Publications (4)7.06 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: Poorly-differentiated carcinomas (PDCs) occupy an intermediate position between differentiated (follicular and papillary) and undifferentiated carcinomas (UDCs) based on morphology and behavior. However, its definition remains unclear, especially in the differentiation of thyroid function. To characterize the hormonal differentiation of PDCs, in addition to the morphological definition, we immunohistochemically investigated the thyroid-stimulating hormone receptor (TSHR) and thyroid transcription factor 1 (TTF-1) as regulators of thyroid hormonal function and differentiation. We comparatively studied their expression in 15 papillary carcinoma (PTC), 8 PDC and 8 UDC cases and further analyzed their correlation to proliferation activity as estimated by the MIB-1 index. All cases of PTC and PDC expressed the TSHR, whereas all cases of UDC did not. Notably, most of the PDCs showed more decreased and heterogeneous expression in the poorly-differentiated component than in the well-differentiated one within the same case. Examining the heterogeneous areas in PDC, we found an inverse relationship between TSHR expression and the MIB-1 index, that is, decreased TSHR expression was correlated to high proliferation. Unexpectedly, TTF-1 expression was observed in almost all of the PTC and PDC cases and in half of the UDC cases; therefore, it was not useful to distinguish PDC from PTC or UDC. In conclusion, we demonstrated that TSHR expression was decreased in PDCs despite conserved TTF-1 expression and that it correlated to the proliferative activity in PDCs.
- [Show abstract] [Hide abstract] ABSTRACT: The main regulating systems of thyroid growth are the mitogen-activated protein kinase (MAPK) signaling pathway and the cAMP signaling pathway. Thyroid papillary carcinoma frequently involves mutations in BRAF or RET/PTC without overlap, which are expected to constitutively activate MAPK signaling. On the other hand, it has been reported that cAMP signaling acts in an inhibitory manner on the proliferation of papillary carcinoma cell lines, although the cAMP pathway physiologically promotes the proliferation of normal follicular cells as well as hormonogenesis. The effect of cAMP on proliferation is attributed to crosstalk with MAPK signaling. However, this phenomenon has not been clearly established in papillary carcinoma with BRAF or RET/PTC mutations. In order to elucidate whether activated cAMP signaling inhibits cell proliferation and affects MAPK signaling in papillary carcinoma, we performed in vitro experiments using two representative cell lines, K1 and TPC-1, which have a BRAF and an RET/PTC mutation, respectively. Elevated cAMP caused by an adenylate cyclase activator suppressed the proliferation of both K1 and TPC-1 cells. Examining the crosstalk between cAMP and MAPK signaling, K1 and TPC-1 cells showed opposite responses to cAMP activation. These responses were blocked by an inhibitor of the cAMP-dependent protein kinase (PKA). In K1 cells, B-Raf might predominate over Raf-1, and the elevated cAMP is thought to promote MAPK phosphorylation through the PKA-mediated activation of Rap1. On the other hand, in TPC-1 cells Raf-1 might predominate and could be inhibited by activated Rap1, resulting in the suppression of MAPK phosphorylation. In conclusion, the proliferation of both papillary carcinoma cell types was significantly suppressed by cAMP signaling, regardless of whether MAPK signaling was activated or inactivated by the PKA-mediated cAMP signaling pathway. There could, however, be other mechanisms by which cAMP signaling inhibits the growth of papillary carcinoma cells.
- [Show abstract] [Hide abstract] ABSTRACT: Thyroid stimulating hormone (TSH) is known to increase intracytoplasmic cyclic adenosine monophosphate (cAMP) and to regulate the growth of normal follicular cells. The aim of this study was to explore the role of the cAMP-mediated signaling pathway stimulated by TSH as a cell growth modulator in human thyroid cancer cells. One papillary thyroid cancer cell line, K1 cells and two anaplastic thyroid cancer cell lines, TTA1 and TTA2 cells were treated with forskolin, which directly activates adenyl cyclase to raise the level of intracellular cAMP. Forskolin suppressed thyroid cancer cell proliferations, especially in K1 cells, in a dose-dependent manner and induced growth arrest at the G0/G1 phase of the cell cycle. We also examined the expression of mitogen activated protein kinase (MAPK) after the forskolin treatment. Forskolin reduced the activation of growth factor induced MAPK activity. In conclusion, we demonstrated that forskolin was involved in G1 arrest and MAPK activation in K1 thyroid cancer cells. Our study suggests that the TSH signal mediated by cAMP acts as a negative regulator in thyroid cancer cells, unlike that in normal follicular cells.
Mitaka-machi, Tokyo, Japan
- Department of Pathology