Galheigo Maria Raquel Unterkircher, Cruz Amanda Rodrigues, Cabral Ágata Silva, Faria Paulo Rogério, Cordeiro Renato Simões, Silva Marcelo José Barbosa, Tomiosso Tatiana Carla, Gonçalves Bianca Fachim, Pinto-Fochi Maria Etelvina, Taboga Sebastião Roberto, Góes Rejane Maira, Ribeiro Daniele Lisboa
Histology Sector, Institute of Biomedical Sciences (ICBIM), Federal University of Uberlândia (UFU), Uberlândia, MG, Brazil.
Immunology Sector, Institute of Biomedical Sciences (ICBIM), Federal University of Uberlândia (UFU), Uberlândia, MG, Brazil.
Prostate. 2016 Jul;76(10):917-26. doi: 10.1002/pros.23181. Epub 2016 Mar 28.
TNF-α is a key cytokine involved in prostate carcinogenesis and is mediated by the TNF-α receptor type 1 (TNFR-1). This receptor triggers two opposite pathways: cell death or cell survival and presents a protective or stimulator role in cancer. Thus, the purpose of this study was to evaluate the role of TNF signaling in chemically induced prostate carcinogenesis in mice.
C57bl/6 wild type (WT) and p55 TNFR-1 knockout mice (KO) were treated with mineral oil (control) or N-methyl N-nitrosurea (MNU) in association with testosterone (MNU+T, single injection of 40 mg/kg and weekly injection 2 mg/kg, respectively) over the course of 6 months. After this induction period, prostate samples were processed for histological and biochemical analysis.
MNU+T treatment led to the development of prostate intraepithelial neoplasia (PIN) and adenocarcinoma (PCa) in both WT and KO animals; however, the incidence of PCa was lower in KO group than in WT. Cell proliferation analysis showed that PCNA levels were significantly lower in the KO group, even after carcinogenesis induction. Furthermore, the prostate of KO animals had lower levels of p65 and p-mTOR after treatment with MNU+T than WT. There was also a decrease in prostate androgen receptor levels after induction of carcinogenesis in both KO and WT mice. Regarding the extracellular matrix in the prostate, KO mice had higher levels of fibronectin and lower levels of matrix metalloproteinase 2 (MMP2) after carcinogenesis. Finally, there was a similar increase in apoptosis in both groups after carcinogenesis, indicating that the TNAFr1 pathway in prostate carcinogenesis presented proliferative, and not apoptotic, stimuli.
TNF-α, through its receptor TNFR-1, promoted cell proliferation and cell survival in prostate by activation of the AKT/mTOR and NFKB pathway, which stimulated prostate carcinogenesis in chemically induced mice. Prostate 76: 917-926, 2016. © 2016 Wiley Periodicals, Inc.
肿瘤坏死因子-α（TNF-α）是参与前列腺癌发生的关键细胞因子，由1型肿瘤坏死因子-α受体（TNFR-1）介导。该受体触发两条相反的信号通路：细胞死亡或细胞存活，在癌症中发挥保护或刺激作用。因此，本研究旨在评估TNF信号在化学诱导的小鼠前列腺癌发生中的作用。
C57bl/6野生型（WT）和p55 TNFR-1基因敲除小鼠（KO）在6个月的时间内分别用矿物油（对照）或与睾酮联合使用的N-甲基N-亚硝基脲（MNU）（MNU+T，分别单次注射40mg/kg和每周注射2mg/kg）进行处理。在这个诱导期之后，对前列腺样本进行组织学和生化分析。
MNU+T处理导致WT和KO动物均发生前列腺上皮内瘤变（PIN）和腺癌（PCa）；然而，KO组的PCa发生率低于WT组。细胞增殖分析表明，即使在致癌诱导后，KO组的增殖细胞核抗原（PCNA）水平也显著较低。此外，MNU+T处理后，KO动物前列腺中的p65和磷酸化雷帕霉素靶蛋白（p-mTOR）水平低于WT组。在KO和WT小鼠致癌诱导后，前列腺雄激素受体水平也均下降。关于前列腺中的细胞外基质，致癌后KO小鼠的纤连蛋白水平较高，基质金属蛋白酶2（MMP2）水平较低。最后，致癌后两组的细胞凋亡均有类似增加，表明前列腺癌发生中的TNAFr1信号通路呈现增殖刺激而非凋亡刺激。
TNF-α通过其受体TNFR-1，通过激活AKT/mTOR和NF-κB信号通路促进前列腺中的细胞增殖和细胞存活，从而在化学诱导的小鼠中刺激前列腺癌发生。前列腺76: 917-926, 2016。© 2016威利期刊公司。
