High Expression of Cancer-IgG Is Associated With Poor Prognosis and Radioresistance via PI3K/AKT/DNA-PKcs Pathway Regulation in Lung Adenocarcinoma

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.

Upregulated Expression of Cancer-Derived Immunoglobulin G Is Associated With Progression in Glioma

“…Previous researchers have discovered that cancer-IgG is an independent poor (28). Later studies also proved this view and further found that cancer-IgG can also play the role of an oncogene through the AKT, FAK, SOX2, and other signaling pathways in cancer (8,9,19,29). Interacting cells in the TME are considered to regulate the characteristics of cancers, such as uncontrolled proliferation, malignant metastasis, and chemoradiotherapy resistance (30).…”

“…The classical immunological theory holds that immunoglobulin G (IgG), which plays a great role in human defense against pathogenic microorganisms, is produced only by B lymphocytes and plasma cells. However, more and more studies have shown that cancer cells can also produce IgG, called cancer-derived immunoglobulin G (cancer-IgG), such as those in breast cancer, colon cancer, cervical cancer, and lung cancer (6)(7)(8)(9). Lee et al immunized mice with the cleavage product of the ovarian cancer cell line OC-3-VGH to obtain the monoclonal antibody (mAb) RP215, which can specifically recognize cancer-IgG by recognizing a special glycosylation site in the constant region of the IgG heavy chain (10).…”

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

“…The PI3K/ AKT/mTOR signaling pathway is hyperactivated or altered in many cancer types (177). Inhibition of the pathway reduces tumor cell radioresistance (178,179). For example, dactolisib, a dual PI3K/ mTOR inhibitor, causes cell cycle arrest in the G2/M phase and improves the radiosensitivity of DU145 cell lines.…”

FCGRT, a cancer-derived immunoglobulin G binding protein, mediates the malignant phenotype of glioma

“…It should be noted that the antigen retrieval solution we used was Tris-EDTA, pH = 8.0. Immunohistochemical scoring criteria can be seen in previous publication from our team [13].…”