Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, P.R. China.
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
Mol Med Rep. 2014 Mar;9(3):1032-6. doi: 10.3892/mmr.2013.1860. Epub 2013 Dec 12.
Hypoxia, a critical regulator of tumor growth and metastasis, induces the transcriptional activation of several pathways involved in proliferation, migration and invasion. Gankyrin was found to be overexpressed, and also promoted the metastasis in breast cancer cells, which is also involved in the regulation of hypoxia inducible factor‑1 and hypoxia‑inducible factor‑1α. The present study showed that gankyrin mRNA and protein expression were increased under hypoxic conditions in the BT474 breast cancer cell line, accompanied with increased ability of cell migration and invasion. Lentivirus‑mediated siRNA targeting gankyrin was transfected into BT474 cells. Wound‑healing and transwell experiments showed that gankyrin deletion abrogated the increased migration and invasion of BT474 cells due to hypoxia. In addition, E‑cadherin was found to be involved in the gankyrin induced invasion of breast cancer cells due to hypoxia. The present study indicated that gankyrin deletion abrogated the increased metastatic potential of breast cancer cells under hypoxic conditions partly through regulating E‑cadherin, suggesting that an improved understanding of gankyrin may offer a potential therapeutic target for the treatment of human breast cancer metastasis.
缺氧是肿瘤生长和转移的关键调节因子,可诱导参与增殖、迁移和侵袭的几个途径的转录激活。研究发现,Gankyrin 过表达,并促进乳腺癌细胞的转移,Gankyrin 还参与了缺氧诱导因子-1 和缺氧诱导因子-1α 的调节。本研究表明,在 BT474 乳腺癌细胞系中,缺氧条件下 Gankyrin mRNA 和蛋白表达增加,伴随着细胞迁移和侵袭能力的增强。用慢病毒介导的 Gankyrin 靶向 siRNA 转染 BT474 细胞。划痕和 Transwell 实验表明,由于缺氧,Gankyrin 缺失消除了 BT474 细胞迁移和侵袭的增加。此外,研究还发现 E-钙黏蛋白参与了缺氧诱导的乳腺癌细胞中 Gankyrin 诱导的侵袭。本研究表明,Gankyrin 缺失部分通过调节 E-钙黏蛋白消除了乳腺癌细胞在缺氧条件下转移潜能的增加,这表明对 Gankyrin 的深入了解可能为治疗人类乳腺癌转移提供一个潜在的治疗靶点。