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] |