Cancer-driven IgG promotes the development of castration-resistant Prostate Cancer though the SOX2-CIgG pathway
Abstract Background: Although Androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer, recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G(CIgG) was found to be induced after ADT, identifying CIgG as a potential CRPC driver gene.Methods: The expression of CIgG and its clinical significance in prostate cancer tissue was analyzed by TCGA database and immunohistochemistry. Subsequently, the sequence features of prostate cell line (LNcap, DU145, PC3) VHDJH rearrangements were analyzed via comparison with the best matching functional germline IgVH, IgDH and IgJH genes. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of prostate cancer cells in vitro and vivo. Cells with high CIgG expression (CIgGhigh) and low CIgG expression (CIgG-/low) from the PC3 cell line were sorted by FACS using a CIgG monoclonal antibody named RP215, then, suspended microsphere, colony formation and drug-resistant assays were performed. A NOD/SCID mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The AR-SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, qRT-PCR, Western blot, luciferase and ChIP assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of prostate cancer in vivo using a Babl/c nude mouse xenograft model.Results: We demonstrated that CIgG was induced by androgen deprivation therapy (ADT) and upregulated by SOX2 [SRY (sex determining region Y)-box 2] in prostate cancer, which may promote the development of CRPC. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through MARK/ERK and AKT in prostate cancer.Conclusion: Our data suggests that CIgG could be a driver of CRPC development, and that targeting the SOX2-CIgG axis may therefore inhibit CRPC development after ADT.
