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1.
Front Immunol ; 14: 1171816, 2023.
Article in English | MEDLINE | ID: mdl-37483610

ABSTRACT

Introduction: BRAFV600E mutations frequently occur in papillary thyroid cancer (PTC). ß-catenin, encoded by CTNNB1, is a key downstream component of the canonical Wnt signaling pathway and is often overexpressed in PTC. BRAFV600E-driven PTC tumors rely on Wnt/ß-catenin signaling to sustain growth and progression. Methods: In the present study, we investigated the tumorigenicity of thyroid cancer cells derived from BRAFV600E PTC mice following Ctnnb1 ablation (BVE-Ctnnb1null). Results: Remarkably, the tumorigenic potential of BVE-Ctnnb1null tumor cells was lost in nude mice. Global gene expression analysis of BVE-Ctnnb1null tumor cells showed up-regulation of NKG2D receptor activating ligands (H60a, H60b, H60c, Raet1a, Raet1b, Raet1c, Raet1d, Raet1e, and Ulbp1) and down-regulation of inhibitory MHC class I molecules H-2L and H-2K2 in BVE-Ctnnb1null tumor cells. In vitro cytotoxicity assay demonstrated that BVE-Ctnnb1wt tumor cells were resistant to NK cell-mediated cytotoxicity, whereas BVE-Ctnnb1null tumor cells were sensitive to NK cell-mediated killing. Furthermore, the overexpression of any one of these NKG2D ligands in the BVE-Ctnnb1wt cell line resulted in a significant reduction of tumor growth in nude mice. Conclusions: Our results indicate that active ß-catenin signaling inhibits NK cell-mediated immune responses against thyroid cancer cells. Targeting the ß-catenin signaling pathway may have significant therapeutic benefits for BRAF-mutant thyroid cancer by not only inhibiting tumor growth but also enhancing host immune surveillance.


Subject(s)
Carcinoma, Papillary , Thyroid Neoplasms , Mice , Animals , Mice, Nude , NK Cell Lectin-Like Receptor Subfamily K/genetics , NK Cell Lectin-Like Receptor Subfamily K/metabolism , beta Catenin/genetics , beta Catenin/metabolism , Carcinoma, Papillary/genetics , Carcinoma, Papillary/metabolism , Up-Regulation , Proto-Oncogene Proteins B-raf , Ligands , Thyroid Neoplasms/pathology , Thyroid Cancer, Papillary/genetics , Wnt Signaling Pathway/physiology , Membrane Proteins/metabolism
2.
J Clin Endocrinol Metab ; 107(3): e1263-e1276, 2022 02 17.
Article in English | MEDLINE | ID: mdl-34632506

ABSTRACT

CONTEXT: Congenital hypothyroidism (CH) is caused by mutations in the genes for thyroid hormone synthesis. In our previous investigation of CH patients, approximately 53% of patients had mutations in either coding exons or canonical splice sites of causative genes. Noncanonical splice-site variants in the intron were detected but their pathogenic significance was not known. OBJECTIVE: This work aims to evaluate noncanonical splice-site variants on pre-messenger RNA (pre-mRNA) splicing of CH-causing genes. METHODS: Next-generation sequencing data of 55 CH cases in 47 families were analyzed to identify rare intron variants. The effects of variants on pre-mRNA splicing were investigated by minigene RNA-splicing assay. RESULTS: Four intron variants were found in 3 patients: solute carrier family 26 member 4 (SLC26A4) c.1544+9C>T and c.1707+94C>T in one patient, and solute carrier family 5 member 5 (SLC5A5) c.970-48G>C and c.1652-97A>C in 2 other patients. The c.1707+94C>T and c.970-48G>C caused exons 15 and 16 skipping, and exon 8 skipping, respectively. The remaining variants had no effect on RNA splicing. Furthermore, we analyzed 28 previously reported noncanonical splice-site variants (4 in TG and 24 in SLC26A4). Among them, 15 variants (~ 54%) resulted in aberrant splicing and 13 variants had no effect on RNA splicing. These data were compared with 3 variant-prediction programs (FATHMM-XF, FATHMM-MKL, and CADD). Among 32 variants, FATHMM-XF, FATHMM-MKL, and CADD correctly predicted 20 (63%), 17 (53%), and 26 (81%) variants, respectively. CONCLUSION: Two novel deep intron mutations have been identified in SLC26A4 and SLC5A5, bringing the total number of solved families with disease-causing mutations to approximately 45% in our cohort. Approximately 46% (13/28) of reported noncanonical splice-site mutations do not disrupt pre-mRNA splicing. CADD provides highest prediction accuracy of noncanonical splice-site variants.


