scholarly journals BRAF V600E Maintains Proliferation, Transformation, and Tumorigenicity of BRAF-Mutant Papillary Thyroid Cancer Cells

2007 ◽  
Vol 92 (6) ◽  
pp. 2264-2271 ◽  
Author(s):  
Dingxie Liu ◽  
Zhi Liu ◽  
Stephen Condouris ◽  
Mingzhao Xing
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Nude Mice ◽  
Braf Mutation ◽  
Soft Agar ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Small Interference Rna

Abstract Context: Although the BRAF V600E mutant can initiate the formation of papillary thyroid cancer (PTC), it is unclear whether it is required to maintain cell proliferation, transformation, and tumor growth of BRAF mutation-harboring PTC. Objective: The aim of the study was to investigate whether BRAF V600E is required for the proliferation, transformation, and tumorigenicity of BRAF mutation-harboring PTC cells. Design: We addressed this issue using BRAF small interference RNA (siRNA) to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. Results: PTC cell proliferation and transformation were suppressed in specific BRAF siRNA clones, but not in control scrambled siRNA clones. Specifically, taking the advantage of stable BRAF knockdown, we were able to show continued suppression of PTC cell proliferation and transformation, or anchorage-independent colony formation in soft agar, after long-term culture. Moreover, we also demonstrated that in vivo tumorigenicity and growth of tumors from the specific BRAF siRNA cell clones in nude mice were suppressed compared with control clones. Conclusions: BRAF V600E is not only an initiator of PTC as demonstrated previously but is also a maintainer of proliferation, transformation, and tumorigenicity of PTC cells harboring BRAF mutation, and growth of tumors derived from such cells continues to depend on BRAF V600E. These results provide further support for potentially effective therapy targeted at BRAF for BRAF mutation-harboring PTC.

scholarly journals METTL14 promotes tumorigenesis by regulating lncRNA OIP5-AS1/miR-98/ADAMTS8 signaling in papillary thyroid cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Xiaoping Zhang ◽  
Dan Li ◽  
Chengyou Jia ◽  
Haidong Cai ◽  
Zhongwei Lv ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Papillary Thyroid ◽  
Qrt Pcr ◽  
The Relationship

Abstract Background Papillary thyroid cancer (PTC) is the most common type of cancer of the endocrine system. Long noncoding RNAs (lncRNAs) are emerging as a novel class of gene expression regulators associated with tumorigenesis. Through preexisting databases available for differentially expressed lncRNAs in PTC, we uncovered that lncRNA OIP5-AS1 was significantly upregulated in PTC tissues. However, the function and the underlying mechanism of OIP5-AS1 in PTC are poorly understood. Methods Expression of lncRNA OIP5-AS1 and miR-98 in PTC tissue and cells were measured by quantitative real-time PCR (qRT-PCR). And expression of METTL14 and ADAMTS8 in PTC tissue and cells were measured by qRT-PCR and western blot. The biological functions of METTL14, OIP5-AS1, and ADAMTS8 were examined using MTT, colony formation, transwell, and wound healing assays in PTC cells. The relationship between METTL14 and OIP5-AS1 were evaluated using RNA immunoprecipitation (RIP) and RNA pull down assay. And the relationship between miR-98 and ADAMTS8 were examined by luciferase reporter assay. For in vivo experiments, a xenograft model was used to investigate the effects of OIP5-AS1 and ADAMTS8 in PTC. Results Functional validation revealed that OIP5-AS1 overexpression promotes PTC cell proliferation, migration/invasion in vitro and in vivo, while OIP5-AS1 knockdown shows an opposite effect. Mechanistically, OIP5-AS1 acts as a target of miR-98, which activates ADAMTS8. OIP5-AS1 promotes PTC cell progression through miR-98/ADAMTS8 and EGFR, MEK/ERK pathways. Furthermore, RIP and RNA pull down assays identified OIP5-AS1 as the downstream target of METTL14. Overexpression of METTL14 suppresses PTC cell proliferation and migration/invasion through inhibiting OIP5-AS1 expression and regulating EGFR, MEK/ERK pathways. Conclusions Collectively, our findings demonstrate that OIP5-AS1 is a METTL14-regulated lncRNA that plays an important role in PTC progression and offers new insights into the regulatory mechanisms underlying PTC development.

