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.
Highlights
Oral cancer, and especially oral squamous cell carcinoma (OSCC), is among the most common cancers worldwide [1]
The results indicate a variety of immunostaining patterns in clinical OSCC samples, reflecting the biological properties of cancer cells
Plasma IGFBP-3 levels were not associated with tissue levels (Supplementary Figure S1) and there were no significant differences in terms of clinical features and prognosis (Supplementary Tables S1 and S2)
Summary
Especially oral squamous cell carcinoma (OSCC), is among the most common cancers worldwide [1]. Despite innovation and advances in diagnostic techniques and treatment, the prognosis for this disease has not improved [2]. Potential malignancy leading to therapeutic resistance has yielded unsatisfactory results. Radiotherapy, currently a predominant component of OSCC treatment, effectively kills cancer cells by inducing DNA damage [3]. OSCC cells frequently develop radioresistance by activating the DNA-damage response, controlling the generation of reactive oxygen species, and modulating immune responses [4]. Radioresistance is a major clinical obstacle for OSCC, the detailed underlying molecular mechanisms are still unknown
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