Subject(s)
Congenital Hypothyroidism/genetics , RNA Splice Sites/genetics , RNA Splicing , Female , Humans , Male , Mutation , Sulfate Transporters/genetics , Symporters/genetics
3.
Mol Cancer Ther ; 20(9): 1603-1613, 2021 09.
Article in English | MEDLINE | ID: mdl-34224366

ABSTRACT

BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). ß-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAF V600E-driven tumors have been speculated to rely on Wnt/ß-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of ß-catenin in BrafV600E -driven thyroid cancer in a transgenic mouse model. In Braf V600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1WT or BVE), overexpression of ß-catenin was observed in thyroid tumors. In Braf V600E mice with Ctnnb1 knockout (BVE-Ctnnb1null), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated 124iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFß pathways and loss of epithelial-mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1null tumors. Treatment with dual ß-catenin/KDM4A inhibitor PKF118-310 dramatically improved the sensitivity of BVE-Ctnnb1WT tumor cells to BRAFV600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo These findings indicate that ß-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAFV600E inhibitors. Simultaneously targeting both Wnt/ß-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAFV600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.


Subject(s)
Indoles/pharmacology , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/pharmacology , Thyroid Cancer, Papillary/prevention & control , Thyroid Neoplasms/prevention & control , Wnt Signaling Pathway/drug effects , beta Catenin/physiology , Animals , Cell Differentiation , Epithelial-Mesenchymal Transition , Mice , Mice, Knockout , Proto-Oncogene Proteins B-raf/genetics , Thyroid Cancer, Papillary/etiology , Thyroid Cancer, Papillary/metabolism , Thyroid Cancer, Papillary/pathology , Thyroid Neoplasms/etiology , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology
4.
Orphanet J Rare Dis ; 16(1): 100, 2021 02 25.
Article in English | MEDLINE | ID: mdl-33632255

ABSTRACT

BACKGROUND: Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients. AIM OF STUDY: We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families. METHODS: Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron-exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis. RESULTS: EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients. CONCLUSION: EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.


Subject(s)
Exostoses, Multiple Hereditary , N-Acetylglucosaminyltransferases/genetics , DNA Mutational Analysis , Exons , Exostoses, Multiple Hereditary/genetics , Humans , Mutation/genetics , Saudi Arabia
5.
Front Genet ; 11: 607517, 2020.
Article in English | MEDLINE | ID: mdl-33329754

ABSTRACT

CONTEXT: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessively inherited disorder due to loss-of-function mutations in the CYP27B1 gene. CYP27B1 encodes an enzyme of 25-hydroxyvitamin D-1α-hydroxylase for converting inactive 25-OHD to biologically active 1,25-(OH)2D. OBJECTIVE: To identify underlying genetic defects in patients with VDDR1A. METHODS: Twelve patients from 7 Turkish and 2 Saudi families were investigated. The coding exons and intron-exon boundaries of the CYP27B1 gene were amplified by Polymerase Chain Reaction (PCR) from peripheral lymphocyte DNA. PCR products were directly sequenced. The consequences of c.590G > A mutation were analyzed by in silico and functional analysis. RESULTS: CYP27B1 mutations were identified in all the patients. Two novel mutations were identified in two separate families: c.171delG (family 7) and c.398_400dupAAT (family 8). The intra-exon deletion of c.171delG resulted in a frameshift and premature stop codon 20 amino acids downstream from the mutation (p.L58Cfs∗20). The intra-exon duplication of c.398_400dupAAT generated a premature stop codon at the mutation site (p.W134∗). A missense c.590G > A (p.G197D) mutation was found in a patient from family 4 and caused a defect in pre-mRNA splicing. As a result, two populations of transcripts were detected: the majority of them with intron 3 retention (83%), and the minority (17%) being properly spliced transcripts with about 16% of wild-type enzymatic activity. The remaining nine patients from six families carried a previously reported c.1319_1325dupCCCACCC (F443Pfs∗24) mutation. Clinically, all the patients need continued calcitriol treatment, which was consistent with inactivation of 25-hydroxy vitamin D1α-hydroxylase activity. CONCLUSION: Two novel frameshift CYP27B1 mutations were identified and predicted to inactivate 25-hydroxyvitamin D-1α-hydroxylase. The loss of enzymatic activity by c.590G > A missense mutation was mainly caused by aberrant pre-mRNA splicing.

