Guo Yingchu, Xu Houqiang, Huang Mengqiu, Ruan Yong
Department of Biomedicine, Medical College, Guizhou University, No. 2708, Huaxi Road South, Huaxi District, Guiyang, 550025, Guizhou, China.
Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guiyang, Guizhou, China.
J Cell Commun Signal. 2023 Sep;17(3):757-772. doi: 10.1007/s12079-022-00717-8. Epub 2022 Dec 27.
Prostate cancer (PCa) has long been the leading cause of cancer-associated deaths among male worldwide. Our previous studies have shown that Bloom syndrome protein (BLM) plays a vital role in PCa proliferation, yet the underlying molecular mechanism remains largely obscure. Mechanistically, BLM directly interacted with hepatoma-derived growth factor (HDGF). Functionally, BLM and HDGF knockdown resulted in the higher impairment of PC3 proliferation, clonogenicity, migration and invasion than that their counterpart with either BLM or HDGF knockdown exclusively. Of note, HDGF overexpression expedited, whereas its knockdown suppressed, PC3 proliferation, clonogenicity, migration and invasion. Additionally, the potentiation or attenuation was partially antagonized upon BLM depletion or overexpression. In line with the vitro data, the impact of BLM and HDGF on tumor growth was investigated in mouse xenograft models. ChIP-seq, dual-luciferase reporter and western blotting assays were employed to expound the regulatory network in PC3 cells. The results unveiled that HDGF activated KRAS and suppressed RhoA transcription, and that the function of HDGF was mediated, in part, by interaction with BLM. Accordingly, the MAPK/ERK pathway was activated. Moreover, the regulation of HDGF on KRAS and RhoA had a signal crosstalk. To recapitulate, BLM and HDGF may serve as novel prognostic markers and potential therapeutic targets in PCa.
前列腺癌（PCa）长期以来一直是全球男性癌症相关死亡的主要原因。我们之前的研究表明，布鲁姆综合征蛋白（BLM）在PCa增殖中起着至关重要的作用，但其潜在的分子机制仍 largely obscure。从机制上讲，BLM直接与肝癌衍生生长因子（HDGF）相互作用。在功能上，与单独敲低BLM或HDGF相比，同时敲低BLM和HDGF对PC3增殖、克隆形成、迁移和侵袭的损害更大。值得注意的是，HDGF过表达加速了PC3的增殖、克隆形成、迁移和侵袭，而敲低HDGF则抑制了这些过程。此外，BLM的缺失或过表达部分拮抗了这种增强或减弱作用。与体外数据一致，在小鼠异种移植模型中研究了BLM和HDGF对肿瘤生长的影响。采用染色质免疫沉淀测序（ChIP-seq）、双荧光素酶报告基因和蛋白质印迹分析来阐述PC3细胞中的调控网络。结果表明，HDGF激活了KRAS并抑制了RhoA转录，并且HDGF的功能部分是通过与BLM相互作用介导的。因此，丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路被激活。此外，HDGF对KRAS和RhoA的调控存在信号串扰。总之，BLM和HDGF可能作为PCa的新型预后标志物和潜在治疗靶点。
