期刊
HUMAN REPRODUCTION
卷 30, 期 1, 页码 61-70出版社
OXFORD UNIV PRESS
DOI: 10.1093/humrep/deu300
关键词
tumor necrosis factor-alpha (TNF-alpha); matrix metalloproteinase (MMP); uterine leiomyoma; extracellular signal-regulated kinase (ERK)
资金
- Program for New Century Excellent Talents in University [NCET-12-0282]
- National Natural Science Foundation of China [81371620]
- Tianjin Natural Science Foundation [12JCZDJC24900]
STUDY QUESTION: Does tumor necrosis factor-alpha (TNF-alpha) differentially regulate matrix metalloproteinase-2 (MMP-2) expression in leiomyomas compared with normal myometrium? SUMMARY ANSWER: TNF-alpha up-regulates MMP-2 expression and stimulates cell migration through the activation of extracellular signal-regulated kinase (ERK) signaling pathway in leiomyoma smooth muscle cells (SMCs), but not in normal myometrial SMCs. WHAT IS KNOWN ALREADY: Uterine leiomyoma, the benign smooth muscle cell tumor, is the single most common indication for hysterectomy. High expression of MMPs or TNF-alpha has been reported in uterine leiomyomas; however, the molecular mechanism underlying these observations remains unknown. STUDY DESIGN, SIZE, DURATION: Samples were obtained between 2009 and 2013 from 12 women of reproductive age at the proliferative phase of the menstrual cycle by hysterectomy. Leiomyomas and matched normal myometrium from each woman were analyzed in vitro. PARTICIPANTS/MATERIALS, SETTING, METHODS: Western blot, RT-qPCR and a wound-healing assay were used to investigate the effects of TNF-alpha on MMP-2 expression and intracellular signal transduction in cultured SMCs from leiomyomas and matched myometrium. MAIN RESULTS AND THE ROLE OF CHANCE: Western blot and RT-qPCR analyses using tissues from clinical patients showed that the levels of MMP-2 protein (P = 0.008) and mRNA (P = 0.009) were significantly higher in uterine leiomyomas compared with their matched myometrium. Treatment with TNF-alpha significantly up-regulated the protein (P = 0.039) and mRNA (P = 0.037) levels of MMP-2 in cultured leiomyoma SMCs but not in matched myometrial SMCs. The extracellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-kappa B) pathways were activated by TNF-alpha in leiomyoma SMCs. Specific inhibitors of the ERK or NF-kB pathway (PD98059 or Bay11-7082) suppressed TNF-alpha-induced MMP-2 expression in leiomyoma SMCs. The wound-healing assay revealed that TNF-alpha promoted the migration of cultured leiomyoma SMCs (P = 0.036); however, PD98059 compromised the cell migration triggered by TNF-alpha. LIMITATIONS, REASONS FOR CAUTION: This study is descriptive and although we observed clear differential regulation of MMP-2 by TNF-alpha at mRNA and protein levels in leiomyoma, future studies are needed to identify why the difference in TNF-alpha response exists between human leiomyoma tissue and normal myometrium. Including some of the experiments such as transfection studies for TNF-alpha and MMP-2 promoter mapping could have added more insight as to why this difference exists. In addition, further studies in vivo are needed to verify the results obtained from primary cultured SMCs. WIDER IMPLICATIONS OF THE FINDINGS: Considering the positive effect of TNF-alpha on leiomyoma SMC migration, strategies targeting TNF-alpha, in parallel with the production of more specific inhibitors of MMPs, may provide alternative therapeutic approaches for the treatment of leiomyoma.
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