title: RCAN1-4 is a thyroid cancer growth and metastasis suppressor.
abstract: Metastasis suppressors are key regulators of tumor growth, invasion, and metastases. Loss of metastasis suppressors has been associated with aggressive tumor behaviors and metastatic progression. We previously showed that regulator of calcineurin 1, isoform 4 (RCAN1-4) was upregulated by the KiSS1 metastatic suppression pathway and could inhibit cell motility when overexpressed in cancer cells. To test the effects of endogenous RCAN1-4 loss on thyroid cancer in vivo, we developed RCAN1-4 knockdown stable cells. Subcutaneous xenograft models demonstrated that RCAN1-4 knockdown promotes tumor growth. Intravenous metastasis models demonstrated that RCAN1-4 loss promotes tumor metastases to the lungs and their subsequent growth. Finally, stable induction of RCAN1-4 expression reduced thyroid cancer cell growth and invasion. Microarray analysis predicted that nuclear factor, erythroid 2-like 3 (NFE2L3) was a pivotal downstream effector of RCAN1-4. NFE2L3 overexpression was shown to be necessary for RCAN1-4-mediated enhanced growth and invasiveness and NEF2L3 overexpression independently increased cell invasion. In human samples, NFE2L3 was overexpressed in TCGA thyroid cancer samples versus normal tissues and NFE2L3 overexpression was demonstrated in distant metastasis samples from thyroid cancer patients. In conclusion, we provide the first evidence to our knowledge that RCAN1-4 is a growth and metastasis suppressor in vivo and that it functions in part through NFE2L3.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.|Ohio State Biochemistry Program.
authors.forename: Chaojie
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Justiniano
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.
authors.forename: Adlina Mohd
authors.initials: AM
authors.lastname: Yusof
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics.
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernández
authors.affiliation: Department of Pathology.
authors.forename: Paul
authors.initials: P
authors.lastname: Wakely
authors.affiliation: Department of Veterinary Biosciences and Comparative Pathology and Mouse Phenotyping Shared Resource, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: La Perle
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.
authors.forename: Neal
authors.initials: N
authors.lastname: Pohlman
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.|Ohio State Biochemistry Program.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
mesh_terms: D000818:Animals; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D004268:DNA-Binding Proteins; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D020033:Protein Isoforms / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C117963:NFE2L3 protein, human; D020033:Protein Isoforms; C108612:RCAN1 protein, human; D012333:RNA, Messenger