Cancer‐driven IgG promotes the development of prostate cancer though the SOX2‐CIgG pathway. Issue 13 (6th July 2020)

• Record Type: Journal Article
• Authors: Qin, Caipeng; Sheng, Zhengzuo; Huang, Xinmei; Tang, Jingshu; Liu, Yang; Xu, Tao; Qiu, Xiaoyan
• Is Part Of: Prostate. Volume 80:Issue 13(2020)
• Page Start: 1134
• Page End: 1144
• Publication Date: 2020-07-06
• Subjects: ADT -- CIgG -- CRPC -- SOX2; Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.24042
• Languages: English
• ISSNs: 0270-4137

Abstract

Abstract: Background: Although androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer (PCa), recurrent castration‐resistant prostate cancer (CRPC) eventually ensues. In this study, cancer‐derived immunoglobulin G (CIgG) is found to be induced after ADT, identifying CIgG as a potential CRPC driver gene. Methods: The expression of CIgG and its clinical significance in PCa tissue was analyzed by The Cancer Genome Atlas database and immunohistochemistry. Subsequently, the sequence features of prostate cell line VHDJH rearrangements were analyzed. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of PCa cells in vitro and vivo. Suspended microsphere, colony formation and drug‐resistant assays were performed using PC3 cells with high CIgG expression (CIgG high ) and low CIgG expression (CIgG ‐/low ), and A nonobese diabetic/severe combined immunodeficiency mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The SOX2‐CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, quantitative reverse transcription‐polymerase chain reaction, Western blot, luciferase, and chromatin immunoprecipitation assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of PCa in vivo using a Babl/c nude mouse xenograft model. Results: CIgG is frequently expressed in PCa and associated with clinicopathological characteristics, moreover, CIgG transcripts with unique patterns of VHDJH rearrangements are found in PCa cells. Functional analyses identified that CIgG was induced by ADT and upregulated by SOX2 (SRY (sex determining region Y)‐box 2) in PCa, promoting the development of PCa. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through mitogen activated protein kinase/extracellular‐signal‐regulated kinase and AKT in PCa. In vivo experiments further demonstrated that depleting CIgG significantly suppressed the growth of PCa cell xenografts. Furthermore, a CIgG monoclonal antibody named RP215 exhibits tumor inhibitory effect as well. Conclusion: Our data suggests that CIgG could be a driver of PCa development, and that targeting the SOX2‐CIgG axis may therefore inhibit PCa development after ADT.