6.
J Clin Endocrinol Metab ; 105(6)2020 06 01.
Article in English | MEDLINE | ID: mdl-31821448

ABSTRACT

CONTEXT: Hypophosphatemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3. OBJECTIVE: A large kindred with 5 HR patients was recruited with dominant inheritance. The study was undertaken to investigate underlying genetic defects in HR patients. DESIGN: Patients and their family members were initially analyzed for PHEX and FGF23 mutations using polymerase chain reaction sequencing and copy number analysis. Exome sequencing was subsequently performed to identify novel candidate genes. RESULTS: PHEX and FGF23 mutations were not detected in the patients. No copy number variation was observed in the genome using CytoScan HD array analysis. Mutations in DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 were also not found by exome sequencing. A novel c.979-96 T>A mutation in the SGK3 gene was found to be strictly segregated in a heterozygous pattern in patients and was not present in normal family members. The mutation is located 1 bp downstream of a highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids, which is part of the protein kinase domain and contains a Thr-320 phosphorylation site that is required for its activation. Protein tertiary structure modelling showed significant structural change in the protein kinase domain following the deletion. CONCLUSIONS: The c.979-96 T>A splice mutation in the SGK3 gene causes exon 13 skipping and deletion of 29 amino acids in the protein kinase domain. The SGK3 mutation may cause autosomal dominant HR.


Subject(s)
Familial Hypophosphatemic Rickets/etiology , Mutation , Phosphates/metabolism , Protein Serine-Threonine Kinases/genetics , Rickets/etiology , Adult , Biomarkers/analysis , Child , Child, Preschool , DNA Mutational Analysis , Familial Hypophosphatemic Rickets/metabolism , Familial Hypophosphatemic Rickets/pathology , Female , Fibroblast Growth Factor-23 , Humans , Kidney/metabolism , Kidney/pathology , Male , Middle Aged , Pedigree , Prognosis , Rickets/metabolism , Rickets/pathology
7.
Bone ; 125: 186-193, 2019 08.
Article in English | MEDLINE | ID: mdl-31102713

ABSTRACT

CONTEXT: X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the PHEX gene and is the most common form of hereditary rickets. The splice-site mutations account for 17% of all reported PHEX mutations. The functional consequence of these splice-site mutations has not been systemically investigated. OBJECTIVE: The current study was undertaken to functionally annotate previously reported 22 splice-site mutations in the PHEX gene. METHODS: PHEX mini-genes with different splice-site mutations were created by site-directed mutagenesis and expressed in HEK293 cells. The mRNA transcripts were analyzed by RT-PCR, cloning, and sequencing. RESULTS: These splicing mutations led to a variety of consequences, including exon skipping, intron retention, and activation of cryptic splice sites. Among 22 splice-site mutations, exon skipping was the most common event accounting for 73% (16/22). Non-canonical splice-site mutations could result in splicing errors to the same extent as canonical splice-site mutations such as c.436+3G>C, c.436+4A>C, c.436+6T>C, c.437-3C>G, c.850-3C>G, c.1080-3C>A, c.1482+5G>C, c.1586+6T>C, c.1645+5G>A, c.1645+6T>C, c.1701-16T>A, c.1768+5G>A, and c.1899+5G>A. Interestingly, non-canonical (c.436+6T>C and c.1586+6T>C) and canonical splice-site mutations (c.1769-1G>C) could generate partial splicing errors (both wild-type and mutant transcripts were detected), resulting in incomplete inactivation of PHEX gene, which may explain the mild disease phenotype reported previously, providing evidence of genotype-phenotype correlation. c.1645C>T (p.R549*) had no impact on pre-mRNA splicing although it is located next to canonical splice donor site GT. CONCLUSIONS: Exon skipping is the most common outcome due to splice-site mutations. Both canonical and non-canonical splice-site mutations can result in either severe or mild RNA splicing defects, contributing to phenotype heterogeneity. Non-canonical splice-site mutations should not be overlooked in genetic screening especially those located within 50 bp from canonical splice site.


