Dataset Information

REG? ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-? pathway.

ABSTRACT: Anaplastic thyroid cancer (ATC) is the most aggressive human thyroid malignancy, characterized by dedifferentiation and resistance to radioiodine therapy. The underlying mechanisms regulating ATC dedifferentiation are largely unknown. Here, we show that REG?, a noncanonical proteasome activator highly expressed in ATC, is an important regulator of differentiation in ATC cells. Ablation of REG? significantly restored expression of thyroid-specific genes, enhanced iodine uptake, and improved the efficacy of 131I therapy in ATC xenograft models. Mechanistically, REG? directly binds to the TGF-? signaling antagonist Smad7 and promotes its degradation, leading to the activation of the TGF-? signal pathway. With gain- and loss-of-function studies, we demonstrate that Smad7 is an important mediator for the REG? function in ATC cell dedifferentiation, which is supported by expression profiles in human ATC tissues. It seems that REG? impinges on repression of thyroid-specific genes and promotion of tumor malignancy in ATC cells by activating the TGF-? signal pathway via degradation of Smad7. Thus, REG? may serve as a novel therapeutic target for allowing radioiodine therapy in anaplastic thyroid cancer patients with poor prognosis.

SUBMITTER: Jiao C

PROVIDER: S-EPMC7205985 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway.

Jiao Chan C Li Lin L Zhang Pei P Zhang Li L Li Ke K Fang Riqun R Yuan Lei L Shi Kaixuan K Pan Linan L Guo Qiannan Q Gao Xiao X Chen Geng G Xu Shichen S Wang Qingwei Q Zuo Di D Wu Wei W Qiao Shanlou S Wang Xiaoshuang X Moses Robb R Xiao Jianru J Li Lei L Dang Yongyan Y Li Xiaotao X

Cell death and differentiation 20190626 2

Anaplastic thyroid cancer (ATC) is the most aggressive human thyroid malignancy, characterized by dedifferentiation and resistance to radioiodine therapy. The underlying mechanisms regulating ATC dedifferentiation are largely unknown. Here, we show that REGγ, a noncanonical proteasome activator highly expressed in ATC, is an important regulator of differentiation in ATC cells. Ablation of REGγ significantly restored expression of thyroid-specific genes, enhanced iodine uptake, and improved the e ...[more]

PMID: 31243343

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Project description:Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and it is less than 2% of thyroid carcinomas (TCs). The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated external beam radiation therapy (EBRT), and chemotherapy, in particular with cisplatin or doxorubicin, achieving about 10 months of median survival. Since ATC is a rare and aggressive tumor, it is still challenging to predict the patient clinical therapy responsiveness. Several genetic mutations have been described in ATC, involved in different molecular pathways linked to tumor progression, and novel therapies acting on these molecular pathways have been investigated, to improve the quality of life in these patients. Here we review the new targeted therapy of ATC. We report interesting results obtained with molecules targeting different pathways: angiogenesis (vandetanib, combretastatin, sorafenib, lenvatinib, sunitinib, CLM94, CLM3, etc.); EGFR (gefitinib, docetaxel); BRAF (dabrafenib/trametinib, vemurafenib); PPARγ agonists (rosiglitazone, pioglitazone, efatutazone); PD-1 and PD-L1 (pembrolizumab); TERT. To escape resistance to monotherapies, the evaluation of combination strategies with radiotherapy, chemotherapy, or targeted drugs is ongoing. The results of clinical trials with dabrafenib and trametinib led to the approval from FDA of this combination for patients with BRAF V600E mutated ATC with locally advanced, unresectable, or metastatic ATC. The anti-PD-L1 antibody immunotherapy, alone or combined with a BRAF inhibitor, has been shown also promising in the treatment of ATC. Furthermore, to increase the therapeutic success and not to use ineffective or even harmful treatments, a real tailored therapy should be pursued, and this can be achieved thanks to the new available genomic analysis methods and to the possibility to test in vitro novel treatments directly in primary cells from each ATC patient. Exploring new treatment strategies is mandatory to improve the survival of these patients, guaranteeing a good quality of life.

Project description:BackgroundAnaplastic thyroid cancer (ATC) is rare, accounting for 1-2% of thyroid malignancies. Median survival is only 3-10 months, and the optimal therapeutic approach has not been established. This study aimed to evaluate outcomes in ATC based on treatment modality.MethodsRetrospective review was performed for patients treated at a single institution between 1990 and 2015. Demographic and clinical covariates were extracted from the medical record. Overall survival (OS) was modeled using Kaplan Meier curves for different treatment modalities. Univariate and multivariate analyses were conducted to assess the relationships between treatment and disease characteristics and OS.Results28 patients with ATC were identified (n = 16 female, n = 12 male; n = 22 Caucasian, n = 6 African-American; median age 70.9). Majority presented as Stage IVB (71.4%). Most patients received multimodality therapy. 19 patients underwent local surgical resection. 21 patients received locoregional external beam radiotherapy (EBRT) with a median cumulative dose of 3,000 cGy and median number of fractions of 16. 14 patients received systemic therapy (n = 11 concurrent with EBRT), most commonly doxorubicin (n = 9). 16 patients were never disease free, 11 patients had disease recurrence, and 1 patient had no evidence of disease progression. Median OS was 4 months with 1-year survival of 17.9%. Regression analysis showed that EBRT (HR: 0.174; 95% CI: 0.050-0.613; p=0.007) and surgical resection (HR: 0.198; 95% CI: 0.065-0.598; p=0.004) were associated with improved OS. Administration of chemotherapy was not associated with OS.ConclusionsAnaplastic thyroid cancer patients receiving EBRT to the thyroid area/neck and/or surgical resection had better OS than patients without these therapies, though selection bias likely contributed to improved outcomes since patients who can undergo these therapies tend to have better performance status. Prognosis remains poor overall, and new therapeutic approaches are needed to improve outcomes.

Dataset Information

REG? ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-? pathway.

Publications

REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway.

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