Thyroid Cancer
Thyroid cancer occurs in the cells of the thyroid and is the most common endocrine malignancy. The normal thyroid gland is a butterfly-shaped gland located at the base of your neck. There are two types of endocrine thyroid cells, follicular thyroid cells and parafollicular C cells. Follicular cells line the colloid follicles, concentrate iodine, and produce thyroid hormones. These hormones regulate your heart rate, blood pressure, body temperature and weight [1].
Thyroid cancer occurs more often in women than in men. There are 4 types of thyroid cancer. Papillary thyroid cancer (PTC) is the most prevalent, accounting for more than 80% all of thyroid cancer cases, and arises from follicular cells. The recent progress in understanding the molecular pathogenesis of thyroid cancer has shown great promise for the development of more effective treatment strategies for thyroid cancer. These studies have reported that thyroid cancer has mainly resulted from the identification of molecular alterations, including the genetic and epigenetic alterations of signaling pathways — such as the MAPK pathway and the PI3K–AKT pathway — which is reshaping thyroid cancer medicine.
Figure 1. Model of the progression of thyroid tumorigenesis driven by the MAPK and PI3K–AKT pathways
*this diagram is derived from publication on Nature Reviews Cancer [2]
As the figure 1 shows, Activation of the MAPK pathway by genetic alterations, such as the BRAFV600E mutation, primarily drives the development of papillary thyroid cancer (PTC) from follicular thyroid cells. By contrast, activation of the PI3K–AKT pathway by genetic alterations, such as mutations in RAS, PTEN and PIK3CA, primarily drives the development of follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC) from follicular thyroid cells. Conversion from FTA to FTC is largely due to increasing activation of the PI3K–AKT pathway.
In this article, we list part of these proteins involved in thyroid cancer based on the information provided by NCG (web resource to analyze duplicability, orthology and network properties of cancer genes).
Here, we display several key targets involved in mechanism of thyroid cancer, including:
- BRAF (B-type Raf kinase), a cytoplasmic serine–threonine protein kinase, is involved in a MAPK signaling pathway acting as an activator and is important for cell growth [3]. BRAF mutations were initially reported in thyroid cancer in 2003 with a frequency ranging from 26% to 44% [4]. Mutations have only been reported in 2 types of thyroid cancer, namely PTC and ATC [5]. BRAF mutations have not been identified in FTC, MTC, benign thyroid adenomas, or hyperplasia [6].
- HRAS (GTPase HRas), one of RAS oncogene, is involved in the activation of Ras protein signal transduction. Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. The RAS oncogene plays a fundamental role in human tumorigenesis [7]. Activating mutations in its three proto-oncogenes (HRAS, KRAS and NRAS) are found in nearly all human cancers. Thyroid cancer is one of the earliest cases where activating RAS mutations were discovered [8]. Among of the three proto-oncogenes, HRAS is one of the most commonly mutated genes in thyroid cancer, particularly the follicular and Hurthle cell subtypes [9].
- EIF1AX (Eukaryotic Translation Initiation Factor 1A X-Linked), an essential eukaryotic translation initiation factor, is a component of the 43S pre-initiation complex (PIC), which mediates the recruitment of the small 40S ribosomal subunit to the 5' cap of messenger RNAs. The EIF1AX gene was recently described as a new thyroid cancer-related gene. Its mutations were mainly reported in poorly diferentiated (PDTC) and anaplastic thyroid cancers (ATC), but also in well-diferentiated thyroid cancer (WDTC) and in benign thyroid lesions [10].
- MTOR (mammalian target of rapamycin) is a serine/threonine kinase that gets inputs from the amino acids, nutrients, growth factor, and environmental cues to regulate varieties of fundamental cellular processes [11]. Catarina Tavares et al. has revealed that phospho-mTOR activation may lead to the activation of the mTORC2 complex in PTC. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression [12].
References
[1] Tobias Carling and Robert Udelsman. Thyroid Cancer [J]. Annu. Rev. Med. 2014. 65:13.1–13.13.
[2] Mingzhao Xing. Molecular pathogenesis and mechanisms of thyroid cancer [J]. Nature Reviews Cancer. 2013, 13(3), 184–199.
[3] Lisa M. Caronia, John E. Phay and Manisha H. Shah. Role of BRAF in Thyroid Oncogenesis [J]. Clinical Cancer Research. 2011, 17(25).
[4] Namba H, Nakashima M, Hayashi T et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers [J]. J Clin Endocrinol Metab. 2003, 88:4393–7.
[5] Hundahl SA, Fleming ID, Fremgen AM et al. National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [J]. Cancer. 1998, 83:2638–48.
[6] Xing M. BRAF mutation in thyroid cancer [j]. Endocr Relat Cancer. 2005, 12:245–62.
[7] Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web [J]. Nat Rev Cancer. 2011, 11:761–74.
[8] Mingzhao Xing. Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer [J]. BMC Medicine. 2016, 14 (12).
[9] Rui Dou, Lili Zhang, Tingxia Lu et al. Identification of a novel HRAS variant and its association with papillary thyroid carcinoma [J]. Oncol Lett. 2018. 15(4): 4511–4516.
[10] J. Simões‑Pereira, M. M. Moura, I. J. Marques et al. The role of EIF1AX in thyroid cancer tumourigenesis and progression [J]. Journal of Endocrinological Investigation. 2018.
[11] Avaniyapuram KannanMurugan. mTOR: Role in cancer, metastasis and drug resistance [J]. Seminars in Cancer Biology. 2019, 59: 92-111.
[12] Catarina Tavares, Catarina Eloy, Miguel Melo et al. mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression [J]. Int J Mol Sci. 2018, 19(5):1448.
