TSH overcomes BrafV600E-induced senescence to promote tumor progression via downregulation of p53 expression in papillary thyroid cancer

Zou, Minjing; Baitei, Essa Y.; Al-Rijjal, Roua A.; Parhar, Ranjit S.; Al‐Mohanna, Futwan; Kimura, Shioko; Pritchard, Catrin; BinEssa, Huda A.; Alzahrani, Ali S.; Al‐Khalaf, Huda H.; Hawwari, Abbas; Mohamed, Ahmed Sh.; Assiri, Abdullah M.; Meyer, Brian F.; Shi, Yufei

doi:10.1038/onc.2015.253

Cited by 36 publications

(27 citation statements)

References 59 publications

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“…The requirement of TSHR signaling in BRAF V600E -induced PTC (11) or other thyroid cancer mouse models (12,42) has been reported in several studies. Furthermore, it has been demonstrated that TSH may trigger advanced clinical tumor stage, extrathyroidal extension, lymph node metastasis, and genomic instability or may endure the oncogeneinduced senescence in the aforementioned mouse models (42,43). Nevertheless, the precise role of TSH in the etiology of PTC remains unknown.…”

Section: Discussionmentioning

confidence: 85%

Partial thyrocyte‐specific Gα _s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice

et al. 2018

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Thyroid function is controlled by thyroid-stimulating hormone (TSH), which binds to its G protein-coupled receptor [thyroid-stimulating hormone receptor (TSHR)] on thyrocytes. TSHR can potentially couple to all G protein families, but it mainly activates the G- and G-mediated signaling cascades. To date, there is a knowledge gap concerning the role of the individual G protein cascades in thyroid pathophysiology. Here, we demonstrate that the thyrocyte-specific deletion of G-protein α subunit (Gα) in adult mice [tamoxifen-inducible G protein α subunit deficient (iTGαKO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGαKO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGαKO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesions with increased proliferation and slightly increased phospho-ERK1/2 staining were found in iTGαKO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gα in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gα deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gα expression. Thus, these mice are a novel model to elucidate the pathophysiological consequences of hypothyroidism and TSHR/G/cAMP-mediated tumorigenesis.-Patyra, K., Jaeschke, H., Löf, C., Jännäri, M., Ruohonen, S. T., Undeutsch, H., Khalil, M., Kero, A., Poutanen, M., Toppari, J., Chen, M., Weinstein, L. S., Paschke, R., Kero, J. Partial thyrocyte-specific Gα deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.

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Section: Discussionmentioning

confidence: 85%

Partial thyrocyte‐specific Gα _s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice

et al. 2018

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“…However, the significance of low TSH levels for thyroid tumorigenesis is controversial. On one hand, Tg-Braf V600E ;Tshr -/- mice [ 27 ] and LSL-Braf V600E ;TPO-Cre;Tshr -/- mice [ 4 ], both of which are unresponsive to TSH stimulation due to a lack of TSH receptor expression, can develop thyroid cancers, albeit less aggressive, but, on the other hand, transplantation of thyroid cancers developed in LSL-Braf V600E ;TPO-Cre mice (with high TSH levels) into nude or syngeneic immuno-competent mice (with normal TSH levels) leads to regression and senescence [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels

et al. 2018

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The BRAFV600E mutation is the most prevalent driver mutation of sporadic papillary thyroid cancers (PTC). It was previously shown that prenatal or postnatal expression of BRAFV600E under elevated TSH levels induced thyroid cancers in several genetically engineered mouse models. In contrast, we found that postnatal expression of BRAFV600E under physiologic TSH levels failed to develop thyroid cancers in conditional transgenic Tg(LNL-BrafV600E) mice injected in the thyroid with adenovirus expressing Cre under control of the thyroglobulin promoter (Ad-TgP-Cre). In this study, we first demonstrated that BrafCA/+ mice carrying a Cre-activated allele of BrafV600E exhibited higher transformation efficiency than Tg(LNL-BrafV600E) mice when crossed with TPO-Cre mice. As a result, most BrafCA/+ mice injected with Ad-TgP-Cre developed thyroid cancers in 1 year. Histologic examination showed follicular or cribriform-like structures with positive TG and PAX staining and no colloid formation. Some tumors also had papillary structure component with lower TG expression. Concomitant PTEN haploinsufficiency in injected BrafCA/+;Ptenf/+ mice induced tumors predominantly exhibiting papillary structures and occasionally undifferentiated solid patterns with normal to low PAX expression and low to absent TG expression. Typical nuclear features of human PTC and extrathyroidal invasion were observed primarily in the latter mice. The percentages of pERK-, Ki67- and TUNEL-positive cells were all higher in the latter. In conclusion, we established novel thyroid cancer mouse models in which postnatal expression of BRAFV600E alone under physiologic TSH levels induces PTC. Simultaneous PTEN haploinsufficiency tends to promote tumor growth and de-differentiation.

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“…The generation of TPO-Braf V600E and Cyp24a1 knockout mice (Cyp24a1 nuU ) have been described previously (27–29). TPO- Braf V600E mice with wild-type Cyp24a1 (BVE Cyp24a1-wt ) developed PTC at approximately 5 weeks of age and were used as PTC tumor controls.…”

Section: Methodsmentioning

confidence: 99%

Cyp24a1 Attenuation Limits Progression of BrafV600E-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor PLX4720

et al. 2017

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CYP24A1, the primary inactivating enzyme for vitamin D, is often overexpressed in human cancers, potentially neutralizing the antitumor effects of calcitriol, the active form of vitamin D. However, it is unclear whether CYP24A1 expression serves as a functional contributor versus only a biomarker for tumor progression. In this study, we investigated the role of CYP24A1 on malignant progression of a murine model of -induced papillary thyroid cancer (PTC). Mice harboring wild-type (BVE) developed PTC at 5 weeks of age. Mice harboring a homozygous deletion of (BVE) exhibited a 4-fold reduction in tumor growth. Notably, we found the tumorigenic potential of BVE-derived tumor cells to be nearly abolished in immunocompromised nude mice. This phenotype was associated with downregulation of the MAPK, PI3K/Akt, and TGFβ signaling pathways and a loss of epithelial-mesenchymal transition (EMT) in BVE cells, associated with downregulation of genes involved in EMT, tumor invasion, and metastasis. While calcitriol treatment did not decrease cell proliferation in BVE cells, it strengthened antitumor responses to the BRAF inhibitor PLX4720 in both BVE and BVE cells. Our findings offer direct evidence that functions as an oncogene in PTC, where its overexpression activates multiple signaling cascades to promote malignant progression and resistance to PLX4720 treatment. .

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TSH overcomes BrafV600E-induced senescence to promote tumor progression via downregulation of p53 expression in papillary thyroid cancer

Cited by 36 publications

References 59 publications

Partial thyrocyte‐specific Gα _s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice

Partial thyrocyte‐specific Gα _s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice

Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels

Cyp24a1 Attenuation Limits Progression of BrafV600E-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor PLX4720

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TSH overcomes BrafV600E-induced senescence to promote tumor progression via downregulation of p53 expression in papillary thyroid cancer

Cited by 36 publications

References 59 publications

Partial thyrocyte‐specific Gα s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice

Partial thyrocyte‐specific Gα s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice

Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels

Cyp24a1 Attenuation Limits Progression of BrafV600E-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor PLX4720

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Partial thyrocyte‐specific Gα _s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice

Partial thyrocyte‐specific Gα _s deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice