Department of Bone and Soft Tissue Neurosurgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
Mol Med Rep. 2018 Mar;17(3):3658-3666. doi: 10.3892/mmr.2017.8296. Epub 2017 Dec 18.
Anoikis resistance is a crucial step in the process of tumor metastasis. This step determines whether the tumor cells will survive when they become detached from the extracellular matrix. However, the specific mechanism of tumor cells to bypass anoikis and become resistant remains to be elucidated. The present study aimed to determine the internal mechanism of bypassing anoikis through comparison of human osteosarcoma cell lines with human normal cell lines. High activating transcription factor 4 (ATF4) and myelocytomatosis oncogene (MYC) expression levels were observed in MG‑63 and U‑2 OS human osteosarcoma cell lines. It is possible that ATF4 and MYC contribute to tumor progression. Subsequently, the expression levels of ATF4 and MYC in HUVEC and CHON‑001 human normal cell lines were upregulated and their adhesion abilities were reduced; whereas their ability to bypass anoikis increased significantly. Simultaneously, after we Following a knock‑down ofATF4 and MYC expression levels in MG‑63 and U‑2 OS human osteosarcoma cell lines, their adhesion ability increased and their ability to bypassing anoikis was significantly reduced. Upregulation of MYC resulted in an upregulation of ATF4, and chromatin immunoprecipitation and luciferase reporter gene technology demonstrated that MYC binds to the promoter of ATF4. These findings suggest that ATF4 regulated by MYC might contribute to resistance to anoikis in human osteosarcoma cells.
失巢凋亡抵抗是肿瘤转移过程中的关键步骤。这一步决定了肿瘤细胞在从细胞外基质上脱离时是否能够存活。然而，肿瘤细胞绕过失巢凋亡并产生抵抗的具体机制仍有待阐明。本研究旨在通过比较人骨肉瘤细胞系与正常人细胞系，确定绕过失巢凋亡的内在机制。在人骨肉瘤细胞系 MG-63 和 U-2 OS 中观察到高激活转录因子 4（ATF4）和髓细胞瘤致癌基因（MYC）的表达水平。ATF4 和 MYC 可能有助于肿瘤的进展。随后，上调 HUVEC 和 CHON-001 正常人细胞系中 ATF4 和 MYC 的表达水平，降低其黏附能力；而它们绕过失巢凋亡的能力显著增加。同时，在敲低 MG-63 和 U-2 OS 人骨肉瘤细胞系中 ATF4 和 MYC 的表达水平后，其黏附能力增加，绕过失巢凋亡的能力显著降低。MYC 的上调导致 ATF4 的上调，染色质免疫沉淀和荧光素酶报告基因技术表明 MYC 结合到 ATF4 的启动子上。这些发现表明，MYC 调控的 ATF4 可能有助于人骨肉瘤细胞对失巢凋亡的抵抗。
