title: Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells.
abstract: Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 reexpression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Choi
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Swapnika
authors.initials: S
authors.lastname: Ramu
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Park
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Eunson
authors.initials: E
authors.lastname: Jung
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Sara
authors.initials: S
authors.lastname: Yang
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Wonhyeuk
authors.initials: W
authors.lastname: Jung
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. Department of Pharmaceutical Engineering, College of Life and Health Sciences, Hoseo University, Asan, Chungnam, Republic of Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Choi
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Sunju
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Kyu Eui
authors.initials: KE
authors.lastname: Kim
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Seong
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Mingu
authors.initials: M
authors.lastname: Hong
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: George
authors.initials: G
authors.lastname: Daghlian
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Eugene
authors.initials: E
authors.lastname: Shin
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Jung In
authors.initials: JI
authors.lastname: Seo
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Vicken
authors.initials: V
authors.lastname: Khatchadourian
authors.affiliation: Department of Dermatology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Mengchen
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Dermatology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Division of Urology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Roger
authors.initials: R
authors.lastname: De Filippo
authors.affiliation: Division of Urology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Kokorowski
authors.affiliation: Division of Urology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Andy
authors.initials: A
authors.lastname: Chang
authors.affiliation: Division of Urology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Steve
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Basic Health Sciences, Federal University of Health Sciences of Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Ana
authors.initials: A
authors.lastname: Bertoni
authors.affiliation: Postgraduate Program in Medicine: Medical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Tania Weber
authors.initials: TW
authors.lastname: Furlanetto
authors.affiliation: Department of Pathology, Kaiser Permanente Medical Center, Fontana, California.
authors.forename: Sung
authors.initials: S
authors.lastname: Shin
authors.affiliation: Bioinformatics Service Program, Norris Medical Library, University of Southern California, Los Angeles, California.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Bioinformatics Service Program, Norris Medical Library, University of Southern California, Los Angeles, California.
authors.forename: Yibu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Alex
authors.initials: A
authors.lastname: Wong
authors.affiliation: Division of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: Chester
authors.initials: C
authors.lastname: Koh
authors.affiliation: Department of Microbiology & Immunology, Department of Otolaryngology, New York Medical College, Valhalla, New York.
authors.forename: Jan
authors.initials: J
authors.lastname: Geliebter
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. young.hong@usc.edu.
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Hong
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002291:Carcinoma, Papillary; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein