Xu Wei, Li Yifan, Ye Xiaojian, Ji Yunhan, Chen Yu, Zhang Xiangyang, Li Zhikun
Department of orthopedic, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Changning District, 200336, Shanghai, People's Republic of China.
Cancer Cell Int. 2021 Nov 27;21(1):630. doi: 10.1186/s12935-021-02340-w.
Osteosarcoma is a primary malignant tumor that mainly affects children and young adults. Transmembrane emp24 trafficking protein 3 (TMED3) may be involved in the regulation of malignant cancer behaviors. However, the role of TMED3 in osteosarcoma remains mysterious. In this study, the potential biological function and underlying mechanism of TMED3 in progression of osteosarcoma was elaborated.
The expression of TMED3 in osteosarcoma was analyzed by immunohistochemical staining. The biological function of TMED3 in osteosarcoma was determined through loss-of-function assays in vitro. The effect of TMED3 downregulation on osteosarcoma was further explored by xenograft tumor model. The molecular mechanism of the regulation of TMED3 on osteosarcoma was determined by gene expression profile analysis.
The expression of TMED3 in osteosarcoma tissues was significantly greater than that in matched adjacent normal tissues. Knockdown of TMED3 inhibited the progression of osteosarcoma by suppressing proliferation, impeding migration and enhancing apoptosis in vitro. We further validated that knockdown of TMED3 inhibited osteosarcoma generation in vivo. Additionally, ribosomal protein S15A (RPS15A) was determined as a potential downstream target for TMED3 involved in the progression of osteosarcoma. Further investigations elucidated that the simultaneous knockdown of RPS15A and TMED3 intensified the inhibitory effects on osteosarcoma cells. Importantly, knockdown of RPS15A alleviated the promotion effects of TMED3 overexpression in osteosarcoma cells.
In summary, these findings emphasized the importance of TMED3/RPS15A axis in promoting tumor progression, which may be a promising candidate for molecular therapy of osteosarcoma.
骨肉瘤是一种主要影响儿童和青年的原发性恶性肿瘤。跨膜emp24转运蛋白3（TMED3）可能参与恶性肿瘤行为的调控。然而，TMED3在骨肉瘤中的作用仍不清楚。本研究阐述了TMED3在骨肉瘤进展中的潜在生物学功能及潜在机制。
采用免疫组织化学染色分析骨肉瘤中TMED3的表达。通过体外功能丧失实验确定TMED3在骨肉瘤中的生物学功能。通过异种移植肿瘤模型进一步探讨下调TMED3对骨肉瘤的影响。通过基因表达谱分析确定TMED3调控骨肉瘤的分子机制。
骨肉瘤组织中TMED3的表达明显高于配对的相邻正常组织。敲低TMED3可通过抑制体外增殖、阻碍迁移和增强凋亡来抑制骨肉瘤的进展。我们进一步验证了敲低TMED3在体内可抑制骨肉瘤的发生。此外，核糖体蛋白S15A（RPS15A）被确定为参与骨肉瘤进展的TMED3的潜在下游靶点。进一步研究表明，同时敲低RPS15A和TMED3可增强对骨肉瘤细胞的抑制作用。重要的是，敲低RPS15A可减轻TMED3过表达对骨肉瘤细胞的促进作用。
总之，这些发现强调了TMED3/RPS15A轴在促进肿瘤进展中的重要性，这可能是骨肉瘤分子治疗的一个有前景的候选靶点。
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