Navigating thyroid cancer complexity: the emerging role of EV-derived non-coding RNAs

Abstract

Thyroid cancer (TC), which arises from the epithelial cells of the thyroid gland, is experiencing a significant increase in incidence globally. TC encompasses various subtypes, including papillary, follicular, medullary, and anaplastic thyroid cancers, each with distinct pathological and clinical features. Extracellular vesicles (EVs), are naturally occurring and nanosized lipid bilayers, and can be secreted by almost all cell types. EVs, comprising microvesicles and exosomes, are pivotal in mediating intercellular communication within the tumor microenvironment. Notably, EVs possess unique properties such as stability in circulation and the ability to traverse biological barriers, enhancing their role as carriers of molecular information. EVs carry non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, which are crucial regulators of gene expression. Recent studies have highlighted the significant role of EV-derived ncRNAs in influencing thyroid cancer progression, metastasis, and immune modulation by mediating intercellular communication within the tumor microenvironment. The expression of EV-derived ncRNAs varies across different stages of thyroid cancer, reflecting potential as biomarkers for diagnosis and targets for therapy. This review delves into the multifaceted roles of EV-ncRNAs in thyroid cancer, emphasizing their impact on tumor growth, metastatic potential, and immune interactions, while also exploring their promising applications in early diagnosis and targeted treatment strategies. Understanding these dynamics is essential for developing innovative interventions to improve patient outcomes in thyroid cancer.

Fig. 1. Overview of the biogenesis, secretion, uptake and composition of exosomes.

Exosomes are small extracellular vesicles formed through the endocytic pathway, involving stages such as early endosomes, multivesicular bodies (MVBs), and intraluminal vesicles (ILVs), which eventually fuse with the cell membrane to release exosomes into the extracellular space. These vesicles carry a variety of biologically active substances, including DNA, mRNAs, non-coding RNAs, proteins, and lipids. Specific protein markers, such as tetraspanins (CD9, CD63, CD81), are used to identify exosomes. The recipient cells uptake, via different pathways, such as cell signaling, membrane fusion, or endocytosis (left). The featured structure and common components of exosomes (right). lncRNA Long-noncoding RNA, miRNA MicroRNA, circRNA circular RNA, MHC Major histocompatibility complex class.

Fig. 2. EVs are included in the TC tumor microenvironment.

The tumor microenvironment of TC is a heterogeneous and dynamic entity with multiple factors and cellular composition. These cells include tumor cells (TC cells, CSCs), immune cells (DC cells, T cells, TAMs, neutrophils), stromal cells (CAFs), as well as exosomes of multiple cellular origin as carriers of intercellular interactions. A key aspect of this environment is the presence of extracellular vesicles (EVs) originating from multiple cell types, which serve as crucial mediators of intercellular communication. Within these EVs, non-coding RNAs (ncRNAs) act as influential regulators of gene expression. EV-derived ncRNAs can significantly impact TC progression by modulating processes such as tumor proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and metastasis, by inducing gene silencing through epigenetic modifications. EVs extracellular vesicles, TC thyroid cancer, DC dendritic cell, TAMs tumor-associated macrophages, CSCs cancer stem cells, CAFs cancer-associated fibroblasts, EMT epithelial-mesenchymal transition.

Fig. 3. The contributions of tumor-derived EV-ncRNAs to TC progression.

EV-ncRNAs play crucial roles in the growth and metastasis of TC by mediating intercellular communication within the tumor microenvironment. EVs carry various ncRNAs, including miRNAs, lncRNAs, and circRNAs, which significantly influence oncogenic processes. For instance, miRNAs such as miR-146b and miR-222 are overexpressed in PTC cell exosomes, negatively affecting cell proliferation. MiR-423-5p, elevated in PTC serum, enhances cell migration and invasion, while miR-21-5p, upregulated under hypoxic conditions, promotes angiogenesis by targeting TGFBI and COL4A1. Additionally, miR-221-3p facilitates proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) by targeting ZFAND5. LncRNAs like CDKN2B-AS1, found in cancer stem cell-derived exosomes, boost TC cell proliferation and invasion through TGF-β1/Smad2/3 signaling, whereas DOCK9-AS2 activates the Wnt/β-catenin pathway, exacerbating PTC progression. CircRNAs, such as circ007293, enriched in PTC patient serum exosomes, promote EMT, invasion, and proliferation by regulating the miR-653-5p/PAX6 axis. These EV-ncRNAs are integral to modifying the tumor microenvironment and driving TC progression.

Fig. 4. The potential of EV-ncRNAs as biomarkers and therapeutic agents in TC.

In diagnosis, EV-derived miRNAs, such as miR-146b-5p, miR-21a-5p, and Let-7 family members, show differential expression in patients with PTC versus benign conditions, offering promising biomarkers for early detection and differentiation. Additionally, circRNAs like hsa_circ_0082002 are elevated in PTC, correlating with lymph node metastasis and serving as potential diagnostic markers. In treatment, EV-ncRNAs contribute to overcoming therapeutic challenges. For instance, exosomal miR-1296-5p is implicated in radioiodine refractory PTC by targeting the Na+/I− symporter. EVs also serve as efficient delivery vehicles for therapeutic agents, such as siRNA and chemotherapeutic drugs, enhancing targeting and reducing side effects. Engineered exosomes carrying miRNAs like miR-152 and miR-30c-5p demonstrate potential in inhibiting tumor growth and metastasis, highlighting their role as innovative therapeutic tools in TC management. Therefore, EV-derived ncRNAs hold significant diagnostic and therapeutic potential in TC, serving as biomarkers for early detection and enhancing treatment efficacy through targeted delivery.