Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer
Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer
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DOI：
10.1158/1535-7163.mct-19-1031
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发表时间：
2020-10-01
影响因子：
5.7
通讯作者：
Gleave, Martin E.
中科院分区：
文献类型：
--
作者：
Kawai, Yoshihisa;Imada, Kenjiro;Gleave, Martin E.
父系表达基因10（PEG 10）与神经内分泌肌肉浸润性膀胱癌（MIBC）相关，MIBC是生存率最低的疾病亚型。在这项工作中，我们进一步表征了412例MIBC患者的癌症基因组图谱数据库中PEG 10的表达模式，发现与其他亚型相比，神经内分泌样MIBC中PEG 10 mRNA水平增强，并与其他神经内分泌标志物高度相关。在82例组织芯片中，PEG 10蛋白水平也与神经内分泌标志物相关。在膀胱癌细胞系中，与亲本细胞相比，耐药细胞中的PEG 10表达被诱导，并且敲低PEG 10使细胞对化疗重新敏感。PEG 10的缺失增加了细胞周期调节因子p21和p27的蛋白水平，并延迟了G1-S期的转变，而PEG 10的过表达增强了癌细胞的增殖。PEG 10沉默也降低了SLUG和SNAIL的水平，导致入侵和迁移减少。在原位膀胱癌模型中，用PEG 10反义寡核苷酸全身治疗延迟了T24异种移植物的进展。总之，MIBC中PEG 10的表达升高可能通过促进存活、增殖和转移而促进疾病进展。靶向PEG 10是一种新的潜在的治疗方法，用于膀胱癌的一个子集。
Paternally expressed gene 10 (PEG10) has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, PEG10 mRNA level was enhanced in neuroendocrine-like MIBC and highly correlated with other neuroendocrine markers. PEG10 protein level also associated with neuroendocrine markers in a tissue microarray of 82 cases. In bladder cancer cell lines, PEG10 expression was induced in drug-resistant compared with parental cells, and knocking down of PEG10 resensitized cells to chemotherapy. Loss of PEG10 increased protein levels of cell-cycle regulators p21 and p27 and delayed G1-S-phase transition, while overexpression of PEG10 enhanced cancer cell proliferation. PEG10 silencing also lowered levels of SLUG and SNAIL, leading to reduced invasion and migration. In an orthotopic bladder cancer model, systemic treatment with PEG10 antisense oligonucleotide delayed progression of T24 xenografts. In summary, elevated expression of PEG10 in MIBC may contribute to the disease progression by promoting survival, proliferation, and metastasis. Targeting PEG10 is a novel potential therapeutic approach for a subset of bladder cancers.