Villalobos-Hernandez A, Bobbala D, Kandhi R, Khan M G M, Mayhue M, Dubois C M, Ferbeyre G, Saucier C, Ramanathan S, Ilangumaran S
Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Prostate Cancer Prostatic Dis. 2017 Mar;20(1):36-47. doi: 10.1038/pcan.2016.50. Epub 2016 Oct 25.
The suppressor of cytokine signaling 1 (SOCS1) gene is repressed in prostate cancer (PCa) by epigenetic silencing and microRNA miR30d. Increased expression of the SOCS1-targeting miR30d correlates with higher biochemical recurrence, suggesting a tumor suppressor role of SOCS1 in PCa, but the underlying mechanisms are unclear. We have shown that SOCS1 inhibits MET receptor kinase signaling, a key oncogenic pathway in cancer progression. Here we evaluated the role of SOCS1 in attenuating MET signaling in PCa cells and tumor growth in vivo.
MET-overexpressing human DU145 and PC3 PCa cell lines were stably transduced with SOCS1, and their growth, migration and invasion of collagen matrix were evaluated in vitro. Cells expressing SOCS1 or the control vector were evaluated for tumor growth in NOD.scid.gamma mice as xenograft or orthotopic tumors.
HGF-induced MET signaling was attenuated in SOCS1-expressing DU145 and PC3 cells. Compared with vector control cells, SOCS1-expressing cells showed reduced proliferation and impaired migration following HGF stimulation. DU145 and PC3 cells showed marked ability to invade the collagen matrix following HGF stimulation and this was attenuated by SOCS1. As xenografts, SOCS1-expressing PCa cells showed significantly reduced tumor growth compared with vector control cells. In the orthotopic tumor model, SOCS1 reduced the growth of primary tumors and metastatic spread. Intriguingly, the SOCS1-expressing DU145 and PC3 tumors showed increased collagen deposition, associated with increased frequency of myofibroblasts.
Our findings support the tumor suppressor role of SOCS1 in PCa and suggest that attenuation of MET signaling is one of the underlying mechanisms. SOCS1 in PCa cells also appears to prevent the tumor-promoting functions of cancer-associated fibroblasts.
细胞因子信号转导抑制因子1（SOCS1）基因在前列腺癌（PCa）中通过表观遗传沉默和微小RNA miR30d被抑制。靶向SOCS1的miR30d表达增加与更高的生化复发相关，提示SOCS1在PCa中具有肿瘤抑制作用，但其潜在机制尚不清楚。我们已经表明，SOCS1抑制MET受体激酶信号传导，这是癌症进展中的关键致癌途径。在此，我们评估了SOCS1在减弱PCa细胞中MET信号传导及体内肿瘤生长中的作用。
用SOCS1稳定转导过表达MET的人DU145和PC3 PCa细胞系，并在体外评估它们的生长、迁移及对胶原基质的侵袭能力。将表达SOCS1或对照载体的细胞作为异种移植瘤或原位肿瘤在NOD.scid.gamma小鼠中评估肿瘤生长情况。
在表达SOCS1的DU145和PC3细胞中，肝细胞生长因子（HGF）诱导的MET信号传导减弱。与载体对照细胞相比，表达SOCS1的细胞在HGF刺激后增殖减少且迁移受损。HGF刺激后，DU145和PC3细胞显示出显著的侵袭胶原基质的能力，而SOCS1可减弱这种能力。作为异种移植瘤，表达SOCS1的PCa细胞与载体对照细胞相比，肿瘤生长显著减少。在原位肿瘤模型中，SOCS1减少了原发性肿瘤的生长和转移扩散。有趣的是，表达SOCS1的DU145和PC3肿瘤显示胶原沉积增加，与肌成纤维细胞频率增加相关。
我们的研究结果支持SOCS1在PCa中的肿瘤抑制作用，并表明减弱MET信号传导是其潜在机制之一。PCa细胞中的SOCS1似乎还能阻止癌症相关成纤维细胞的促肿瘤功能。
