Molecular Pathways Associated with Aggressiveness of Papillary Thyroid Cancer

Abstract

The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAF-mediated events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets, show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC.

Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers

“…They regulate gene expression at the post-transcriptional level by binding to imperfectly complementary sequences within target mRNAs, often in the 3¢-untranslated regions, thereby leading to degradation or translational suppression (32). Although definitive studies are currently lacking, miRs may nevertheless have potential as prognostic indicators in PTC, thereby optimizing the surgical management of patients with PTC (28,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44).…”

MicroRNA Expression and Association with Clinicopathologic Features in Papillary Thyroid Cancer: A Systematic Review

“…The recent expansion of knowledge and efforts to genetically characterize PTCs by The Cancer Genome Atlas Research Network (TCGA) Thyroid working group and others have revealed that microRNAs may play an important role in PTC prognosis (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). MicroRNAs (miR) are small non-protein coding RNA molecules that are 21-25 nucleotides in length.…”

“…Previous studies have reported that specific miRs are associated with aggressive clinicopathologic features of PTC, such as those listed above in addition to BRAF mutation. However, other studies failed to report any significant 4 4 association (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(21)(22)(23)(24)(25).…”

“…Despite the inconclusive studies in the literature, the incorporation of specific miR expression panels into the surgical management algorithm of PTC in order to improve perioperative decision-making has been suggested (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(21)(22)(23)(24)(25). To our knowledge, however, there is no published systematic review examining the clinicopathologic significance of miRs in PTCs.…”

Mps1 is associated with the BRAFV600E mutation but does not rely on the classic RAS/RAF/MEK/ERK signaling pathway in thyroid carcinoma

“…PTC generally has an indolent course and favorable prognosis (9). However, there remain 20-30% of patients where PTC recrudesces and became resistant to radioactive iodine treatment, particularly in patients with advanced thyroid carcinoma, yielding poor prognosis and shorter survival (10,11). Therefore, there is an urgent requirement to elucidate the molecular mechanism underlying thyroid carcinoma progression and to improve the survival rate of patients with thyroid carcinoma.…”