New biomarkers: prospect for diagnosis and monitoring of thyroid disease

Abstract

After the metabolic syndrome and its components, thyroid disorders represent the most common endocrine disorders, with increasing prevalence in the last two decades. Thyroid dysfunctions are distinguished by hyperthyroidism, hypothyroidism, or inflammation (thyroiditis) of the thyroid gland, in addition to the presence of thyroid nodules that can be benign or malignant. Thyroid cancer is typically detected via an ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) and cytological examination of the specimen. This approach has significant limitations due to the small sample size and inability to characterize follicular lesions adequately. Due to the rapid advancement of high-throughput molecular biology techniques, it is now possible to identify new biomarkers for thyroid neoplasms that can supplement traditional imaging modalities in postoperative surveillance and aid in the preoperative cytology examination of indeterminate or follicular lesions. Here, we review current knowledge regarding biomarkers that have been reliable in detecting thyroid neoplasms, making them valuable tools for assessing the efficacy of surgical procedures or adjunctive treatment after surgery. We are particularly interested in providing an up-to-date and systematic review of emerging biomarkers, such as mRNA and non-coding RNAs, that can potentially detect thyroid neoplasms in clinical settings. We discuss evidence for miRNA, lncRNA and circRNA dysregulation in several thyroid neoplasms and assess their potential for use as diagnostic and prognostic biomarkers.

Keywords: biomarkers; circRNA; lncRNA; mRNA; miRNA; non-coding RNAs; thyroid cancer; thyroid disorders.

Figure 1

Types of thyroid diseases. Hypothyroidism is a medical condition in which the thyroid gland produces insufficient levels of thyroid hormones, and hyperthyroidism is a medical condition caused by high levels of thyroid hormones in the blood. Thyroid nodules are small lesions within the thyroid gland, and goiter is a thyroid gland enlargement that can be diffuse or nodular. Thyroid cancer is the most common endocrine malignancy and the ninth most common cancer. Depending on the origin, it is classified as differentiated thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer. Some adaptations and new terminology exist in the 2022 WHO classification of thyroid tumors. Thyroiditis is inflammation of the thyroid gland, associated with normal, high or low levels of thyroid hormones in the blood.

Figure 2

Overview of Identification of Biomarkers of Thyroid Neoplasms. A conventional approach for detecting and monitoring thyroid neoplasms relies on fine-needle aspiration biopsy (FNAB) and measurements of traditional biochemical markers, such as TSH, FT4, Tg, TgAb, and TPOAB. Novel RNA-based markers of thyroid neoplasms are identified by expression profiling of the thyroid gland tissue and/or blood samples of patients using high-throughput platforms for RNA analysis and identification, such as next-generation sequencing. Other emerging biomarkers of thyroid neoplasms are identified using flow cytometry, ELISA assays, genetic tests, and immunohistological analyses.

Figure 3

Mechanism of action of miRNAs. miRNAs are transcribed from DNA sequences into primary miRNAs (pri-miRNAs), which undergo endolytic processes to produce mature miRNAs. Pri-miRNAs are transcribed in the nucleus by RNA polymerase II and cut to approximately 70 nucleotide-long pre-miRNA molecules that are exported to the cytoplasm by the endoribonuclease DROSHA or by components of the splicing machinery. Mature miRNA duplexes are produced after further processing by the type III endoribonuclease DICER, which is associated with RNA-binding proteins. The mature miRNA guide strand joins with proteins to form the silencing complex, which binds to complementary sequences on target mRNA. Depending on the level of complementarity between miRNA and target mRNAs, two outcomes are possible: target mRNA slicing or translational inhibition, with subsequent target mRNA decay.

Figure 4

Mechanisms of action of lncRNAs. lncRNAs can regulate gene expression by (A) serving as precursors of miRNAs to affect the regulation of miRNAs directly; (B) acting as a sponge of miRNAs and inhibiting the degradation of mRNAs targeted by miRNAs; (C) lncRNAs can also function as scaffolds to form ribonucleoprotein (RNP) complexes; (D) lncRNA can inhibit the binding of a transcriptional regulatory factor, by directly interacting with them and acting as a “decoy”, which abolishes their action.

Figure 5

Mechanisms of actions of circRNA. circRNA can regulate gene expression by (A) acting as miRNA sponges; (B) interacting with various cellular proteins; (C) interfering with protein translation; (D) modulating protein-protein interactions; and (E) modifying the transcription of genes.