Heat shock proteins HSP90, HSP70 and GRP78 expression in medullary thyroid carcinoma

Soudry, Ethan; Shavit, Sagit Stern; Hardy, Britta; Morgenstern, Sarah; Hadar, Tuvia; Feinmesser, Raphael

doi:10.1016/j.anndiagpath.2016.11.003

Cited by 24 publications

(22 citation statements)

References 29 publications

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“…Hsp90 and control β-actin RNA and cDNA were prepared by the manufacturer's recommended protocol using reverse transcriptase and random hexamers from a RevertAid First Strand cDNA Synthesis Kit (Fermentas). The previously reported primers used for quantifying Hsp90 mRNA expression were synthesized by TaKaRa (Dalian, China) 38 . The PCR reaction was also performed with rTaq (TaKaRa) in a DNA thermal cycler (Maxygen) according to a standard protocol as reported in a previous study 38 .…”

Section: Methodsmentioning

confidence: 99%

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3′-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells

Sun

Huang

et al. 2018

Theranostics

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Rationale: Cardenolides have potential as anticancer drugs. 3′-epi-12β-hydroxyfroside (HyFS) is a new cardenolide structure isolated by our research group, but its molecular mechanisms remain poorly understood. This study investigates the relationship between its antitumor activities and autophagy in lung cancer cells.Methods: Cell growth and proliferation were detected by MTT, lactate dehydrogenase (LDH) release, 5-ethynyl-20-deoxyuridine (EDU) and colony formation assays. Cell apoptosis was detected by flow cytometry. Autophagic and signal proteins were detected by Western blotting. Markers of autophagy and autophagy flux were also detected by immunofluorescence, transmission electron microscopy and acridine orange staining. Real time RT-PCR was used to analyze the gene expression of Hsp90. Hsp90 ubiquitination was detected by coimmunoprecipitation. The antitumore activities of HyFS were observed in nude mice.Results: HyFS treatment inhibited cell proliferation and induced autophagy in A549 and H460 lung cancer cells, but stronger inhibition of cell proliferation and induction of cell apoptosis were shown when HyFS-mediated autophagy was blocked. The Hsp90/Akt/mTOR axis was found to be involved in the activation of HyFS-mediated autophagy. Evidence of direct interaction between Hsp90 and Akt was observed. HyFS treatment resulted in decreased levels of heat shock protein 90 (Hsp90) and phosphorylated Akt, overexpression of Hsp90 increased activation of autophagy, and inhibition of Hsp90 expression decreased autophagy. In addition, ubiquitin-mediated degradation of Hsp90 and subsequent dephosphorylation of its client protein Akt were also found in HyFS-treated lung cancer cells. Moreover, combination treatment with HyFS and chloroquine showed remarkably increased tumor inhibition in both A549- and H460-bearing mice.Conclusion: Our results demonstrate that HyFS induced cytoprotective autophagy through ubiquitin-mediated degradation of Hsp90, which further blocked the Akt/mTOR pathway in lung cancer cells. Thus, a combination of a HyFS-like cardenolide and an autophagic inhibitor is a potential alternative approach for the treatment of lung cancer.

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Section: Methodsmentioning

confidence: 99%

“…The previously reported primers used for quantifying Hsp90 mRNA expression were synthesized by TaKaRa (Dalian, China) 38 . The PCR reaction was also performed with rTaq (TaKaRa) in a DNA thermal cycler (Maxygen) according to a standard protocol as reported in a previous study 38 .…”

Section: Methodsmentioning

confidence: 99%

3′-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells

Sun

Huang

et al. 2018

Theranostics

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“…GRP78 (which is also known as HSPA5) is reported to be involved in ER stress and overexpression of many types of human cancers, such as hepatocellular carcinoma, esophageal cancer, gastric cancer and prostate cancer. Besides, high expression of GRP78 showed strong association with medullary thyroid carcinoma [16][17]. Several studies have also shown that the expression of GRP78 is related to invasion and metastasis of human cancers.…”

Section: Introductionmentioning

confidence: 86%

“…Recent molecular and pathological studies have reported that glucose-regulated protein (GRP78) is involved in tumor development and progression [16][17][18][19][20][21][22]. GRP78 (which is also known as HSPA5) is reported to be involved in ER stress and overexpression of many types of human cancers, such as hepatocellular carcinoma, esophageal cancer, gastric cancer and prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma

