Department of Orthopedic, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Department of Orthopedic, Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China.
Oncol Rep. 2019 May;41(5):2729-2738. doi: 10.3892/or.2019.7078. Epub 2019 Mar 19.
PDZ domain containing 2 (PDZD2) is a multi-PDZ domain protein that promotes the proliferation of insulinoma cells, and is upregulated during prostate tumorigenesis. However, the function of PDZD2 in other cancers, including osteosarcoma (OS), remains unclear. Dysregulation of microRNAs (miRNAs) contributes to tumor initiation, proliferation and metastasis, via the regulation of their target genes. The present study investigated the functions of miR-363 and PDZD2 in MG-63 OS cells. The results revealed that MG-63 cells contained low levels of miR-363, and that overexpression of miR-363 in MG-63 cells significantly inhibited the vitality, proliferation, and colony formation ability of the cells, but promoted their apoptosis and G1/S arrest by regulating proliferating cell nuclear antigen (PCNA) and caspase-3 expression. Additionally, miR-363 impaired the migration and invasion of MG-63 cells by regulating the epithelial-mesenchymal transition (EMT) phenotype. Notably, a bioinformatics analysis and luciferase reporter assay indicated that PDZD2 was a direct target of miR-363. miR-363 overexpression reduced PDZD2 protein levels and knockdown of PDZD2 suppressed the colony formation, migration and invasion of MG-63 cells, but promoted their apoptosis by regulating expression of PCNA, caspase-3, and the EMT phenotype. In vivo studies further confirmed that miR-363 functioned as tumor suppressor, by inhibiting tumor growth, promoting cell apoptosis, and reducing PDZD2 and PCNA levels and the prevalence of the EMT phenotype in tumor tissues. The present data demonstrated that downregulation of the tumor suppressor miR-363 may be involved in the development of osteosarcoma via regulation of PDZD2.
PDZ 域包含 2 （PDZD2）是一种多 PDZ 域蛋白，可促进胰岛素瘤细胞的增殖，并在前列腺肿瘤发生过程中上调。然而，PDZD2 在其他癌症中的功能，包括骨肉瘤（OS），仍然不清楚。microRNAs（miRNAs）的失调通过调节其靶基因促进肿瘤的起始、增殖和转移。本研究探讨了 miR-363 和 PDZD2 在 MG-63 骨肉瘤细胞中的功能。结果表明，MG-63 细胞中 miR-363 的水平较低，并且 miR-363 在 MG-63 细胞中的过表达显著抑制了细胞的活力、增殖和集落形成能力，但通过调节增殖细胞核抗原（PCNA）和半胱天冬酶-3 的表达促进了细胞的凋亡和 G1/S 期阻滞。此外，miR-363 通过调节上皮-间充质转化（EMT）表型来损害 MG-63 细胞的迁移和侵袭。值得注意的是，生物信息学分析和荧光素酶报告基因实验表明，PDZD2 是 miR-363 的直接靶标。miR-363 过表达降低了 PDZD2 蛋白水平，PDZD2 的敲低抑制了 MG-63 细胞的集落形成、迁移和侵袭，但通过调节 PCNA、半胱天冬酶-3 和 EMT 表型来促进细胞凋亡。体内研究进一步证实，miR-363 通过抑制肿瘤生长、促进细胞凋亡以及降低肿瘤组织中 PDZD2 和 PCNA 水平和 EMT 表型的发生率，作为肿瘤抑制因子发挥作用。本数据表明，肿瘤抑制因子 miR-363 的下调可能通过调节 PDZD2 参与骨肉瘤的发生。
