Introduction
Thyroid cancer is a frequently occurring malignancy of the endocrine system with an increasing incidence worldwide. Early and accurate diagnosis, as well as reliable prognostic markers, are crucial for optimal management and treatment of thyroid cancer patients. In recent years, the insulin-like growth factor-II mRNA-binding protein 3 (IMP3) has emerged as a promising biomarker in various cancers, including thyroid.
What Is IMP3?
IMP3 is an oncofetal protein (proteins present only during fetal development but found in adults with certain kinds of cancer) that plays a critical role in RNA trafficking, translation, and cellular growth and migration. Recent studies have revealed the role of IMP3 expression in thyroid cancers and its role in diagnosis and prognosis.
How Is IMP3 Expressed in Different Thyroid Cancer Types?
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Papillary Thyroid Carcinoma (PTC): Overexpression of IMP3 has been consistently observed in PTC samples, particularly in the cytoplasm of tumor cells. Higher IMP3 levels correlate with more aggressive tumor behavior and advanced disease stages.
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Follicular Thyroid Carcinoma (FTC): Several studies have reported elevated IMP3 levels in FTC samples with cytoplasmic localization. Higher IMP3 expression is associated with more aggressive tumor behavior and higher metastasis rates.
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Anaplastic Thyroid Carcinoma (ATC): High levels of IMP3 expression have been reported in ATC samples, predominantly in the cytoplasm. IMP3 expression is linked to epithelial-to-mesenchymal transition (EMT), contributing to tumor invasion and metastasis.
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Medullary Thyroid Carcinoma (MTC): Limited studies have shown elevated IMP3 expression in MTC samples, particularly in advanced or metastatic cases.
What Are the Diagnostic Implications of IMP3 in Thyroid Cancer?
IMP3 immunohistochemistry (IHC) has shown high sensitivity and specificity in distinguishing malignant thyroid lesions from benign ones, particularly in differentiating PTC and FTC from benign nodules and follicular adenomas.
What Are the Prognostic Implications of IMP3 in Thyroid Cancer?
High IMP3 expression is associated with larger tumor size, extrathyroidal extension, lymph node metastasis, advanced tumor stage, shorter overall survival, and reduced disease-free survival in thyroid cancer patients, suggesting its potential as a prognostic marker.
What Are the Potential Mechanisms of IMP3 in Thyroid Cancer?
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RNA Trafficking and Translation: IMP3 may lead to dysregulated translation of oncogenic mRNAs, promoting tumor growth and metastasis.
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Epithelial-to-mesenchymal transition (EMT): IMP3 overexpression is associated with EMT-related changes, contributing to tumor invasion and metastasis.
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Angiogenesis and Hypoxia Response: IMP3 may contribute to the formation of new blood vessels and adaptation to hypoxic conditions, promoting tumor growth and metastasis.
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Regulation of Cancer Stem Cell Properties: IMP3 may regulate cancer stem cell properties, such as self-renewal and drug resistance, contributing to tumor recurrence and therapy resistance.
What are the Mechanisms of Action of IMP3?
The underlying mechanisms by which IMP3 contributes to thyroid cancer development and progression remain incompletely understood, though various potential mechanisms have been suggested.
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RNA Trafficking and Translation: As an RNA-binding protein, IMP3 plays a crucial role in the trafficking and translation of specific mRNAs involved in cell growth, migration, and invasion. Overexpression of IMP3 in thyroid cancer cells may lead to dysregulated translation of oncogenic mRNAs, promoting tumor growth and metastasis.
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Epithelial-to-Mesenchymal Transition (EMT): IMP3 has been implicated in regulating EMT, which allows epithelial cells to acquire a more invasive and migratory phenotype. In thyroid cancer, particularly ATC, IMP3 overexpression has been associated with EMT-related changes, such as reduced E-cadherin expression and heightened vimentin and N-cadherin expression.
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Angiogenesis and Hypoxia Response: IMP3 has been shown to regulate angiogenesis and hypoxia response in various cancers, including thyroid cancer. Overexpression of IMP3 may contribute to the formation of new blood vessels and adaptation to hypoxic conditions, promoting tumor growth and metastasis.
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Regulation of Stem Cell Properties: Some studies have suggested that IMP3 may regulate cancer stem cell (CSC) properties, such as self-renewal and drug resistance. In thyroid cancer, high IMP3 expression has been associated with the expression of CSC markers, potentially leading to tumor recurrence and therapy resistance.
How Is IMP3 Related to Treatment Response in Thyroid Cancer?
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Radioactive Iodine (RAI) Therapy: High IMP3 levels are associated with decreased RAI uptake and reduced treatment efficacy, potentially due to its involvement in regulating sodium-iodide symporter (NIS) expression.
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Targeted Therapy: High IMP3 expression may be associated with resistance to BRAF inhibitors in BRAF-mutated thyroid cancers and may regulate signaling pathways targeted by multi-kinase inhibitors like Sorafenib and Lenvatinib.
What Are the Potential Therapeutic Implications of IMP3 in Thyroid Cancer?
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IMP3 and microRNA Regulation: IMP3 interacts with microRNAs involved in cell proliferation, invasion, and metastasis, presenting potential therapeutic targets.
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IMP3 and Cellular Signaling Pathways: IMP3 is implicated in dysregulated signaling pathways (PI3K/AKT, MAPK, NF-κB) in thyroid cancer, which could be targeted therapeutically.
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IMP3 as a Therapeutic Target: Strategies such as RNA interference (RNAi) or small molecule inhibitors targeting IMP3 have shown promise in preclinical studies, resulting in reduced cell proliferation, migration, and invasion in thyroid cancer cell lines.
What Are the Technical Challenges of Using IMP3 in Thyroid Cancer?
One of the significant challenges in utilizing IMP3 as a biomarker for thyroid cancer is the technical variability observed in studies. Different antibodies, clones, or technical variations can lead to inconsistencies in the detection and quantification of IMP3 expression. This variability can affect the reliability of IMP3 as a consistent biomarker for thyroid cancer. To address this issue, standardized protocols for IMP3 expression analysis are needed. This includes using consistent antibodies, clones, and technical procedures across studies to ensure comparability and reliability of results.
Conclusion
The insulin-like growth factor-II mRNA-binding protein 3 (IMP3) has emerged as a promising biomarker in thyroid cancers, particularly papillary and follicular thyroid carcinoma. While the exact mechanisms underlying the role of IMP3 in thyroid cancer development and progression are not fully elucidated, it appears to be involved in processes such as RNA trafficking and translation, epithelial-to-mesenchymal transition, angiogenesis, and the regulation of cancer stem cell properties. Further research is needed to fully understand the molecular pathways and interactions involving IMP3 in thyroid cancer and explore its potential as a therapeutic target.
