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IGF2BP3 as a Prognostic Biomarker and Regulator of Metastasis in Merkel Cell Carcinoma

ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive skin cancer with frequent development of metastases, however effective treatment options for advanced disease are often missing. In this study, we investigated the clinical significance and functional impact of the Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in MCC. Our results revealed elevated IGF2BP3 expression in metastases as compared to primary tumors. High IGF2BP3 levels in primary MCCs were associated with shorter disease-specific survival. In an MCC xenograft model, lung metastases exhibited increased IGF2BP3 expression. Functional studies showed that IGF2BP3 primarily regulates cell migration and invasion in MCC. We identified 281 direct RNA targets of IGF2BP3 with enriched functions linked to metastasis-related processes and several targets overlapped with genes differentially expressed between MCC primary tumors and metastases, implying that IGF2BP3 and its targets contribute to tumor progression. Inhibition or silencing of bromodomain-containing protein 4 (BRD4) reduced IGF2BP3 expression, suggesting BRD4 as a potential regulator of IGF2BP3. Our study underscores the role of IGF2BP3 in MCC metastasis and its potential as a prognostic biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280116 | GEO | 2025/02/05

REPOSITORIES: GEO

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Project description:Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens. However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood. To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs. MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC. Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy. We used microarrays to characterize global gene expression patterns related to Merkel cell polyomavirus status in Merkel cell carcinoma. Furthermore, we compared Merkel cell carcinoma to less aggressive primary cutaneous carcinomas. We utilized flash-frozen tumor tissue from primary Merkel cell carcinomas, metastatic Merkel cell carcinomas, primary cutaneous squamous cell carcinomas, and basal cell carcinomas. Merkel cell carcinoma cell lines, which represent a pure population of tumor cells, were also included. Merkel cell polyomavirus status was determined at the DNA and RNA level using multiple primers for viral T-antigen and capsid protein sequences. This Series represents two analyses - one with new Samples normalized together, and another with some of the new Samples re-normalized with Samples previously submitted under Series GSE13355. The latter group contain 'renormalized' in the titles.

Project description:Background: Circular RNAs (circRNAs) represent a newly identified class of non-coding RNAs that can be secreted into body fluids via exosomes and subsequently detected. While the function of circPRMT5 has been partially elucidated in certain tumor types, its role and underlying mechanisms in head and neck squamous cell carcinoma (HNSCC) remain inadequately understood. Furthermore, the diagnostic potential of circPRMT5 in saliva necessitates additional investigation.Methods: The expression of circPRMT5 was quantified using qRT-PCR. The biological function of circPRMT5 in HNSCC progression was confirmed both in vitro and in vivo. RNA sequencing (RNA-Seq) was used to find downstream targets for circPRMT5-IGF2BP3. IGF2BP3 and SERPINE1 expression levels were assessed using qRT-PCR, Western blotting, and immunohistochemistry. Additionally, the localization and interaction of circPRMT5, IGF2BP3 protein, and SERPINE1 in HNSCC were evaluated using RNA-FISH, immunofluorescence (IF), and RNA immunoprecipitation (RIP) assays. Ultimately, saliva exosomes were collected, identified and assessed using Western Blot, electron microscopy, particle size analysis and qRT-PCR.Results: Findings revealed that circPRMT5 was upregulated in HNSCC and promoted its proliferation and metastasis in vitro and in vivo. Mechanistically, circPRMT5 stabilized IGF2BP3 protein, which in turn stabilized SERPINE1 mRNA. Notably, the proliferative, invasive, and migratory effects of circPRMT5 in HNSCC were contingent upon the involvement of IGF2BP3 and SERPINE1. Furthermore, circPRMT5 levels were significantly elevated in the saliva of HNSCC patients, and positively correlated with increased lymph node metastasis and advanced T stage. These findings underscored the high diagnostic and predictive potential of circPRMT5 in HNSCC.Conclusions: CircPRMT5 plays a crucial role in promoting HNSCC proliferation and metastasis via the IGF2BP3-SERPINE1 pathway. It serves as a noninvasive diagnostic biomarker, indicating its potential as a valuable diagnostic and therapeutic target for HNSCC patients.

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IGF2BP3 as a Prognostic Biomarker and Regulator of Metastasis in Merkel Cell Carcinoma

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