BRAFV600E Transduction of an SV40-Immortalized Normal Human Thyroid Cell Line Induces Dedifferentiated Thyroid Carcinogenesis in a Mouse Xenograft Model

Kim, Minjun; Kim, Su Jin; Xu, Zhen; Ha, Seong Yun; Byeon, Jae Hwan; Kang, Eun-Jin; Shin, Sug Kyun; Yoo, Seong Keun; Jee, Hyeon Gun; Yoon, Sang Gab; Yi, Jin Wook; Bae, Jeong Mo; Yu, Hyeong Won; Chai, Young Jun; Cho, Sun Wook; Choi, June Young; Lee, Kyu Eun; Han, Wonshik

doi:10.1089/thy.2019.0301

Cited by 6 publications

(9 citation statements)

References 47 publications

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“…Deregulated activation of the BRAF V600E-dependent MAPK/ERK effectors is best recognized in the mechanisms underlying melanoma genesis and the growth of papillary thyroid cancer [32,55,56]. A predominantly similar phenotype is caused by the V600E mutation, including enhanced invasion, proliferation, and metastasis [32,55,56]. Our studies showed a significant similarity of the influence of BRAF V600E on the characteristics of THLE-2 cells, which may indicate a strong invasive and migration effect of this mutation in the liver tissue.…”

Section: Discussionsupporting

confidence: 59%

“…Constant activation of the MAPK/ERK pathway promotes cell migration, proliferation, and the tumor microenvironment [54]. Deregulated activation of the BRAF V600E-dependent MAPK/ERK effectors is best recognized in the mechanisms underlying melanoma genesis and the growth of papillary thyroid cancer [32,55,56]. A predominantly similar phenotype is caused by the V600E mutation, including enhanced invasion, proliferation, and metastasis [32,55,56].…”

Section: Discussionmentioning

confidence: 99%

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Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression

Śmiech

Leszczyński

Wardell

et al. 2022

IJMS

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The accumulation of mutations in cancer driver genes, such as tumor suppressors or proto-oncogenes, affects cellular homeostasis. Disturbances in the mechanism controlling proliferation cause significant augmentation of cell growth and division due to the loss of sensitivity to the regulatory signals. Nowadays, an increasing number of cases of liver cancer are observed worldwide. Data provided by the International Cancer Genome Consortium (ICGC) have indicated many alterations within gene sequences, whose roles in tumor development are not well understood. A comprehensive analysis of liver cancer (virus-associated hepatocellular carcinoma) samples has identified new and rare mutations in B-Raf proto-oncogene (BRAF) in Japanese HCC patients, as well as BRAF V600E mutations in French HCC patients. However, their function in liver cancer has never been investigated. Here, using functional analysis and next generation sequencing, we demonstrate the tumorigenic effect of BRAF V600E on hepatocytes (THLE-2 cell line). Moreover, we identified genes such as BMP6, CXCL11, IL1B, TBX21, RSAD2, MMP10, and SERPIND1, which are possibly regulated by the BRAF V600E-mediated, mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. Through several functional assays, we demonstrate that BRAF L537M, D594A, and E648G mutations alone are not pathogenic in liver cancer. The investigation of genome mutations and the determination of their impact on cellular processes and functions is crucial to unraveling the molecular mechanisms of liver cancer development.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression

Śmiech

Leszczyński

Wardell

et al. 2022

IJMS

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“…Nthy/ BRAF WT (human thyroid cell lines which harbor wild type BRAF gene [Nthy/WT]) and Nthy/ BRAF V600E (Nthy/V600E) are newly established cell lines expressing either BRAF WT or BRAF V600E by lentiviral transduction of human thyroid cell line Nthy-ori 3-1 [ 28 , 29 ]. Nthy/vector was not included because its functional activities such as colony formation and invasion were not observed in the previous study [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

BRAFV600E Mutation Enhances Estrogen-Induced Metastatic Potential of Thyroid Cancer by Regulating the Expression of Estrogen Receptors

