SNORD89 promotes stemness phenotype of ovarian cancer cells by regulating Notch1-c-Myc pathway

Wenjing Zhu,Jumin Niu,Lin Zhao,Miao He,Yuanyuan Yan,Zhaojin Yu,Xuemei Lv,Liwen Zhang,Yuzong Chen,Longyang Jiang,Qian Wei,Yue Fan,Jia Bi,Jian Ding,Fangxiao Liu,Hong Huo,Jing Zhang,Minjie Wei

doi:10.1186/s12967-019-2005-1

Abstract

BackgroundOvarian cancer is the leading cause of death in gynecological cancer. Cancer stem cells (CSCs) contribute to the occurrence, progression and resistance. Small nucleolar RNAs (SnoRNAs), a class of small molecule non-coding RNA, involve in the cancer cell stemness and tumorigenesis.MethodsIn this study, we screened out SNORNAs related to ovarian patient’s prognosis by analyzing the data of 379 cases of ovarian cancer patients in the TCGA database, and analyzed the difference of SNORNAs expression between OVCAR-3 (OV) sphere-forming (OS) cells and OV cells. After overexpression or knockdown SNORD89, the expression of Nanog, CD44, and CD133 was measured by qRT-PCR or flow cytometry analysis in OV, CAOV-3 (CA) and OS cells, respectively. CCK-8 assays, plate clone formation assay and soft agar colony formation assay were carried out to evaluate the changes of cell proliferation and self-renewal ability. Scratch migration assay and trans-well invasion analysis were used for assessing the changes of migration and invasion ability.ResultsHigh expression of SNORD89 indicates the poor prognosis of ovarian cancer patients and was associated with patients’ age, therapy outcome. SNORD89 highly expressed in ovarian cancer stem cells. The overexpression of SNORD89 resulted in the increased stemness markers, S phase cell cycle, cell proliferation, invasion and migration ability in OV and CA cells. Conversely, these phenomena were reversed after SNORD89 silencing in OS cells. Further, we found that SNORD89 could upregulate c-Myc and Notch1 expression in mRNA and protein levels. SNORD89 deteriorates the prognosis of ovarian cancer patients by regulating Notch1-c-Myc pathway to promote cell stemness and acts as an oncogene in ovarian tumorigenesis. Consequently, SNORD89 can be a novel prognostic biomarker and therapeutic target for ovarian cancer.

Highlights

Ovarian cancer is the leading cause of death in gynecological cancer
Screening SNORNAs related to prognosis in ovarian cancer patients To find which SNORNAs are related to poor prognosis of ovarian cancer, we used The Cancer Genome Atlas (TCGA) database to analyze the relationship between of SNORNAs expression and overall survival for 379 ovarian cancer patients
Based on the retrieval of SNORic database, we found that SNORD89 was correlated with 178 mRNAs and participated in splicing of 43 mRNAs in ovarian cancer

Summary

Introduction

Ovarian cancer is the leading cause of death in gynecological cancer. Cancer stem cells (CSCs) contribute to the occurrence, progression and resistance. Ovarian cancer is the leading cause of death in gynecological cancer, since patients with early stage ovarian cancer do not have symptoms of discomfort and 75% of patients have reached advanced stage (stage III or IV) [1]. It was estimated about 295,414 new cases and 184,799. Zhu et al J Transl Med (2019) 17:259 classified as box C/D SNORNAs and box H/ACA SNORNAs [7, 8]. They are combined with a set of core proteins to form SNORNP. It was reported that the expression levels of C/D box SNORNAs in acutemyelogenous leukaemia (AML) patients were highly related to in vivo frequency of leukaemic stem cells [20]

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