Li Zhanchun, Xiao Jie, Hu Kongzu, Wang Gang, Li Maoqiang, Zhang Jidong, Cheng Guangqi
Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
Int J Mol Sci. 2015 Jan 22;16(2):2294-306. doi: 10.3390/ijms16022294.
F-box and WD repeat domain-containing 7 (FBXW7) is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS) cases were significantly lower than those in normal bone tissues. Clinical analysis indicated that FBXW7 was expressed at lower levels in OS patients with advanced clinical stage, high T classification and poor histological differentiation. Furthermore, we demonstrated that high expression of FBXW7 was correlated with a better 5-year survival of OS patients. Multivariate Cox regression analysis indicated that FBXW7 was an independent prognostic marker in OS. Our in vitro studies showed that FBXW7 overexpression inhibited cell cycle transition and cell proliferation, and promoted apoptosis in both U2OS and MG-63 cells. In a nude mouse xenograft model, FBXW7 overexpression slowed down tumor growth by inducing apoptosis and growth arrest. Mechanistically, FBXW7 inversely regulated oncoprotein c-Myc and cyclin E levels in both U2OS and MG-63 cells. Together these findings suggest that FBXW7 may serve as a prognostic biomarker and inhibit tumor progression by inducing apoptosis and growth arrest in OS.
含F-box和WD重复结构域7（FBXW7）是包括乳腺癌、结直肠癌、胃癌和肝细胞癌在内的人类癌症中的一种强大的肿瘤抑制因子。在本研究中，我们发现骨肉瘤（OS）病例中FBXW7蛋白的表达和mRNA水平显著低于正常骨组织。临床分析表明，FBXW7在临床分期晚、T分级高和组织学分化差的OS患者中表达较低。此外，我们证明FBXW7的高表达与OS患者更好的5年生存率相关。多变量Cox回归分析表明FBXW7是OS中的一个独立预后标志物。我们的体外研究表明，FBXW7过表达抑制细胞周期转变和细胞增殖，并促进U2OS和MG-63细胞的凋亡。在裸鼠异种移植模型中，FBXW7过表达通过诱导凋亡和生长停滞减缓肿瘤生长。机制上，FBXW7在U2OS和MG-63细胞中反向调节癌蛋白c-Myc和细胞周期蛋白E的水平。这些发现共同表明，FBXW7可能作为一种预后生物标志物，并通过诱导OS细胞凋亡和生长停滞来抑制肿瘤进展。