scholarly journals Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

2015 ◽  
Vol 33 (1) ◽  
pp. 42-50 ◽  
Author(s):  
Mingzhao Xing ◽  
Ali S. Alzahrani ◽  
Kathryn A. Carson ◽  
Young Kee Shong ◽  
Tae Yong Kim ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Multicenter Study ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Disease Stage ◽  
Papillary Thyroid ◽  
Recurrence Rates

Purpose To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). Patients and Methods This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). Results The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation–positive and 11.6% (125 of 1,082) of BRAF V600E mutation–negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation–positive versus –negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation–positive versus –negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. Conclusion This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

scholarly journals Preoperative Factors Associated with Extrathyroidal Extension in Papillary Thyroid Cancer

2020 ◽  
Vol 9 (5) ◽  
pp. 256-262 ◽  
Author(s):  
Chi-Yu Kuo ◽  
Po-Sheng Yang ◽  
Ming-Nan Chien ◽  
Shih-Ping Cheng
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Tumor Size ◽  
Braf Mutation ◽  
Extrathyroidal Extension ◽  
Additive Models ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Factors Associated ◽  
Preoperative Factors

Objective: Extrathyroidal extension may not be accurately recognized during thyroidectomy and can increase the risk of positive margins and even recurrence. This study aimed to investigate the preoperative factors associated with extrathyroidal extension. Methods: We analyzed 887 patients with papillary thyroid cancer (PTC) who underwent surgery in the period of 2005–2017. Binary logistic regression analyses and generalized additive models were used to identify associations. Results: Minimal extrathyroidal extension was present in 233 (26%) patients and advanced extrathyroidal extension was found in 60 (7%) patients. Age, BMI, and tumor size were independent predictors of all or advanced extrathyroidal extension. Among the 493 patients whose BRAF mutation status was available, age (OR = 1.025), BMI (OR = 1.091), tumor size (OR = 1.544), and BRAF V600E mutation (OR = 2.311) were independently associated with extrathyroidal extension. Conclusions: Older age, a greater BMI, a larger tumor size, and presence of the BRAF mutation were predictive of extrathyroidal extension. These factors should be taken into consideration in decision-making before surgery is performed.

scholarly journals THE BRAF MUTATION V600E IN PAPILLARY THYROID CANCER, CLINICAL-MORPHOLOGICALPARALLELES AND PROGNOSIS

2017 ◽  
Vol 22 (1) ◽  
pp. 15-20
Author(s):  
A. A Ivanov ◽  
A. M Avdalyan ◽  
V. J Gerval’d ◽  
E. L Lushnikova ◽  
Yu. N Zorkina ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Lymph Nodes ◽  
Papillary Thyroid Cancer ◽  
Braf Mutation ◽  
Negative Impact ◽  
Morphological Characteristics ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Ki 67 ◽  
Regional Lymph Nodes

On the material of the 67 cases of papillary thyroid cancer (PTC) authors executed the study of the interrelationship between the BRAF mutation V600E and the forecast, biomolecular and morphological characteristics of the disease. There was implemented the analysis of samples for the presence of 7 KRAS gene mutations, 4 mutations of the PIK3CA gene, mutation BRAF V600E with the revealing of the interrelationship between such biomolecular markers for proliferation and apoptosis as Ki-67, p53, Bcl2. Also there was performed chromogenic hybridization (CISH method) in situ to study the status of the HER2 gene. There was determined the interrelationship between BRAF mutation V600E and clinical indices of prognosis: tumor sizes, capsule invasion, presence of metastases in regional lymph nodes. In addition, there was evaluated the interrelationship between BRAF mutation V600E and 10-years survival rate. No mutation were identified in KRAS, PI3K genes. BRAF mutation V600E was identified in 50 cases (75%). The frequency of V600E in women accounted of 75 ± 6.4%, in men - 67 ± 27.1%. In patients with the presence of V600E the size of a node was slightly less than in the absence of mutations and in 76% of cases did not reach the average value of 1.8 cm. Invasion into the capsule was identified in 35 ± 12.7% cases with a positive BRAF mutation V600E status and in 56 ± 8.4% - in cases with a negative status. Metastases in regional lymph nodes occurred in 36 ± 11.6% in patients with V600E and in 47 ± 18.9% of cases without this mutation. There was obtained the interrelationship between V600E and Ki-67: the average level of the proliferative activity in the presence of the given mutation was 4.4 ± 0.6%, in the absence - 9.4 ± 3.9%. No interrelationship was obtained between V600E and other biomolecular parameters or this interrelationship was tendentious in character. In terms of 10-years survival the groups with or without V600E statistically did not differ. Based on the data, it was possible to say about the absence of the negative impact of V600E on the prognosis in PTC patients

scholarly journals Long noncoding RNA LINC00284 facilitates cell proliferation in papillary thyroid cancer via impairing miR-3127-5p targeted E2F7 suppression

