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Published on: April 22, 2019
Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell
Junki Sakata1, Akiyuki Hirosue1, Ryoji Yoshida1
1Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Abstract:
Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) modulates various cell functions through IGF-dependent or independent mechanisms. However, its biological roles in the radiosensitivity of oral squamous cell carcinoma (OSCC) remain largely unknown. The purpose of this study was to determine the clinical significance and molecular mechanisms of the association between IGFBP-3 and OSCC radiosensitivity. We performed an immunohistochemical analysis of IGFBP-3 in 52 OSCC specimens from patients treated with preoperative chemoradiotherapy and surgery (phase II study). Associations between IGFBP-3 expression and clinicopathological features were also evaluated. In addition, we examined the effects of IGFBP-3 on post-X-ray irradiation radiosensitivity and DNA damage in vitro. High IGFBP-3 expression was significantly correlated with poor chemoradiotherapy responses and prognosis. With IGFBP-3 knockdown, irradiated OSCC cells exhibited significantly higher radiosensitivity compared with that of control cells. Moreover, IGFBP-3 depletion in OSCC cells reduced phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which is required for DNA double-strand break repair during non-homologous end joining. These findings indicate that IGFBP-3 may have a significant role in regulating DNA repair and is be a potential biomarker for predicting clinical response to radiotherapy and prognosis in OSCC.
Insights
Insulin-like growth factor binding protein-3 (IGFBP-3) is linked to poor outcomes in oral cancer patients treated with radiation. Lowering IGFBP-3 enhances cancer cell radiosensitivity by impairing DNA repair.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) influences cell functions via IGF-dependent and independent pathways.
- The role of IGFBP-3 in the radiosensitivity of oral squamous cell carcinoma (OSCC) is not well understood.
Purpose of the Study:
- To investigate the clinical significance of IGFBP-3 in OSCC radiosensitivity.
- To elucidate the molecular mechanisms underlying the association between IGFBP-3 and OSCC radiosensitivity.
Main Methods:
- Immunohistochemical analysis of IGFBP-3 in 52 OSCC patient specimens treated with chemoradiotherapy.
- In vitro studies examining the effects of IGFBP-3 on radiosensitivity and DNA damage post-irradiation.
- Assessment of DNA-PKcs phosphorylation in IGFBP-3 depleted OSCC cells.
Main Results:
- High IGFBP-3 expression correlated with poor response to chemoradiotherapy and adverse prognosis.
- IGFBP-3 knockdown significantly increased radiosensitivity in irradiated OSCC cells.
- IGFBP-3 depletion reduced DNA-PKcs phosphorylation, indicating impaired DNA double-strand break repair.
Conclusions:
- IGFBP-3 plays a role in regulating DNA repair mechanisms in OSCC.
- IGFBP-3 may serve as a predictive biomarker for radiotherapy response and prognosis in OSCC patients.
