机构：[1]Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 205 E Spokane Falls Blvd, PBS 421, Spokane, WA 99202, USA[2]Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China[3]Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China四川大学华西医院[4]Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA[5]Department of Pathology, Xijing Hospital, Medical University of the Air Force, Xi’an, Shaanxi 710032, China[6]Lawrence J. Ellison Institute for Transformative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
The tumor microenvironment plays a critical role in prostate cancer (PC) development and progression. Inappropriate activation of the stroma potentiates the growth and transformation of epithelial tumor cells. Here, we show that upregulation of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, in stromal cells elevates production of reactive oxygen species, triggers an inflammatory response including activation of IL-6, and promotes tumorigenesis in vitro and in vivo. Mechanistically, MAOA enhances IL-6 transcription through direct Twist1 binding to a conserved E-box element at the IL-6 promoter. MAOA in stromal fibroblasts provides tumor cell growth advantages through paracrine IL-6/STAT3 signaling. Tissue microarray analysis revealed co-expression correlations between individual pairs of proteins of the stromal MAOA-induced Twist1/IL-6/STAT3 pathway in clinical specimens. Downstream of stromal MAOA, STAT3 also promotes cell stemness and transcriptionally activates expression of cancer stem cell marker CD44 in PC cells. MAOA inhibitor treatment effectively suppressed prostate tumor growth in mice in a stroma-specific targeted manner. Collectively, these findings characterize the contribution of MAOA to stromal activation in PC pathogenesis and provide a rationale for targeting MAOA in stromal cells to treat PC.
基金：
This work was supported by a Concern Foundation
CONquer canCER Now Award, the Department of Defense Prostate
Cancer Research Program grant W81XWH-15-1-0493, the NIH/NCI
grant R37CA233658, and the WSU start-up fund to B.J.W.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|1 区医学
小类|1 区生化与分子生物学1 区肿瘤学1 区遗传学2 区细胞生物学
最新[2023]版：
大类|1 区医学
小类|1 区生化与分子生物学1 区遗传学2 区细胞生物学2 区肿瘤学
第一作者：
第一作者机构：[1]Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 205 E Spokane Falls Blvd, PBS 421, Spokane, WA 99202, USA[2]Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Li Jingjing,Pu Tianjie,Yin Lijuan,et al.MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness.[J].Oncogene.2020,39(16):3305-3321.doi:10.1038/s41388-020-1217-4.
APA：
Li Jingjing,Pu Tianjie,Yin Lijuan,Li Qinlong,Liao Chun-Peng&Wu Boyang Jason.(2020).MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness..Oncogene,39,(16)
MLA：
Li Jingjing,et al."MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness.".Oncogene 39..16(2020):3305-3321
医学