title: Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance.
abstract: Gremlin 1 is one of the bone morphogenetic protein (BMP) antagonists and is also related to differentiation in combination with BMPs and is associated with various types of diseases. Gremlin 1 is overexpressed in various types of human cancers and has been reported to play a role in cervical cancer oncogenesis. However, there is no report concerning the relationship between Gremlin 1 and cervical cancer stem cells (CSCs). The objective of the present study was to identify the clinical significance of Gremlin 1 in cervical cancer and its effects on CSC-like properties in vitro. Clinical samples were obtained. Gremlin 1 mRNA expression levels in the cervical cancer tissues were measured by RT-qPCR and assessed for correlation with their clinical prognosis [overall survival (OS), progression-free survival (PFS)] and with other prognostic factors. In vitro, cervical cancer, CaSki cells, exposed to Gremlin 1 (1,000 ng/ml) for 24 h were evaluated for expression of undifferentiated-cell markers (Nanog, Oct3/4, Sox2) by RT-qPCR, the population of ALDH-positive cells by flow cytometry and sphere-forming ability on a ultra-low attachment culture dish. Cervical cancer tissues from 104 patients were collected. A high mRNA expression level of Gremlin 1 was an independent poor prognostic factor of PFS but not of OS. A high mRNA expression level of Gremlin 1 was correlated with bulky (>4 cm) tumors. The Nanog mRNA expression level was significantly increased in the CaSki cells exposed to Gremlin 1 (P=0.0008) but not Oct3/4 and Sox2 mRNA expression levels. The population of ALDH-positive cells in the Gremlin 1-exposed cells was 1.41-fold higher compared with the control (P=0.0184). Sphere-forming ability was increased when 1,000 Gremlin 1-exposed cells were seeded (P=0.0379). In cervical cancer, it is suggested that Gremlin 1 may have a role in clinical recurrence and maintaining CSC-like properties.
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Asaha
authors.initials: A
authors.lastname: Fujimoto
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Nishida
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Juri
authors.initials: J
authors.lastname: Takahashi
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nagasaka
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins