasion. The expression of MSLN correlated well with MMP-7 expression in human ovarian cancer tissues. Overexpressing MSLN or ovarian cancer cells treated with MSLN showed enhanced migration and invasion of cancer cells through the induction of MMP-7. MSLN regulated the expression of MMP-7 through the ERK (extracellular-signal-regulated kinase) 1/2, Akt and JNK (c-Jun N-terminal kinase) pathways. The expression of MMP-7 and the migrating ability of MSLN-treated ovarian cancer cells were suppressed by ERK1/2- or JNK-specific inhibitors, or a decoy AP-1 (activator protein 1) oligonucleotide in in vitro experiments, whereas in vivo animal experiments also demonstrated that mice treated with MAPK (mitogen-activated protein kinase)/ERK- or JNK-specific inhibitors could decrease intratumour MMP-7 expression, delay tumour growth and extend the survival of the mice. In conclusion, MSLN enhances ovarian cancer invasion by MMP-7 expression through the MAPK/ERK and JNK signal transduction pathways. Blocking the MSLN-related pathway could be a potential strategy for inhibiting the growth of ovarian cancer.
authors: Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Ming-Cheng
authors: MC
authors: Chang
authors: Chi-An
authors: CA
authors: Chen
authors: Pao-Jen
authors: PJ
authors: Chen
authors: Ying-Cheng
authors: YC
authors: Chiang
authors: Yu-Li
authors: YL
authors: Chen
authors: Tsui-Lien
authors: TL
authors: Mao
authors: Han-Wei
authors: HW
authors: Lin
authors: Wen-Hsien
authors: WH
authors: Lin Chiang
authors: Wen-Fang
authors: WF
authors: Cheng
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D017931:DNA Primers; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D061965:Matrix Metalloproteinase Inhibitors; C000715528:Msln protein, mouse; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D000090204:Mesothelin