Table 1.

Molecular abnormalities and deregulated signaling pathways involved in TC.

Signaling Pathway	Research Findings	References
TSH-R	TSH stimulates the production of other growth factors (VEGF, amyloid precursors)	[42,43]
	TSH/cAMP cooperates with insulin and IGF-1 to regulate thyroid cell proliferation, cell cycle progression and the expression of Tg, TTF-1 and TSH-R mRNA levels	[41,45,49]
	Serum TSH levels directly correlate to TC incidence in patients with thyroid nodules	[46,47]
	TSH cooperates with oncogenic BRAF to induce thyroid tumorigenesis, partially via cAMP	[48]
MAPK	MAPK is activated as a consequence of aberrant expression of proto-oncogenes such as Ret, NTRK, RAS and BRAF	[51,52]
	RET/PTC rearrangement is present in 5–30% of PTCs	[53]
	Ras mutations and PAX-8/PPAR-γ translocation are present in PTCs follicular variant	[53]
	BRAF is mutated in 35–60% of PTCs	[53]
	BRAF mutation and p53 alterations have been found in ATCs	[53]
PI3-K/AKT/PTEN	Several growth factors such as insulin/IGF-1, EGF, HGF activate PI3-K/AKT/PTEN signaling pathway	[41]
	PI3-K/AKT/PTEN signaling is essential for thyrocytes proliferation under TSH stimulation	[55,56]
	PTEN inactivation is present in about 40% of PDTCs and more than 50% of highly aggressive TCs	[57]
	Point mutations or copy number changes of PIK3CA and AKT1 have been found in ~23% of ATCs sometimes together with either RAS or BRAF mutations	[58]
	AKT1 activation is more evident in invasive region of TCs, in lymph nodes or distant metastasis	[58]
	PI3-K/AKT deregulation upregulates Wnt/β-catenin pathway, inducing de-differentiation	[59]
mTOR/p70S6K	TSH proliferative signaling involves mTOR kinase without activating AKT1	[62]
	mTOR downstream effectors are required for the mitogenic response triggered by TSH/cAMP and PI3-K on thyroid follicles	[55,62]
	Many TCs modify the upstream control of mTOR activity becoming cAMP/TSH independent and unresponsive to PKA control	[65]
Insulin/IGF system	Insulin/IGF system contributes to generate proliferative responses mediated by TSH	[41,45,66,68]
	Insulin/IGF system together with cAMP, modulates the expression of TTF-2	[67]
	The overexpression of IGF-1, IGF-1R, IGF-2 and IR in TC cells induces cellular transformation, proliferation and apoptosis suppression	[71]
	Overexpression of IR-A is a feature of poorly differentiated, anaplastic or stem-like TC cells	[16,19]
	IGF-1R expression decreases with cancer de-differentiation	[72]
	IGF-2/IR-A loop exerts a more important role than the IGF-1/IGF-1R loop in thyroid cells de-differentiation, stemness, tumor progression and metastasis	[73]
	HRs (likely HR-A) are present both in well differentiated and in poorly differentiated/undifferentiated PTCs	[18,75]
	HRs affect cancer responses to both insulin and IGFs	[18,74]
	Insulin/IGF system crosstalks with other pro-mitogenic signaling pathways such as MAPK, PI3-K, JAK/STAT cascades	[70]