Wang Danning, Gao Jinlan, Zhao Chenyang, Li Sen, Zhang Di, Hou Xiaoyu, Zhuang Xinbin, Liu Qi, Luo Yang
The Research Center for Medical Genomics, Key Laboratory of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang, China.
Front Oncol. 2020 Nov 6;10:560572. doi: 10.3389/fonc.2020.560572. eCollection 2020.
The cell cycle protein cyclin G2 is considered a tumor suppressor. However, its regulatory effects and potential mechanisms in oral cancers are not well understood. This study aimed to investigate the effect of cyclin G2 on oral squamous cell carcinoma (OSCC). The data from 80 patients with OSCC were utilized to predict the abnormal expression of cyclin G2. The proliferation and metastasis were determined by a cell counting Kit-8 assay, flow cytometry, a wound-healing assay, and a cell invasion assay. The expression of key proteins and genes associated with the cyclin G2 signaling pathways was determined by western blotting and real-time PCR, respectively. The orthotopic nude mice model was established by a mouth injection of SCC9 cells overexpressing cyclin G2. We showed that the low level of cyclin G2 in OSCC, which is negatively correlated with clinical staging, was a negative prognostic factor for the disease. We also found that cyclin G2 inhibited the proliferation, metastasis, and blocked the cell cycle at G1/S of OSCC cells, suggesting that cyclin G2 has an inhibitory effect in OSCC. Mechanistically, cyclin G2 inhibited the growth and metastasis of OSCC by binding to insulin-like growth factor binding protein 3 (IGFBP3) and regulating the focal adhesion kinase (FAK) -SRC-STAT signal transduction pathway. Cyclin G2 competed with integrin to bind to IGFBP3; the binding between integrin and IGFBP3 was reduced after cyclin G2 overexpression, thereby inhibiting the phosphorylation of FAK and SRC. These results showed that cyclin G2 inhibited the progression of OSCC by interacting with IGFBP3 and that it may be a new target for OSCC treatment.
细胞周期蛋白cyclin G2被认为是一种肿瘤抑制因子。然而，其在口腔癌中的调节作用和潜在机制尚未完全明确。本研究旨在探讨cyclin G2对口腔鳞状细胞癌（OSCC）的影响。利用80例OSCC患者的数据预测cyclin G2的异常表达。通过细胞计数试剂盒-8法、流式细胞术、伤口愈合试验和细胞侵袭试验来测定增殖和转移情况。分别通过蛋白质免疫印迹法和实时荧光定量PCR法测定与cyclin G2信号通路相关的关键蛋白和基因的表达。通过口腔注射过表达cyclin G2的SCC9细胞建立原位裸鼠模型。我们发现，OSCC中cyclin G2水平较低，且与临床分期呈负相关，是该疾病的不良预后因素。我们还发现，cyclin G2抑制OSCC细胞的增殖、转移，并使细胞周期阻滞在G1/S期，提示cyclin G2在OSCC中具有抑制作用。机制上，cyclin G2通过与胰岛素样生长因子结合蛋白3（IGFBP3）结合并调节粘着斑激酶（FAK）-SRC-STAT信号转导通路来抑制OSCC的生长和转移。Cyclin G2与整合素竞争结合IGFBP3；cyclin G2过表达后，整合素与IGFBP3之间的结合减少，从而抑制FAK和SRC的磷酸化。这些结果表明，cyclin G2通过与IGFBP3相互作用抑制OSCC的进展，可能是OSCC治疗的新靶点。