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Bin Zhou ◽  
Yugang Ge ◽  
Qing Shao ◽  
Liyi Yang ◽  
Xin Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Noncoding Rna ◽  
The Cancer Genome Atlas ◽  
G1 Arrest ◽  
Papillary Thyroid ◽  
Bioinformatics Analyses

AbstractAccumulating evidence has suggested that long noncoding RNAs (lncRNAs) exert crucial modulation roles in the biological behaviors of multiple malignancies. Nonetheless, the specific function of lncRNA LINC00284 in papillary thyroid cancer (PTC) remains not fully understood. The objective of this research was to explore the influence of LINC00284 in PTC and elucidate its potential mechanism. The Cancer Genome Atlas (TCGA), gene expression omnibus (GEO) datasets were used to analyze LINC00284 expression differences in thyroid cancer and normal samples, followed by the verification of qRT-PCR in our own PTC and adjacent non-tumor tissues. The impacts of LINC00284 on PTC cell growth were detected in vitro via CCK-8, colony formation, EdU assays, and in vivo via a xenograft tumor model. Bioinformatics analyses and biological experiments were conducted to illuminate the molecular mechanism. We found that LINC00284 expression was remarkably increased in PTC tissues and its overexpression was closely correlated with larger tumor size. In addition, silencing LINC00284 could effectively attenuate PTC cell proliferation, induce apoptosis and G1 arrest in vitro, as well as suppress tumorigenesis in mouse xenografts. Mechanistic investigations showed that LINC00284 acted as a competing endogenous RNA (ceRNA) for miR-3127-5p, thus resulting in the disinhibition of its endogenous target E2F7. In short, our findings indicated that LINC00284–miR-3127-5p–E2F7 axis exerted oncogenic properties in PTC and may offer a new promising target for the diagnosis and therapy of PTC.

scholarly journals BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment

2017 ◽  
Vol 110 (4) ◽  
pp. 362-370 ◽  
Author(s):  
Yueye Huang ◽  
Shen Qu ◽  
Guangwu Zhu ◽  
Fei Wang ◽  
Rengyun Liu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Risk Stratification ◽  
Papillary Thyroid Cancer ◽  
Braf Mutation ◽  
Hazard Ratio ◽  
Braf V600e ◽  
Independent Effect ◽  
Papillary Thyroid ◽  
Wild Type ◽  
Recurrence Rates

Abstract Background Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow–up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher’s exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

scholarly journals Concomitant BRAF Mutation in Hairy Cell Leukemia and Papillary Thyroid Cancer

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5140-5140
Author(s):  
Shehab Mohamed ◽  
Mohamed A Yassin ◽  
Abdulqadir Jeprel Nashwan ◽  
Halima El Omri ◽  
Firyal Ibrahim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Hairy Cell Leukemia ◽  
Braf Mutation ◽  
Braf V600e ◽  
Hairy Cell ◽  
Papillary Thyroid ◽  
Cell Leukemia ◽  
Cell Neoplasm

