Sebastian Aimy, Hum Nicholas R, Hudson Bryan D, Loots Gabriela G
Lawrence Livermore National Laboratories, Physical and Life Sciences Directorate, Livermore, CA 94550, USA.
School of Natural Sciences, University of California, Merced, CA 95343, USA.
Microarrays (Basel). 2015 Oct 29;4(4):503-19. doi: 10.3390/microarrays4040503.
Dynamic interaction between prostate cancer and the bone microenvironment is a major contributor to metastasis of prostate cancer to bone. In this study, we utilized an in vitro co-culture model of PC3 prostate cancer cells and osteoblasts followed by microarray based gene expression profiling to identify previously unrecognized prostate cancer-bone microenvironment interactions. Factors secreted by PC3 cells resulted in the up-regulation of many genes in osteoblasts associated with bone metabolism and cancer metastasis, including Mmp13, Il-6 and Tgfb2, and down-regulation of Wnt inhibitor Sost. To determine whether altered Sost expression in the bone microenvironment has an effect on prostate cancer metastasis, we co-cultured PC3 cells with Sost knockout (Sost(KO)) osteoblasts and wildtype (WT) osteoblasts and identified several genes differentially regulated between PC3-Sost(KO) osteoblast co-cultures and PC3-WT osteoblast co-cultures. Co-culturing PC3 cells with WT osteoblasts up-regulated cancer-associated long noncoding RNA (lncRNA) MALAT1 in PC3 cells. MALAT1 expression was further enhanced when PC3 cells were co-cultured with Sost(KO) osteoblasts and treatment with recombinant Sost down-regulated MALAT1 expression in these cells. Our results suggest that reduced Sost expression in the tumor microenvironment may promote bone metastasis by up-regulating MALAT1 in prostate cancer.
前列腺癌与骨微环境之间的动态相互作用是前列腺癌转移至骨的主要原因。在本研究中，我们利用PC3前列腺癌细胞和成骨细胞的体外共培养模型，随后基于微阵列进行基因表达谱分析，以识别此前未被认识的前列腺癌与骨微环境之间的相互作用。PC3细胞分泌的因子导致成骨细胞中许多与骨代谢和癌症转移相关的基因上调，包括Mmp13、Il-6和Tgfb2，以及Wnt抑制剂Sost的下调。为了确定骨微环境中Sost表达的改变是否对前列腺癌转移有影响，我们将PC3细胞与Sost基因敲除（Sost(KO)）的成骨细胞和野生型（WT）成骨细胞共培养，并鉴定了PC3-Sost(KO)成骨细胞共培养物和PC3-WT成骨细胞共培养物之间差异调节的几个基因。将PC3细胞与WT成骨细胞共培养可上调PC3细胞中与癌症相关的长链非编码RNA（lncRNA）MALAT1。当PC3细胞与Sost(KO)成骨细胞共培养时，MALAT1表达进一步增强，用重组Sost处理可下调这些细胞中MALAT1的表达。我们的结果表明，肿瘤微环境中Sost表达的降低可能通过上调前列腺癌中的MALAT1来促进骨转移。
