Sato Masakazu, Kawana Kei, Fujimoto Asaha, Yoshida Mitsuyo, Nakamura Hiroe, Nishida Haruka, Inoue Tomoko, Taguchi Ayumi, Takahashi Juri, Adachi Katsuyuki, Nagasaka Kazunori, Matsumoto Yoko, Wada-Hiraike Osamu, Oda Katsutoshi, Osuga Yutaka, Fujii Tomoyuki
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo‑ku, Tokyo 1138655, Japan.
Oncol Rep. 2016 Jan;35(1):391-7. doi: 10.3892/or.2015.4367. Epub 2015 Oct 30.
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.
Gremlin 1是骨形态发生蛋白（BMP）拮抗剂之一，还与BMP联合诱导分化有关，并与多种疾病相关。Gremlin 1在多种人类癌症中过度表达，据报道在宫颈癌发生过程中发挥作用。然而，尚无关于Gremlin 1与宫颈癌干细胞（CSCs）之间关系的报道。本研究的目的是确定Gremlin 1在宫颈癌中的临床意义及其对体外CSC样特性的影响。获取了临床样本。通过RT-qPCR测量宫颈癌组织中Gremlin 1 mRNA表达水平，并评估其与临床预后[总生存期（OS）、无进展生存期（PFS）]以及其他预后因素的相关性。在体外，将暴露于Gremlin 1（1000 ng/ml）24小时的宫颈癌CaSki细胞，通过RT-qPCR评估未分化细胞标志物（Nanog、Oct3/4、Sox2）的表达，通过流式细胞术评估醛脱氢酶（ALDH）阳性细胞群体，并在超低附着培养皿上评估其成球能力。收集了104例患者的宫颈癌组织。Gremlin 1的高mRNA表达水平是PFS的独立不良预后因素，但不是OS的独立不良预后因素。Gremlin 1的高mRNA表达水平与体积较大（>4 cm）的肿瘤相关。暴露于Gremlin 1的CaSki细胞中Nanog mRNA表达水平显著升高（P=0.0008），但Oct3/4和Sox2 mRNA表达水平未升高。与对照组相比，暴露于Gremlin 1的细胞中ALDH阳性细胞群体高1.41倍（P=0.0184）。接种1000个暴露于Gremlin 1的细胞时，成球能力增强（P=0.0379）。在宫颈癌中，提示Gremlin 1可能在临床复发和维持CSC样特性中发挥作用。