Abstract Hairy cell leukemia (HCL) is an uncommon but distinct form of mature B-cell neoplasm that originates from activated late B-cells. It represents only 2% of all adult lymphoid leukemia; patients are predominantly middle-aged to elderly males with a median age of 50 years and is characterized by pancytopenia, monocytopenia and usually associated with massive splenomegaly. HCL associated with BRAF mutation 100% of cases, it's associated with hematological and oncological malignancies such as melanoma and papillary thyroid cancer with positive BRAF in 40 % of cases. Although the association of both cancers (HCL & papillary thyroid cancer) with BRAF mutation is well established in the literature, up to our knowledge, this specific combination has not been previously reported in one patient. Here we report a case of 48-year old Lebanese male, who presented to with bilateral hip pain and found to have lytic bone lesions on both x-ray and MRI. HIS CBC were normal and abdominal US didn't show any splenomegaly. Work-up for myeloma were negative. Bone marrow examination and flow cytometry results confirmed the diagnosis of hairy cell leukemia. The patient treated with cladrabine. Patient responded but have continues fever, PUO included Piston tomography showed abnormal uptake in thyroid. Ultrasound and final needle aspiration diagnose him as case of papillary thyroid cancer. He was treated with total thyroidectomy and followed up with RAI 30 micori. We sent BRAF from both bone marrow biopsy and thyroid tissue which turn out positive in both. The mutation results in substitution of adenine for thymine at position 1799 in exon 15 of the BRAF that replaces Valine (V) by glutamate (E) at amino acid 600(BRAF V600E). Although the BRAF V600E mutation is frequently present in different neoplasms, such as melanoma, papillary thyroid cancer, non-small cell lung cancer, colorectal cancer and Langerhans cell histiocytosis (X), within the lymphoid neoplasms, the BRAFV600E mutation is found to be highly specific for HCL and testing for this mutation is particularly useful in differentiating classic HCL from other B- cell neoplasm with overlapping features, such as HCL variant Mutation in BRAF (particularly V600E) in HCL remarkably increase the BRAF kinase activity renders the protein constitutively active, phosphorylating then ERK as a monomers independent from upstream regulatory signals or in a RAS-independent manner leading to constitutive activation of RAF-MEK-ERK signaling pathway and enhanced survival of leukemic hairy cells, similar to what occurs in other BRAF-mutated tumors as papillary thyroid carcinomas Other BRAF mutations outside exon 15 were rarely reported as exon 11 F468C and D449E mutations. We emphasize on the link of BRAF mutation in HCL and papillary thyroid cancer. The biology has been established but never in real clinical case. We recommend having high clinical suspicion and sending BRAF mutation in those types of cancers and link it with other possible abnormal findings, as might detect more cases of similar association. Disclosures No relevant conflicts of interest to declare.

A mouse model of BRAF V600E mutated papillary thyroid cancer imitating sporadic conditions

2018 ◽  
Author(s):  
Iva Jakubikova ◽  
Elin Schoultz ◽  
Ellen Johansson ◽  
Shawn Liang ◽  
Konrad Patyra ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Papillary Thyroid Cancer ◽  
Braf V600e ◽  
Papillary Thyroid

scholarly journals A 5′-tRNA halve, tiRNA-Gly promotes cell proliferation and migration via binding to RBM17 and inducing alternative splicing in papillary thyroid cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Litao Han ◽  
Hejing Lai ◽  
Yichen Yang ◽  
Jiaqian Hu ◽  
Zhe Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Alternative Splicing ◽  
Papillary Thyroid Cancer ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Papillary Thyroid ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background tRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor are attracting more and more attention, but researches concerning the mechanisms in tiRNAs-mediated tumorigenesis are rarely. The direct regulatory relationship between tiRNAs and splicing-related proteins remain elusive. Methods Papillary thyroid carcinoma (PTC) associated tRNA fragments were screened by tRNA fragments deep sequencing and validated by qRT-PCR and Northern Blot in PTC tissues. The biological function of tRNA fragments were assessed by cell counting kit, transwells and subcutaneous transplantation tumor of nude mice. For mechanistic study, tRNA fragments pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining were performed. Results Herein, we have identified a 33 nt tiRNA-Gly significantly increases in papillary thyroid cancer (PTC) based on tRFs & tiRNAs sequencing. The ectopic expression of tiRNA-Gly promotes cell proliferation and migration, whereas down-regulation of tiRNA-Gly exhibits reverse effects. Mechanistic investigations reveal tiRNA-Gly directly bind the UHM domain of a splicing-related RNA-binding protein RBM17. The interaction with tiRNA-Gly could translocate RBM17 from cytoplasm into nucleus. In addition, tiRNA-Gly increases RBM17 protein expression via inhibiting its degradation in a ubiquitin/proteasome-dependent way. Moreover, RBM17 level in tiRNA-Gly high-expressing human PTC tissues is upregulated. In vivo mouse model shows that suppression of tiRNA-Gly decreases RBM17 expression. Importantly, tiRNA-Gly can induce exon 16 splicing of MAP4K4 mRNA leading to phosphorylation of downstream signaling pathway, which is RBM17 dependent. Conclusions Our study firstly illustrates tiRNA-Gly can directly bind to RBM17 and display oncogenic effect via RBM17-mediated alternative splicing. This fully novel model broadens our understanding of molecular mechanism in which tRNA fragment in tumor cells directly bind RNA binding protein and play a role in alternative splicing.

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