Kim

et al. 2022

Endocrinol Metab

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Background: Cross-talk between mitogen-activated protein kinase and estrogen has been reported; however, the role of BRAFV600E in the estrogen responsiveness of thyroid cancer is unknown. We elucidated the effect of BRAFV600E on the estrogen-induced increase in metastatic potential in thyroid cancer.Methods: Using a pair of cell lines, human thyroid cell lines which harbor wild type BRAF gene (Nthy/WT) and Nthy/BRAFV600E (Nthy/V600E), the expression of estrogen receptors (ERs) and estrogen-induced metastatic phenotypes were evaluated. Susceptibility to ERα- and ERβ-selective agents was evaluated to confirm differential ER expression. ESR expression was analyzed according to BRAFV600E status and age (≤50 years vs. >50 years) using The Cancer Genome Atlas (TCGA) data.Results: Estradiol increased the ERα/ERβ expression ratio in Nthy/V600E, whereas the decreased ERα/ERβ expression ratio was found in Nthy/WT. BRAFV600E-mutated cell lines showed a higher E2-induced increase in metastatic potential, including migration, invasion, and anchorage-independent growth compared with Nthy/WT. An ERα antagonist significantly inhibited migration in Nthy/V600E cells, whereas an ERβ agonist was more effective in Nthy/WT. In the BRAFV600E group, ESR1/ESR2 ratio was significantly higher in younger age group (≤50 years) compared with older age group (>50 years) by TCGA data analysis.Conclusion: Our data show that BRAFV600E mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulating ER expression. Therefore, BRAFV600E might be used as a biomarker when deciding future hormone therapies based on estrogen signaling in thyroid cancer patients.

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“…Normal human thyroid follicular cell line Nthy‐ori 3.1, 31 and PTC cell lines B‐CPAP (primary and well differentiated) 32 and KTC‐1 (metastatic and refractory to radio iodine) 33 were kindly provided by the National Collection of Authenticated Cell Cultures of the Chinese Academy of Sciences. B‐CPAP and KTC‐1 were cultured under the circumstance of 5% CO 2 , 37°C, in RPMI Medium 1640 (Invitrogen) with 10% FBS (Gibco), non‐essential amino acids (Invitrogen), Glutamax (Invitrogen), and Sodium Pyruvate (Invitrogen, 11,360,070) added.…”

Section: Methodsmentioning

confidence: 99%

A novel prognostic model for papillary thyroid cancer based on epithelial–mesenchymal transition‐related genes

Cao

Pan

et al. 2022

Cancer Medicine

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Background The frequent incidence of postsurgical recurrence issues in papillary thyroid cancer (PTC) patients is a primary concern considering the low cancer‐related mortality. Previous studies have demonstrated that epithelial–mesenchymal transition (EMT) activation is closely related to PTC progression and invasion. In this study, we aimed to develop a novel EMT signature and ancillary nomogram to improve personalized prediction of progression‐free interval (PFI). Methods First, we carried out a differential analysis of PTC samples and pairwise normal thyroid samples to explore the differentially expressed genes (DEGs). The intersection of the DEGs with EMT‐related genes (ERGs) were identified as differentially expressed EMT‐related genes (DE‐ERGs). We determined PFI‐related DE‐ERGs by Cox regression analysis and then established a novel gene classifier by LASSO regression analysis. We validated the signature in external datasets and in multiple cell lines. Further, we used uni‐ and multivariate analyses to identify independent prognostic characters. Results We identified 244 prognosis‐related DE‐ERGs. The 244 DE‐ERGs were associated with several pivotal oncogenic processes. We also constructed a novel 10‐gene signature and relevant prognostic model for recurrence prediction of PTC. The 10‐gene signature had a C‐index of 0.723 and the relevant nomogram had a C‐index of 0.776. The efficacy of the signature and nomogram was satisfying and closely correlated with relevant clinical parameters. Furthermore, the signature also had a unique potential in differentiating anaplastic thyroid cancer (ATC) samples. Conclusions The novel EMT signature and nomogram are useful and convenient for personalized management for thyroid cancer.

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BRAF^V600E Transduction of an SV40-Immortalized Normal Human Thyroid Cell Line Induces Dedifferentiated Thyroid Carcinogenesis in a Mouse Xenograft Model

Cited by 6 publications

References 47 publications

Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression

Oncogenic Mutation BRAF V600E Changes Phenotypic Behavior of THLE-2 Liver Cells through Alteration of Gene Expression

BRAFV600E Mutation Enhances Estrogen-Induced Metastatic Potential of Thyroid Cancer by Regulating the Expression of Estrogen Receptors

A novel prognostic model for papillary thyroid cancer based on epithelial–mesenchymal transition‐related genes

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