Cancer-Osteoblast Interaction Reduces Sost Expression in Osteoblasts and Up-Regulates lncRNA MALAT1 in Prostate Cancer.
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.
Lawrence Livermore National Laboratories, Physical and Life Sciences Directorate, Livermore, CA 94550, USA. asebastian2@ucmerced.edu.|School of Natural Sciences, University of California, Merced, CA 95343, USA. asebastian2@ucmerced.edu.
Aimy
A
Sebastian
Lawrence Livermore National Laboratories, Physical and Life Sciences Directorate, Livermore, CA 94550, USA. hum3@llnl.gov.
Nicholas R
NR
Hum
Lawrence Livermore National Laboratories, Physical and Life Sciences Directorate, Livermore, CA 94550, USA. bryandhudson@gmail.com.
Bryan D
BD
Hudson
Lawrence Livermore National Laboratories, Physical and Life Sciences Directorate, Livermore, CA 94550, USA. loots1@llnl.gov.|School of Natural Sciences, University of California, Merced, CA 95343, USA. loots1@llnl.gov.
Gabriela G
GG
Loots
Il6; MALAT1; Mmp13; PC3; Sost; Tgfb2; co-culture; osteoblast; prostate cancer