Zhao

Kang

Xun

et al. 2020

Preprint

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Background: Thyroid cancer (TC) is the most common type of endocrine malignancy tumor and the incidence of it is increasing over years. Conventional surgery, radiotherapy and chemotherapy are difficult to improve the significant effects of it due to aggression and metastasis of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), which are regarded as the most malignant type of TC. Glucose-regulated protein (GRP78) is the key molecule of tumor growth, apoptosis and metastasis. However, the underlying mechanisms of GRP78 on TC still require discussion. This study aimed to explore the role of GRP78 and its potential mechanism in TC.Results: GRP78 expression was increased in TC tissues when compared with adjacent normal tissues. Besides, down-regulation of GRP78 significantly inhibited the metastatic and proliferative ability of ATC cells in in vitro studies. In addition, tunicamycin-induced ER stress up-regulated the expression of GRP78, PERK and XBP1 as well as reversed the metastatic ability of GRP78 in ATC cells. Bioinformatics and statistical analysis of gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for RNA-sequencing data from si-GRP78 and si-control showed that GRP78 might regulate the ability of metastasis through extracellular matrix (ECM) remodeling in ATC cells, as well as the expression of ECM components such as COL1A1 and MMP13 were shown to be highly relevant to ATC. The analysis of GEPIA database confirmed high genomic amplification of MMP13 and COL1A1 in TC tissues and showed correlation with TNM stage. Further western blotting analysis showed that MMP13 might be the target of GRP78 in ATC cells and ER stress could activate the expression of MMP13 that was suppressed by the GRP78 depletion.Conclusions: GRP78 acts as an important regulator of metastasis under ER stress. In addition, the function of GRP7 might be mediated by ECM remodeling in ATC cells, implicating it as a therapeutic target in TC.

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“…Expression of somatostatin receptors 2A and 5 correlates with advanced stages [109]. Heat shock proteins HSP70, HSP90 and GRP78 are upregulated in MC in comparison with normal thyroid tissues [110]. Upregulation of cancer/testis antigens is seen, contrasting with negative normal thyroid tissues and goitre as well as with rare expression in PC and FC.…”

Section: Immunohistochemistry Of Thyroid Neoplasmsmentioning

confidence: 99%

Thyroid Nodules in Diagnostic Pathology: From Classic Concepts to Innovations

Fridrihsone¹,

Štrumfa²,

Strumfs³

et al. 2018

Histopathology - An Update

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Thyroid nodules are frequent in general population, found in 3.7-7% of people by palpation and 42-67% by ultrasonography (US). The differential diagnosis ranges from papillary (PC), follicular (FC) and medullary (MC) carcinomas to follicular adenoma (FA) and colloid goitre. Cancer risk in thyroid nodules varies: 5% in masses found by palpation, 1.6-15% by US, 3.9-11.3% by computed tomography (CT), 5-6% by magnetic resonance imaging (MRI) and 30-50% by positron emission tomography (PET). The final diagnosis depends on fine needle aspiration (FNA) findings and histopathology. The recent WHO classification (2017) is based on classic morphology, including assessment of invasion and nuclei. New entities are defined to designate tumours with doubtful invasion or controversial nuclear features. By immunohistochemistry, PC expresses HBME-1, TROP-2, CITED1 and CK19. Notably, PC can stain for CD20. MC is recognised by neuroendocrine differentiation. To distinguish FA vs. FC, evaluation of HBME-1, p27 and galectin has been suggested. Regarding miRNAs, miR-146b, miR-222, miR-221 and miR-181b are upregulated, while miR-145, miR-451, miR-613 and miR-137 are downregulated in PC. FC features downregulated miR-199a-5p and upregulated miR-197 and miR-346. In MC, miR-21 and miR-129-5p are downregulated. In addition, increased systemic inflammatory reaction can be poor prognostic factor in thyroid cancer. The aim of this chapter is to review classic and innovative histopathology of thyroid nodules for diagnostic pathology practice and research in multidisciplinary thyroid teams.

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Heat shock proteins HSP90, HSP70 and GRP78 expression in medullary thyroid carcinoma

Cited by 24 publications

References 29 publications

3′-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells

3′-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells

Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma

Thyroid Nodules in Diagnostic Pathology: From Classic Concepts to Innovations

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