p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone
p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone
复制标题
p62过表达促进肿瘤基质细胞增殖并与骨巨细胞瘤复发相关
DOI：
10.3892/ol.2020.11947
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发表时间：
2020-10-01
期刊：
影响因子：
2.9
通讯作者：
Zhang, Jing
中科院分区：
文献类型：
--
作者：
Liu, Shu;Ye, Fan;Zhang, Jing
骨巨细胞瘤（GCTB）是一种中度（局部侵袭性）骨肿瘤，术后复发率>30%。GCTB复发最终是由于肿瘤基质（NS）细胞的增殖。然而，NS细胞增殖调控的确切机制仍不清楚。p62蛋白是一种多功能的衔接蛋白，在骨肿瘤和代谢性骨病中发挥积极作用。本研究采用逆转录-定量PCR和蛋白质印迹法分别检测8对新鲜GCTB肿瘤组织和癌旁正常松质骨组织中p62 mRNA和蛋白的表达水平。p62表达水平和患者预后之间的关系进行了分析，随后在54个石蜡包埋肿瘤标本的免疫组化测定。从GCTB原代细胞培养物中分离NS细胞，并使用体外细胞增殖、迁移和侵袭测定来评估p62的作用。结果表明，p62 mRNA和蛋白在肿瘤组织中呈高表达。p62高表达与GCTB复发显著相关（P=0.001）。p62高表达组5年无复发生存率明显低于p62低表达组（P<0.001）。考克斯回归分析显示p62表达是GCTB患者无复发生存的独立预后指标（P<0.001）。体外实验表明，下调p62表达可抑制NS细胞的增殖、侵袭和迁移，并促进其凋亡。总之，发现p62过表达通过促进NS细胞增殖与GCTB复发相关。因此，p62可能是一个新的预后指标，并为GCTB的潜在治疗靶点。
Giant cell tumor of bone (GCTB) is an intermediate (locally aggressive) bone tumor with a recurrence rate of >30% following surgery. GCTB recurrence is ultimately due to the proliferation of neoplastic stromal (NS) cells. However, the precise mechanism underlying the regulation of NS cell proliferation remains unknown. p62 protein is a multifunctional adaptor protein that exerts a positive role in bone tumors and metabolic bone diseases. In the present study, the mRNA and protein expression levels of p62 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in 8 paired fresh GCTB tumor tissues and adjacent normal cancellous bone tissues. The association between p62 expression level and patient prognosis was subsequently analyzed in 54 paraffin-embedded tumor specimens by immunohistochemistry assay. NS cells were isolated from GCTB primary cell culture, and the role of p62 was evaluated using in vitro cell proliferation, migration and invasion assays. The results revealed that p62 mRNA and protein were overexpressed in tumor tissues. High p62 expression levels were significantly associated with the recurrence of GCTB (P=0.001). The patients in the high p62 expression group had shorter 5-year recurrence-free survival rates compared with the patients in the low p62 expression group (P<0.001). Cox regression analysis identified p62 expression as an independent prognostic indicator of the recurrence-free survival of patients with GCTB (P<0.001). The in vitro experiments revealed that p62 downregulation inhibited NS cell proliferation, invasion and migration, and promoted apoptosis. In conclusion, it was found that p62 overexpression is associated with the recurrence of GCTB via the promotion of NS cell proliferation. Therefore, p62 could be a novel prognostic indicator, and a potential therapeutic target for GCTB.