title: KRAS(G12D)-mediated oncogenic transformation of thyroid follicular cells requires long-term TSH stimulation and is regulated by SPRY1.
abstract: KRAS(G12D) can cause lung cancer rapidly, but is not sufficient to induce thyroid cancer. It is not clear whether long-term serum thyroid stimulating hormone (TSH) stimulation can promote KRAS(G12D)-mediated thyroid follicular cell transformation. In the present study, we investigated the effect of long-term TSH stimulation in KRAS(G12D) knock-in mice and the role of Sprouty1 (SPRY1) in KRAS(G12D)-mediated signaling. We used TPO-KRAS(G12D) mice for thyroid-specific expression of KRAS(G12D) under the endogenous KRAS promoter. Twenty TPO-KRAS(G12D) mice were given anti-thyroid drug propylthiouracil (PTU, 0.1% w/v) in drinking water to induce serum TSH and 20 mice were without PTU treatment. Equal number of wild-type littermates (TPO-KRAS(WT)) was given the same treatment. The expression of SPRY1, a negative regulator of receptor tyrosine kinase (RTK) signaling, was analyzed in both KRAS(G12D)-and BRAF(V600E)-induced thyroid cancers. Without PTU treatment, only mild thyroid enlargement and hyperplasia were observed in TPO-KRAS(G12D) mice. With PTU treatment, significant thyroid enlargement and hyperplasia occurred in both TPO-KRAS(G12D) and TPO-KRAS(WT) littermates. Thyroids from TPO-KRAS(G12D) mice were six times larger than TPO-KRAS(WT) littermates. Distinct thyroid histology was found between TPO-KRAS(G12D) and TPO-KRAS(WT) mice: thyroid from TPO-KRAS(G12D) mice showed hyperplasia with well-maintained follicular architecture whereas in TPO-KRAS(WT) mice this structure was replaced by papillary hyperplasia. Among 10 TPO-KRAS(G12D) mice monitored for 14 months, two developed follicular thyroid cancer (FTC), one with pulmonary metastasis. Differential SPRY1 expression was demonstrated: increased in FTC and reduced in papillary thyroid cancer (PTC). The increased SPRY1 expression in FTC promoted TSH-RAS signaling through PI3K/AKT pathway whereas downregulation of SPRY1 by BRAF(V600E) in PTC resulted in both MAPK and PI3K/AKT activation. We conclude that chronic TSH stimulation can enhance KRAS(G12D)-mediated oncogenesis, leading to FTC. SPRY1 may function as a molecular switch to control MAPK signaling and its downregulation by BRAF(V600E) favors PTC development.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Minjing
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Essa Y
authors.initials: EY
authors.lastname: Baitei
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Roua 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: Ranjit S
authors.initials: RS
authors.lastname: Parhar
authors.affiliation: Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Futwan A
authors.initials: FA
authors.lastname: Al-Mohanna
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Catrin
authors.initials: C
authors.lastname: Pritchard
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Huda
authors.initials: H
authors.lastname: BinEssa
authors.affiliation: Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Azizah A
authors.initials: AA
authors.lastname: Alanazi
authors.affiliation: Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Alzahrani
authors.affiliation: Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akhtar
authors.affiliation: Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Abdullah M
authors.initials: AM
authors.lastname: Assiri
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Shi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D011905:Genes, ras; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013961:Thyroid Gland / Q000166:cytology*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*; D013972:Thyrotropin / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D013972:Thyrotropin; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf