BRAF-Oncogene-Induced Senescence and the Role of Thyroid-Stimulating Hormone Signaling in the Progression of Papillary Thyroid Carcinoma

Abstract

Oncogene-induced senescence (OIS) explains the phenomenon of cellular senescence triggered by the action of oncogenes. It is a mechanism adopted by a cell to inhibit progression of benign tumors into malignancy, occurs in premalignant lesions, and is almost never present in malignant lesions. BRAF mutations occur in about 40-45% of all papillary thyroid carcinomas (PTCs) and of which 99.7% is the BRAFV600E mutation. A unique phenotype of the BRAFV600E mutation is the upregulation of the thyroid-stimulating hormone receptor (TSHR) on thyrocyte membranes. Despite the overexpression of the receptor, BRAFV600E cells undergo cell cycle arrest leading to OIS via a negative feedback signaling mechanism. A simultaneous increase in serum thyroid-stimulating hormone (TSH) in response to hypothyroidism (common in autoimmune diseases such as Hashimoto's thyroiditis) would cause senescent tumor cells to overcome OIS and proceed towards malignancy, hence showing the importance of TSH/TSHR signaling in the development of PTCs. Increase in TSH/TSHR signaling triggers an increase in levels of downstream enzymes such as manganese superoxide dismutase (MnSOD) and dual-specific phosphatase 6 (DUSP6) which eventually results in the production of oncogenic proteins such as c-Myc. Therefore, the detection of these genetic alterations as effective biomarkers for premalignant lesions of PTC is important in clinical settings and techniques such as polymerase chain reaction-mediated restriction fragment length polymorphism (PCR-RFLP) and real-time PCR can be used to detect the BRAFV600E point mutation and overexpression of TSHR, MnSOD, and DUSP6, respectively.

DNA hypermethylation in disease: mechanisms and clinical relevance

“…They generated a mouse colonderived organoid model with a Braf V600E mutant proto-oncogene that could be experimentally activated. Braf is a MAPK signalling gene whose upregulatory mutation can lead to either cell proliferation or, in pre-malignant lesions, to tumoursuppressing cell senescence (oncogene-induced senescence) [165]. Tao et al found that colon organoids expressing Braf V600E display a dysplastic phenotype when cultured for 2-3 months after Braf V600E activation.…”

On the basis of Hashimoto's thyroiditis, to form papillary thyroid carcinoma, metastasized and then to de-differentiate into poorly differentiated squamous cell carcinoma

“…So far, we have only seen one case reported regarding BRAF mutation (c.1799 T>A;1801_1812del) in primary SCC of the thyroid (27). As we know that BRAF mutations, especially, BRAF V600E mutation is the most common molecular genetic change in PTC (28)(29)(30)(31)(32). Therefore, we believe that the SCC in the metastatic foci of this case may be evolved from the tall-cell subtype of PTC.…”

In the Basis of Hashimoto’s Thyroiditis, to Form Papillary Thyroid Carcinoma, Metastasized and Then to De-Differentiate into Poorly Differentiated Squamous Cell Carcinoma

“…So far, we have only seen one case reported regarding BRAF mutation (c.1799 T > A; 1801_1812del) in primary SCC of the thyroid [27]. As we know that BRAF mutations, especially, BRAF V600E mutation is the most common molecular genetic change in PTC [28] [29] [30] [31] [32]. Therefore, we believe that the SCC in the metastatic foci of this case may be evolved from the tall-cell subtype of PTC.…”