Abstract
BackgroundLung adenocarcinoma (LUAD) is the dominant type of lung neoplasms, and radiotherapy is its mainstay treatment, yet poor prognosis caused by radioresistance remains problematic. Cancer-derived immunoglobulin G (cancer-IgG) has been detected in multiple cancers and plays important roles in carcinogenesis. This study aimed to demonstrate that cancer-IgG is associated with poor prognosis of LUAD and to identify its role in radioresistance.MethodsCancer-IgG expression was detected by immunohistochemistry from 56 patients with stage III LUAD and by western blot and immunofluorescence in LUAD cell lines and in a human bronchial epithelial cell line. The effects of cancer-IgG silencing on the proliferation and apoptosis of PC9 and H292 cells were evaluated by plate cloning and apoptosis assay; the effects of cancer-IgG silencing on DNA damage repair ability and radiosensitivity were evaluated by colony-forming assay, γH2AX immunofluorescence, and neutral comet assay. Finally, we used the protein phosphorylation microarray and western blot to explore mechanisms involving cancer-IgG that increased radioresistance.ResultsCancer-IgG is widely expressed in stage III LUAD, and the overall survival and disease-free survival of patients with positive expression are notably lower than those of patients with negative expression, indicating the associations between cancer-IgG and poor prognosis as well as radioresistance. The expression of cancer-IgG in the four LUAD cell lines was located mainly on the cell membrane and cytoplasm and not in the normal lung epithelial cell. Knockdown of cancer-IgG in PC9 and H292 cells resulted in increased apoptosis and negatively affected cancer cell proliferation. After irradiation, silencing of cancer-IgG showed a decrease in colonies as well as increases in the Olive tail moment and γH2AX foci in nucleus, indicating that the knockdown of cancer-IgG resulted in a decrease in the damage repair ability of DNA double-strand breaks in LUAD cells and an enhanced radiosensitivity. The expression of p-AKT, p-GSK3β, and p-DNA-PKcs decreased in the knockdown group after radiotherapy, suggesting that cancer-IgG could affect radiotherapy resistance by mediating double-strand breaks damage repair in LUAD cells through the PI3K/AKT/DNA-PKcs pathway.ConclusionsThis study revealed that cancer-IgG regulates PI3K/AKT/DNA-PKcs signaling pathways to affect radioresistance of LUAD and associated with poor prognosis.
Highlights
Lung cancer represents the highest cancer incidence and remains the leading cause of cancer mortality worldwide [1]
Knockdown of cancer-IgG inhibited the expression of the p-DNA-PKcs protein (Figure 5B), suggesting that the damage repair ability of double-strand breaks (DSBs) in lung adenocarcinoma (LUAD) cells decreased, and radiotherapy resistance was downregulated. These results suggest that cancer-IgG can mediate radiotherapy resistance in LUAD cells via the PI3K/AKT/DNA-PKcs pathway and that radiosensitivity can be promoted by knocking down the expression of cancer-IgG
We presented evidence that the absence of cancerIgG downregulates the phosphorylation of key proteins in the PI3K/AKT/DNA-PKcs pathway and attenuates the radiotherapy resistance of LUAD cells
Summary
Lung cancer represents the highest cancer incidence and remains the leading cause of cancer mortality worldwide [1]. Many large-scale clinical studies conducted in recent years involving patients with NSCLC (including LUAD) confirmed the survival time and quality-of-life improvements gained as a result of radiotherapy, and these results contributed to the definition of radiotherapy as a standard therapy for NSCLC [4,5,6]. Local recurrence, as well as poor prognosis of patients resulting from radioresistance observed in tumor cells, has become a major factor restricting the efficacy and additional development of radiotherapy; the 5-year survival rate of NSCLC remains less than 30% [7]. Lung adenocarcinoma (LUAD) is the dominant type of lung neoplasms, and radiotherapy is its mainstay treatment, yet poor prognosis caused by radioresistance remains problematic. This study aimed to demonstrate that cancer-IgG is associated with poor prognosis of LUAD and to identify its role in radioresistance
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