RESUMEN
Cancer stem cells (CSCs) play significant roles in tumor initiation. MicroRNA-135a (miR-135a) induced the formation of a CD133+ subpopulation from a human papillomavirus-immortalized cervical epithelial cell line. Compared with the CD133- cells, the CD133+ cells expressed higher levels of miR-135a and OCT4, exhibited significantly higher tumorsphere forming capacity and the time required for tumorsphere formation was shortened in the second generation. Serum induction suppressed the expression of CD133, OCT4 and miR-135a, but increased expression of involucrin in the miR-135a-induced CD133+ cells. The miR-135a-induced CD133+ cells were tumorigenic in a limiting dilution approach in vivo. The cells expressed significantly higher level of active ß-catenin and OCT4 than the CD133- counterpart. Wnt3a enhanced the expression of OCT4 and CD133 in cervical cancer cells but failed to enhance CD133 transcription in normal cervical cells. Wnt3a stimulation also increased tumorsphere size and self-renewal of miR-135a-induced CD133+ subpopulation. Wnt/ß-catenin inhibition suppressed tumorsphere formation while Wnt3a partially nullified the inhibitory effect. Taken together, miR-135a induced the formation of a subpopulation of cells with CSC properties both in vitro and in vivo and the Wnt/ß-catenin signaling pathway is essential to maintain its tumorigenicity.
Asunto(s)
Antígeno AC133/metabolismo , Biomarcadores de Tumor/genética , MicroARNs/genética , Células Madre Neoplásicas/patología , Neoplasias del Cuello Uterino/patología , Antígeno AC133/genética , Animales , Apoptosis , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Objective To evaluate the role and efficacy of preventing bone mineral loss in patients with endometriosis treated by gonadotrophin-releasing hormone analogues (GnRH-a) combined with addback therapy.Methods Prospective,randomized controlled studies of the use of GnRHa with add-back therapy in treatment of endometriosis were enrolled in this study from Medline,Embase,Cochrane library,China National Knowledge Internet (CNKI),Chinese Biological Medicine Disk (CBM) and Data Base of Wanfang.After quality assessment and data extraction,meta-analysis were conducted in the change of BMD,reproductive hormone (E2) and visual pain score (VAS) by Stata 11.0 software.Results A total of 785patients from 13 randomized controlled trail (RCT) studies enrolled in this study after exclude no following up,poor quality and repeat published studies.377 patients were in group of GnRH-a with add-back treatment and 408 patients were in group of GnRna alone.The findinds were showed in meta-analysis:(1) there was a significant difference in percentage change of bone mineral density (BMD) between two groups,the addback therapy was more effective in prevention of bone loss which was (SMD =0.223,95％ CI:0.003 to 0.443,P =0.047).(2) There was no significant difference in the level of reproductive hormone between two groups (SMD =-0.053,95％ CI:-0.479 to 0.373,P =0.807).(3) There was also no significant difference in the visual pain score between the two groups (SMD =-0.157,95％ CI:-0.474 to 0.160,P=0.332).Conclusions GnRH-a with add-back therapy have been shown to be more effective in preventing loss of BMD than GnRH-a treatment alone.However,the long term effect of preventing BMD should be studied.