Abstract
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.
Highlights
Oral squamous cell carcinoma (OSCC) is the sixth most common malignant tumor in the world and the most common malignant oral cancer tumor, accounting for more than 90% of oral cancer cases
We found that the combination between integrin and insulin-like growth factor binding protein 3 (IGFBP3), the phosphorylation of focal adhesion kinase (FAK) and SRC and the FAKSRC-STAT axis were negatively regulated after cyclin G2 overexpression
These results indicated that cyclin G2 functioned as a tumor suppressor in OSCC through its interaction with IGFBP3 and the subsequent blockage of the connection between integrin and IGFBP3, the phosphorylation of FAK and the FAK-SRC-STAT signaling pathways
Summary
Oral squamous cell carcinoma (OSCC) is the sixth most common malignant tumor in the world and the most common malignant oral cancer tumor, accounting for more than 90% of oral cancer cases. The cure rate of early OSCC exceeds 80%, more than 70% of patients with advanced OSCC cannot be cured [4, 5].It is generally believed that OSCC has a high potential for local invasion and lymph node metastasis, and clinical staging plays an important role in the survival prediction of OSCC patients [6].the precise mechanisms leading to OSCC are not fully understood. Cyclin G2 is a potential cancer suppressor gene whose expression may be associated with the pathological process underlying tumor development [9].The expression levels of cyclin G2 are reduced in thyroid, breast, kidney, stomach, esophageal, pancreatic, and other tumors according to early reports [7, 8, 10,11,12,13]. The exact role that cyclin G2 plays in OSCC and other cancers is still unknown
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