Background: Cancer-derived immunoglobulin G (CIgG) has been detected in various cancers and plays important roles in carcinogenesis. The present study aimed to investigate its clinical significance in pancreatic ductal adenocarcinoma (PDAC). Methods: Using tissue microarrays (TMAs) and immunohistochemistry, we assessed CIgG expression in 326 patients who underwent surgical resection for PDAC. The associations between CIgG expression and clinicopathological features and clinical outcomes were analyzed. Functional experiments were also performed to investigate the effect of CIgG on PDAC cells. Results: High CIgG expression was related to poor tumor differentiation and metastasis during follow-up and was associated with poor disease-free survival (DFS) and overall survival (OS). A multivariate Cox regression analysis identified high CIgG expression as an independent prognostic factor for DFS and OS. The incorporation of CIgG expression improved the accuracy of an established prognosis prediction model for 1-year OS and 2-year OS. In vitro studies showed that knocking down CIgG profoundly suppressed the proliferation, migration, and invasion capacity of PDAC cells. Conclusions: CIgG contributes to the malignant behaviors of PDAC and offers a powerful prognostic predictor for these patients.

Objective Currently, no satisfactory targets for colorectal cancer or markers for immunotherapy and diagnosis and prognosis are available. Immunoglobulin G (IgG) is widely expressed in many cancers, and it promotes cancer progression. This study explored the role of cancer-derived IgG (CIgG) in colorectal cancer. Methods First, using a monoclonal antibody to CIgG, we examined the expression levels of CIgG in colorectal cancer cell lines by western blot and immunofluorescence analyses and in tissue specimens by immunohistochemistry. Second, the variable region gene was amplified by nested polymerase chain reaction (PCR), and PCR products were sequenced and analyzed. Third, we investigated the effect of CIgG on colorectal cancer cells by cell proliferation, wound healing, migration and invasion assays, and colony formation assay. Fourth, we performed in vivo tumorigenicity experiments to explore the effect of CIgG on tumorigenicity. Finally, we used RNA-seq analysis and co-immunoprecipitation experiments to further clarify possible mechanisms of CIgG. Results We found that CIgG is widely expressed in colorectal cancer cells, and the overexpression of CIgG indicates significantly poor colorectal cancer prognosis. Furthermore, CIgG knockdown significantly inhibits the proliferation, migration and invasion ability of cells, and tumor growth in vivo . RNA-seq analysis indicated that CIgG knockdown results primarily in changes in expression of apical junction and epithelial-mesenchymal transition-related genes. CIgG may be involved in colorectal cancer invasion and metastasis through interacting with E-cadherin. Conclusions CIgG is a potential human oncogene in colorectal cancer and that it has potential for application as a novel target in targeted therapy and a marker for prognostic evaluation.

BackgroundAlthough 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.MethodsThe 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 (CIgGhigh) 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.ResultsCIgG 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.ConclusionOur 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.

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Elevated IgG expression in cancer cells has been implicated in exacerbated malignancy and poor clinical prognosis. Accumulating evidence indicates that a nonconventional sialylation modification is critical for the function of cancer-derived IgG, indicating the need for a better understanding of the regulatory mechanisms that control the expression and function of sialylated cancer IgG (SIA-cIgG). Here, we conducted genome-wide CRISPR activation screening and identified OCT4 and SOX2 as the key factors that promote SIA-cIgG expression. Functional investigation revealed that SIA-cIgG reciprocally stimulated SOX2 by activating the c-Met/Akt/Erk signaling axis, constituting a self-propagating loop of SIA-cIgG/c-Met/SOX2/SIA-cIgG signaling. This signaling loop was highly active in stem-like cells from many epithelial cancers and was crucial for cancer stemness in vitro and in vivo. Notably, the monoclonal antibody RP215, which specifically recognizes the Asn162 sialylation-related epitope on SIA-cIgG, effectively blocked the SIA-cIgG-driven signaling loop. Furthermore, RP215 significantly inhibited lung cancer cell stemness and tumor growth in a patient-derived xenograft model. In conclusion, these findings revealed a self-propagating c-Met/SOX2/SIA-cIgG signaling loop that promotes cancer stemness, identifying novel therapeutic strategies for cancer treatment.