HER4 promotes the growth and metastasis of osteosarcoma via the PI3K/AKT pathway
HER4 promotes the growth and metastasis of osteosarcoma via the PI3K/AKT pathway
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DOI：
10.1093/abbs/gmaa004
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发表时间：
2020-04-01
影响因子：
3.7
通讯作者：
Lin, Jianhua
中科院分区：
文献类型：
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作者：
Li, Xiaodong;Huang, Qingshan;Lin, Jianhua
骨肉瘤是最常见的原发恶性骨肿瘤，好发于青少年。根据我们以前的研究报告，HER4提示原发性骨肉瘤预后不良。然而，其在骨肉瘤发病机制中的作用机制尚未得到研究。本研究的目的是探讨HER4在骨肉瘤中的作用以及是否涉及PI3K/AKT通路。本研究采用免疫印迹法检测HER4蛋白在骨肉瘤组织和骨肉瘤细胞系中的表达。CCK8和Transwell法检测HER4对骨肉瘤细胞增殖、迁移和侵袭的影响。通过裸鼠成瘤实验和免疫荧光法检测HER4对骨肉瘤生长和转移的影响。免疫印迹和免疫荧光检测PI3K/AKT信号通路在HER4调控骨肉瘤生长和转移中的作用。我们发现HER4蛋白在临床骨肉瘤标本和骨肉瘤细胞中高表达。HER4在体外对骨肉瘤细胞的增殖、迁移、侵袭以及体内骨肉瘤的生长和转移均有明显的促进作用。HER4过表达上调磷酸化蛋白激酶B、增殖标记物Ki67和转移细胞标记物基质金属蛋白酶9的表达。值得注意的是，PI3K/AKT抑制剂LY294002通过下调PAKT、Ki67和MMP9的表达，显著抑制了HER4的作用。此外，LY294002还可明显阻断HER4诱导的肿瘤恶性程度上调的作用。本研究提示HER4可能通过PI3K/AKT途径促进骨肉瘤的生长和转移。HER4/PI3K/AKT通路可能成为骨肉瘤治疗的潜在靶点。
Osteosarcoma is the most common primary malignant bone tumor, which occurs in adolescents. As reported by our previous studies, HER4 indicates a poor prognosis of primary osteosarcoma. However, its mechanisms in the pathogenesis of osteosarcoma have not yet been studied. The purpose of this study was to investigate the role of HER4 in osteosarcoma and whether the PI3K/AKT pathway is involved. In this study, western blot analysis was used to investigate the expression of HER4 protein in osteosarcoma tissues and cell lines. CCK8 and transwell assays were used to detect the effects of HER4 on the proliferation, migration, and invasion of osteosarcoma cells in vitro. The effects of HER4 on the growth and metastasis of osteosarcoma in vivo were detected by tumor formation and immunofluorescence in nude mice. The role of the PI3K/AKT pathway in HER4 regulation of the growth and metastasis of osteosarcoma was examined by western blot analysis and immunofluorescence assay. We found that HER4 protein was highly expressed in clinical osteosarcoma specimens and osteosarcoma cells. HER4 markedly promoted the proliferation, migration, and invasion of osteosarcoma cells in vitro as well as the growth and metastasis of osteosarcoma in vivo. HER4 overexpression upregulated the expression of phosphorylated protein kinase B (pAKT), proliferation marker antigen Ki67, and metastasis cell marker matrix metalloproteinase 9 (MMP9). Notably, PI3K/AKT inhibitor LY294002 significantly inhibited the effects of HER4 via the downregulation of pAKT, Ki67, and MMP9. Moreover, LY294002 markedly blocked the effects of HER4-induced upregulation of tumor malignancy. The present study suggests that HER4 may promote the growth and metastasis of osteosarcoma via the PI3K/AKT pathway. The HER4/PI3K/AKT pathway could serve as a potential target for the treatment of osteosarcoma.