Here, we identify Janus kinase/signal transducers and activators of transcription (STAT) and phosphatidyl inositol 3-kinase (PI3K)/AKT as the down-stream pathways through which these cytokines confer resistance to cell death in thyroid cancer.
Recent novel and promising findings include additional abnormalities in key pathways associated with thyroid tumorigenesis (RET-Ras-BRAF-MEK; RET-beta-cateinin; TRK-PI3K-AKT; and MDM-p53-PTEN), single-nucleotide polymorphisms associated with thyroid cancer susceptibility, epigenetic silencing, alternative splicing, and gene expression abnormalities.
The genes, coding the signaling cascade proteins (e.g., RET, RAS, BRAF, PI3K, PTEN, AKT), are mutated or aberrantly expressed in thyroid cancer derived from follicular thyroid cell.
Our review of the literature strongly supports this notion in that a polymorphism in one microRNAs (miR-146a) predisposes to thyroid carcinoma, whereas numerous other microRNAs are involved in signaling (mainly PTEN/PI3K/AKT and T3/THRB) that is central to thyroid carcinogenesis.
In vitro results suggest that the inhibition of either RAS-MAPK-ERK or PI3K-AKT-mTOR components may confer sensitivity of thyroid cancer cells to classic chemotherapeutics.
Thyroid cancer cells lose TSH/cAMP dependency of mTOR signaling and cell growth. mTOR activity is not decreased by the MEK or AKT inhibitors in the RAS or BRAF human thyroid cancer cell lines.
In addition, expression of Sin1 and activation of AKT kinase were analyzed in fresh-frozen tissue samples (normal/tumor), primary cell cultures (papillary thyroid carcinoma [PTC]), and an established thyroid cancer cell line (medullary thyroid carcinoma) by Western blotting.
MicroRNA-126 suppresses proliferation of undifferentiated (BRAF(V600E) and BRAF(WT)) thyroid carcinoma through targeting PIK3R2 gene and repressing PI3K-AKT proliferation-survival signalling pathway.
In these cell lines, both active ERK and active AKT kinase proteins were found in BRAF V600E mutated thyroid carcinoma cells by immunofluorescent staining and Western blots experiments.
Taken together, these results suggest that knockdown of HPIP inhibits the proliferation, migration and EMT by suppressing the PI3K/AKT pathway, and HPIP may be a potential therapeutic target for the treatment of thyroid carcinoma.
In this review article, the role of different signaling pathways of PI3K/AKT in thyroid cancers, with the emphasis on the PI3K/AKT/mammalian target of rapamycin (mTOR), PI3K/AKT/forkhead box O (FOXO) and PI3K/AKT/phosphatase and tensin homolog deleted on chromosome ten (PTEN) pathways, and various therapeutic strategies targeting these pathways have been summarized.
The aim of this study is to identify its expression, function, and molecular mechanism in thyroid cancer. microRNA-137 (miR-137) downregulation was observed in thyroid cancer tissues compared with normal thyroid tissues. miR-137 mimics downregulated B-CPAP cell proliferation, colony formation ability, and invasion, with suppressed expression of cyclin E, MMP2, p-ERK, and p-AKT. miR-137 inhibitor transfection in TPC-1 cell line showed the opposite effects.
Increased activation of alternative proliferation pathways (as determined by the increase of AKT kinase activity) counteracts the effect of BRAF kinase inhibition in thyroid carcinomas.
Substantial improvement in the understanding of the oncogenic pathways in thyroid cancer has led to identification of specific molecular alterations, including mutations of BRAF and RET in papillary thyroid cancer, mutation of RAS and rearrangement of PPARG in follicular thyroid cancer, mutation of RET in medullary thyroid cancer, and mutations of TP53 and in the phosphatidylinositol 3'-kinase (PI3K)/AKT1 pathway in anaplastic thyroid cancer.
Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent and to evaluate biomarkers of treatment response.<b>Experimental Design:</b> CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway.
Interestingly, the exposure of thyroid carcinoma cells to PLX4032 resulted in a rapid feedback activation of EGFR signaling with parallel activation of AKT phosphorylation.