Subject(s)
Familial Hypophosphatemic Rickets/genetics , Mutation/genetics , PHEX Phosphate Regulating Neutral Endopeptidase/genetics , Exons/genetics , Extracellular Matrix Proteins/genetics , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/genetics , HEK293 Cells , Humans , Introns/genetics , Phosphoproteins/genetics , Phosphoric Diester Hydrolases/genetics , Pyrophosphatases/genetics , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction
8.
J Clin Endocrinol Metab ; 103(5): 1889-1898, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29546359

ABSTRACT

Context: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective: To identify the mutation spectrum of CH-causing genes. Methods: Fifty-five patients from 47 families were studied by next-generation exome sequencing. Results: Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. Conclusions: TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.


Subject(s)
Antiporters/genetics , Congenital Hypothyroidism/diagnosis , Congenital Hypothyroidism/genetics , Molecular Diagnostic Techniques , Mutation , Sulfate Transporters/genetics , Adolescent , Child , Child, Preschool , Consanguinity , DNA Mutational Analysis , Family , Female , High-Throughput Nucleotide Sequencing , Humans , Infant , Infant, Newborn , Male , Molecular Diagnostic Techniques/methods , Neonatal Screening/methods , Pedigree , Saudi Arabia , Thyroid Dysgenesis/genetics , Young Adult
9.
PLoS One ; 13(3): e0193388, 2018.
Article in English | MEDLINE | ID: mdl-29505567

ABSTRACT

BACKGROUND: Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed. METHODOLOGY: Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions. RESULTS: Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families. CONCLUSIONS: This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood.


Subject(s)
Familial Hypophosphatemic Rickets/genetics , Mutation , PHEX Phosphate Regulating Neutral Endopeptidase/genetics , Pedigree , Sodium-Phosphate Cotransporter Proteins, Type IIc/genetics , Adult , Base Sequence , Child , Child, Preschool , Female , Fibroblast Growth Factor-23 , Humans , Male , Middle Aged
10.
Clin Endocrinol (Oxf) ; 87(1): 103-112, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28383812

ABSTRACT

CONTEXT: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3. OBJECTIVE: To investigate underlying genetic defects in patients with hypophosphataemic rickets. METHODS: We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis. RESULTS: A total of 14 patients were studied. PHEX mutations were identified in 12 patients from seven families. Five of them were novel mutations present in eight patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40-kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748 fs*48). Four patients had previously reported mutations: c.1768+1G>A and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining two families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEX g.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids. CONCLUSIONS: Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.


Subject(s)
Chloride Channels/genetics , DNA Mutational Analysis , Fibroblast Growth Factors/genetics , PHEX Phosphate Regulating Neutral Endopeptidase/genetics , Rickets, Hypophosphatemic/genetics , Family , Female , Fibroblast Growth Factor-23 , Gene Dosage , Humans , Male , Pedigree , Turkey
11.
Cancer Res ; 77(8): 2161-2172, 2017 04 15.
Article in English | MEDLINE | ID: mdl-28242615

ABSTRACT

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 BrafV600E -induced papillary thyroid cancer (PTC). Mice harboring wild-type Cyp24a1 (BVECyp24a1-wt) developed PTC at 5 weeks of age. Mice harboring a homozygous deletion of Cyp24a1 (BVECyp24a1-null) exhibited a 4-fold reduction in tumor growth. Notably, we found the tumorigenic potential of BVECyp24a1-null-derived tumor cells to be nearly abolished in immunocompromised nude mice. This phenotype was associated with downregulation of the MAPK, PI3K/Akt, and TGFß signaling pathways and a loss of epithelial-mesenchymal transition (EMT) in BVECyp24a1-null cells, associated with downregulation of genes involved in EMT, tumor invasion, and metastasis. While calcitriol treatment did not decrease cell proliferation in BVECyp24a1-null cells, it strengthened antitumor responses to the BRAFV600E inhibitor PLX4720 in both BVECyp24a1-null and BVECyp24a1-wt cells. Our findings offer direct evidence that Cyp24a1 functions as an oncogene in PTC, where its overexpression activates multiple signaling cascades to promote malignant progression and resistance to PLX4720 treatment. Cancer Res; 77(8); 2161-72. ©2017 AACR.


Subject(s)
Carcinoma/drug therapy , Carcinoma/enzymology , Indoles/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/pharmacology , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/enzymology , Vitamin D3 24-Hydroxylase/metabolism , Animals , Carcinoma/genetics , Carcinoma, Papillary , Disease Progression , Female , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Nude , Mice, Transgenic , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Thyroid Cancer, Papillary , Thyroid Neoplasms/genetics , Vitamin D3 24-Hydroxylase/genetics
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