Laboratorio de inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina.
Antioxid Redox Signal. 2020 Jun 10;32(17):1243-1258. doi: 10.1089/ars.2019.7879. Epub 2020 Jan 20.
Bone is the most frequent site of prostate cancer (PCa) metastasis. Tumor cells interact with the bone microenvironment interrupting tissue balance. Heme oxygenase-1 (HO-1; encoded by ) appears as a potential target in PCa maintaining the cellular homeostasis. Our hypothesis is that HO-1 is implicated in bone physiology and modulates the communication with PCa cells. Here we aimed at (i) assessing the physiological impact of gene knockout (KO) on bone metabolism and (ii) determining the alterations of the transcriptional landscape associated with tumorigenesis and bone remodeling in cells growing in coculture (PCa cells with primary mouse osteoblasts [PMOs] from BALB/c , , and mice). Histomorphometric analysis of mice bones exhibited significantly decreased bone density with reduced remodeling parameters. A positive correlation between expression and , , , and was observed in PMOs. Flow cytometry studies revealed two populations of PMOs with different reactive oxygen species (ROS) levels. The high ROS population was increased in PMOs compared with , but was significantly reduced in PMOs , suggesting restrained ROS tolerance in KO cells. Gene expression was altered in PMOs upon coculture with PCa cells, showing a pro-osteoclastic profile. Moreover, HO-1 induction in PCa cells growing in coculture with PMOs resulted in a significant modulation of key bone markers such as and . We here demonstrate the direct implications of HO-1 expression in bone remodeling and how it participates in the alterations in the communication between bone and prostate tumor cells.
骨骼是前列腺癌（PCa）转移最常见的部位。肿瘤细胞与骨微环境相互作用，破坏组织平衡。血红素加氧酶-1（HO-1；由 编码）似乎是维持细胞内稳态的 PCa 的潜在靶点。我们的假设是，HO-1 参与骨生理学，并调节与 PCa 细胞的通讯。在这里，我们旨在：（i）评估 基因敲除（KO）对骨代谢的生理影响，（ii）确定与肿瘤发生和骨重塑相关的转录谱的改变，这些改变与在共培养物中生长的细胞有关（PCa 细胞与来自 BALB/c、C57BL/6、和 小鼠的原代小鼠成骨细胞[PMOs]）。 对 小鼠骨骼的组织形态计量学分析显示，骨密度显著降低，重塑参数减少。在 PMOs 中观察到 表达与 、 、 和 呈正相关。流式细胞术研究显示，PMOs 中有两种具有不同活性氧（ROS）水平的细胞群。与 相比，PMOs 中的高 ROS 群体增加，但在 PMOs 中显著减少，表明 KO 细胞的 ROS 耐受受到限制。与 PCa 细胞共培养后，PMOs 的基因表达发生改变，表现出促破骨细胞的特征。此外，在与 PMOs 共培养的 PCa 细胞中诱导 HO-1 表达导致关键骨标志物如 和 的显著调节。 我们在这里证明了 HO-1 表达在骨重塑中的直接影响，以及它如何参与骨与前列腺肿瘤细胞之间通讯的改变。
