title: TSH overcomes Braf(V600E)-induced senescence to promote tumor progression via downregulation of p53 expression in papillary thyroid cancer.
abstract: The BRAF(V600E) mutation is found in approximately 40% of papillary thyroid cancers (PTC). Mice with thyroid-specific expression of Braf(V600E) (TPO-Braf(V600E)) develop PTC rapidly with high levels of serum thyroid-stimulating hormone (TSH). It is unclear to what extent the elevated TSH contributes to tumor progression. To investigate the progression of Braf(V600E)-induced PTC (BVE-PTC) under normal TSH, we transplanted BVE-PTC tumors subcutaneously into nude and TPO-Braf(WT) mice. Regression of the transplanted tumors was observed in both nude and TPO-Braf(WT) mice. They were surrounded by heavy lymphocyte infiltration and oncogene-induced senescence (OIS) was demonstrated by strong β-gal staining and absence of Ki-67 expression. In contrast, BVE-PTC transplants continued to grow when transplanted into TPO-Braf(V600E) mice. The expression of Trp53 was increased in tumor transplants undergoing OIS. Trp53 inactivation reversed OIS and enabled tumor transplants to grow in nude mice with characteristic cell morphology of anaplastic thyroid cancer (ATC). PTC-to-ATC transformation was also observed in primary BVE-PTC tumors. ATC cells derived from Trp53 knockout tumors had increased PI3K/AKT signaling and became resistant to Braf(V600E) inhibitor PLX4720, which could be overcome by combined treatment of PI3K inhibitor LY294002 and PLX4720. In conclusion, BVE-PTC progression could be contained via p53-dependent OIS and TSH is a major disruptor of this balance. Simultaneous targeting of both MAPK and PI3K/AKT pathways offer a better therapeutic outcome against ATC. The current study reinforces the importance of rigorous control of serum TSH in PTC patients.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: E Y
authors.initials: EY
authors.lastname: Baitei
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: R A
authors.initials: RA
authors.lastname: Al-Rijjal
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: R S
authors.initials: RS
authors.lastname: Parhar
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: F A
authors.initials: FA
authors.lastname: Al-Mohanna
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Biochemistry, University of Leicester, Lancaster Road, Leicester, UK.
authors.forename: C
authors.initials: C
authors.lastname: Pritchard
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: H A
authors.initials: HA
authors.lastname: Binessa
authors.affiliation: Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: A S
authors.initials: AS
authors.lastname: Alzahrani
authors.affiliation: Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: H H
authors.initials: HH
authors.lastname: Al-Khalaf
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: A
authors.initials: A
authors.lastname: Hawwari
authors.affiliation: Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Akhtar
authors.affiliation: Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: A M
authors.initials: AM
authors.lastname: Assiri
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: B F
authors.initials: BF
authors.lastname: Meyer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology*; D016922:Cellular Senescence; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*; D013972:Thyrotropin / Q000097:blood / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
chemical_list: D002867:Chromones; D007211:Indoles; D009025:Morpholines; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; D013972:Thyrotropin; D016159:Tumor Suppressor Protein p53; C528407:PLX 4720; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C514862:Akt1 protein, mouse; C482119:BRAF protein, human