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

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.

Knockdown of LINC00511 promotes radiosensitivity of thyroid carcinoma cells via suppressing JAK2/STAT3 signaling pathway

“…Furthermore, it has been elucidated that lncRNAs modulate the radioresistance of tumors through modulating gene expression, 32 and signaling pathways against radiotherapy in tumors. 21,33,34 Thereupon, we attempted to explore the association between LINC00511 and JAK2/STAT3 signaling pathway. Our paper displayed that LINC00511 regulated JAK2/ STAT3 signaling pathway and JAK2 expression was upregulated when given 4Gy irradiation in thyroid carcinoma, where the association of JAK2/STAT3 signaling pathway with radioresistance was probed for the first time.…”

Hypoxia in Lung Cancer Management: A Translational Approach

“…In the context of lung cancer, mesenchymal markers such as vimentin, and EMT transcription factors such as TWIST1 (Twist family BHLH transcription factor 1) or Snail were found overexpressed in hypoxic lung specimens while epithelial markers such as E-cadherin were repressed compared to non-hypoxic samples [ 64 , 65 , 66 , 67 , 68 , 69 ]. Such close relationships between EMT and hypoxia could thus be involved in aggressive phenotypes and resistance sustained by mesenchymal polarization [ 70 , 71 , 72 ]. Considering more frequent hypoxic features in mesenchymal tumours and higher aggressiveness and metastatic properties allocated to non-epithelial specimens, hypoxia appears as an important mechanism supporting therapy resistance such as chemoresistance in hypoxic tumours.…”

Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer

“…High levels of IGF1R expression are positively correlated with radiation resistance in cervical, prostate, lung, HPVnegative head and neck cancers, and melanoma (10,(13)(14)(15)(16)(17). Studies have shown that the higher IGF1R expression, the higher the grade of various tumors and the lower the survival rate (18)(19)(20).…”