Insulin‑like growth factor‑1 receptor knockdown enhances radiosensitivity via the HIF‑1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells

Liu,Xiaoxing; Chen,Haiyan; Xu,Xin; Ye,Ming; Cao,Hongbin; Xu,Lei; Hou,Yanli; Tang,Jianmin; Zhou,Di; Bai,Yongrui; Ma,Xiumei

doi:10.3892/ol.2018.8705

Insulin‑like growth factor‑1 receptor knockdown enhances radiosensitivity via the HIF‑1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells

Authors:
- Xiaoxing Liu
- Haiyan Chen
- Xin Xu
- Ming Ye
- Hongbin Cao
- Lei Xu
- Yanli Hou
- Jianmin Tang
- Di Zhou
- Yongrui Bai
- Xiumei Ma
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Affiliations: Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
Published online on: May 11, 2018 https://doi.org/10.3892/ol.2018.8705
Pages: 1332-1340

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Abstract

Insulin‑like growth factor‑1 receptor (IGF‑1R) is a cell membrane receptor involved in cell proliferation and apoptosis, which is highly expressed in lung squamous cell carcinoma (SCC). The present study aimed to observe the influence of IGF‑1R silencing on the radiosensitivity of SCC and investigate the potential mechanisms involved. Human lung SCC H520 cells with relatively high expression of IGF‑1R were used. IGF‑1R expression was silenced using short hairpin RNA. The influence of IGF‑1R silencing on radiosensitivity and apoptosis was assessed using a clone formation assay and flow cytometry. The expression levels of proteins relevant in DNA damage repair and hypoxic signaling pathways were analyzed using western blotting. Decreased expression of IGF‑1R led to an increase in the sensitivity of H520 cells to irradiation. Molecular analysis showed that the reduced expression of IGF‑1R decreased the protein expression of ataxia‑telangiectasia mutated (ATM), H2A histone family member X (H2AX) and p53 binding protein 1 (53BP1), which are associated with the DNA repair pathway. Furthermore, 53BP1 is also known to be involved in apoptosis. Proteins involved in the hypoxic pathway, including hypoxia inducible factor 1 α (HIF‑1α), matrix metallopeptidase 9 (MMP‑9) and vascular endothelial growth factor A (VEGFA) were also involved in the radiosensitivity. In conclusion, decreased expression of IGF‑1R leads to improved radiosensitivity of SCC cells, and the underlying mechanism may be associated with the decreased expression of proteins involved in ATM/H2AX/53BP1 DNA damage repair and the HIF‑1α/MMP‑9 hypoxic pathway, which results in the induction of apoptosis and increased radiosensitivity. These findings suggest that targeting of IGF‑1R may represent a novel approach for lung SCC radiation treatment.

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