title: PROX1 Promotes Secretory Granule Formation in Medullary Thyroid Cancer Cells.
abstract: Mechanisms of endocrine secretory granule (SG) formation in thyroid C cells and medullary thyroid cancer (MTC) cells have not been fully elucidated. Here we directly demonstrated that PROX1, a developmental homeobox gene, is transcriptionally involved in SG formation in MTC, which is derived from C cells. Analyses using gene expression databases on web sites revealed that, among thyroid cancer cells, MTC cells specifically and highly express PROX1 as well as several SG-forming molecule genes. Immunohistochemical analyses showed that in vivo MTC and C cells expressed PROX1, although follicular thyroid cancer and papillary thyroid cancer cells, normal follicular cells did not. Knockdown of PROX1 in an MTC cells reduced SGs detected by electron microscopy, and decreased expression of SG-related genes (chromogranin A, chromogranin B, secretogranin II, secretogranin III, synaptophysin, and carboxypeptidase E). Conversely, the introduction of a PROX1 transgene into a papillary thyroid cancer and anaplastic thyroid cancer cells induced the expression of SG-related genes. Reporter assays using the promoter sequence of chromogranin A showed that PROX1 activates the chromogranin A gene in addition to the known regulatory mechanisms, which are mediated via the cAMP response element binding protein and the repressor element 1-silencing transcription factor. Furthermore, chromatin immunoprecipitation-PCR assays demonstrated that PROX1 binds to the transcriptional regulatory element of the chromogranin A gene. In conclusion, PROX1 is an important regulator of endocrine SG formation in MTC cells.
authors.affiliation: Department of Pathology (J.I., T.C., Y.A., H.K.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Diagnostic Pathology (T.Y.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University, Shinjuku, Tokyo 101-0062, Japan; and Department of Anatomy (H.S.), St Marianna University School of Medicine, Kanagawa 216-8511, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishii
authors.affiliation: Department of Pathology (J.I., T.C., Y.A., H.K.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Diagnostic Pathology (T.Y.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University, Shinjuku, Tokyo 101-0062, Japan; and Department of Anatomy (H.S.), St Marianna University School of Medicine, Kanagawa 216-8511, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yazawa
authors.affiliation: Department of Pathology (J.I., T.C., Y.A., H.K.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Diagnostic Pathology (T.Y.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University, Shinjuku, Tokyo 101-0062, Japan; and Department of Anatomy (H.S.), St Marianna University School of Medicine, Kanagawa 216-8511, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Pathology (J.I., T.C., Y.A., H.K.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Diagnostic Pathology (T.Y.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University, Shinjuku, Tokyo 101-0062, Japan; and Department of Anatomy (H.S.), St Marianna University School of Medicine, Kanagawa 216-8511, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shishido-Hara
authors.affiliation: Department of Pathology (J.I., T.C., Y.A., H.K.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Diagnostic Pathology (T.Y.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University, Shinjuku, Tokyo 101-0062, Japan; and Department of Anatomy (H.S.), St Marianna University School of Medicine, Kanagawa 216-8511, Japan.
authors.forename: Yuu
authors.initials: Y
authors.lastname: Arimasu
authors.affiliation: Department of Pathology (J.I., T.C., Y.A., H.K.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Diagnostic Pathology (T.Y.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University, Shinjuku, Tokyo 101-0062, Japan; and Department of Anatomy (H.S.), St Marianna University School of Medicine, Kanagawa 216-8511, Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Pathology (J.I., T.C., Y.A., H.K.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Diagnostic Pathology (T.Y.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University, Shinjuku, Tokyo 101-0062, Japan; and Department of Anatomy (H.S.), St Marianna University School of Medicine, Kanagawa 216-8511, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kamma
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000378:metabolism; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043423:Carboxypeptidase H / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000378:metabolism; D002291:Carcinoma, Papillary; D047369:Chromatin Immunoprecipitation; D053379:Chromogranin A / Q000235:genetics; D053378:Chromogranin B / Q000235:genetics; D002864:Chromogranins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D053381:Secretogranin II / Q000235:genetics; D022142:Secretory Vesicles / Q000235:genetics*; D016708:Synaptophysin / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D053379:Chromogranin A; D053378:Chromogranin B; D002864:Chromogranins; D018398:Homeodomain Proteins; C506135:SCG2 protein, human; C506136:SCG3 protein, human; C569014:SYP protein, human; D053381:Secretogranin II; D016708:Synaptophysin; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D043423:Carboxypeptidase H