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.

中文翻译：

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HER4通过PI3K / AKT途径促进骨肉瘤的生长和转移。

骨肉瘤是最常见的原发性恶性骨肿瘤，好发于青少年。如我们先前的研究报道，HER4提示原发性骨肉瘤的预后不良。但是，其在骨肉瘤发病机理中的机制尚未研究。这项研究的目的是调查HER4在骨肉瘤中的作用以及是否涉及PI3K / AKT途径。在这项研究中，蛋白质印迹分析用于研究骨肉瘤组织和细胞系中HER4蛋白的表达。使用CCK8和transwell分析检测HER4对体外骨肉瘤细胞增殖，迁移和侵袭的影响。通过裸鼠的肿瘤形成和免疫荧光检测HER4对体内骨肉瘤生长和转移的影响。通过蛋白质印迹分析和免疫荧光分析法检测了PI3K / AKT途径在HER4调节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在体外显着促进骨肉瘤细胞的增殖，迁移和侵袭，并在体内促进骨肉瘤的生长和转移。HER4过表达上调了磷酸化蛋白激酶B（pAKT），增殖标志物抗原Ki67和转移细胞标志物基质金属蛋白酶9（MMP9）的表达。值得注意的是，PI3K / AKT抑制剂LY294002通过下调pAKT，Ki67和MMP9来显着抑制HER4的作用。此外，LY294002显着阻断了HER4诱导的肿瘤恶性上调的作用。本研究表明HER4可能通过PI3K / AKT途径促进骨肉瘤的生长和转移。HER4 / PI3K / AKT途径可作为治疗骨肉瘤的潜在靶点。