LncRNA ADAMTS9-AS2 regulates ovarian cancer progression by targeting miR-182-5p/FOXF2 signaling pathway

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Abstract

Increasing studies revealed that aberrant expression of long non-coding RNAs (lncRNAs) play critical roles in ovarian cancer (OC) progression. However, the roles and underlying mechanisms of ADAMTS9-AS2 in OC remain unclear. In the present study, we showed that ADAMTS9-AS2 expression was significantly decreased in OC tissues and cell lines. Low ADAMTS9-AS2 expression was correlated with advanced FIGO stage, lymph-node metastasis, and poor overall survival of OC patients. Function assays showed that ADAMTS9-AS2 reduced OC cells proliferation, invasion, and epithelial-mesenchymal transition (EMT) processes in vitro and restrained tumor growth in vivo. The underlying mechanism studies indicated that ADAMTS9-AS2 functioned as a competing endogenous RNA (ceRNA) for miR-182-5p to promote cell proliferation and invasion. In addition, we revealed that FOXF2 acted as a direct target of miR-182-5p and mediated the effects of ADAMTS9-AS2 on OC cells progression. Taken together, our data suggested that lncRNA ADAMTS9-AS2 decreased OC progression by regulating miR-182-5p/FOXF2 axis, indicating ADAMTS9-AS2 could serve as a potential therapeutic target for OC treatment.

Introduction

Ovarian cancer (OC) is the most lethal tumor type of female gynecologic malignancy with lower incidence rate but higher mortality rate worldwide [1]. Despite great advancement in therapeutic approaches including surgery, radiotherapy, and chemotherapy, the 5-year survival rate remains unsatisfactory due to the absence of specific symptoms in the early stages of OC [2,3]. Therefore, it is urgent to determine the underlying mechanisms and develop new strategies for OC treatment.

Annotation of the results of large-scale sequencing of the human genome has indicated that only 2% of our genomes are actively transcribed into protein-coding RNAs, and the majority of remaining transcripts are non-coding RNAs (ncRNA) [4]. Long non-coding RNAs (lncRNAs) are a group of ncRNAs (ncRNA) >200 nucleotides (nt) in length, have been increasingly reported in a variety of cancer types [5]. Increasing studies showed that dysregulation of lncRNAs play important roles in a wide range of biological processes, such as differentiation, proliferation and carcinogenesis [6,7]. However, the functions and underlying mechanisms of ADAMTS9-AS2 in OC have not been clearly elucidated.

Recently, lots of studies showed that miR-182-5p was aberrant expressed in many tumors. For example, Hirata et al. showed that miR-182-5p promoted cell invasion and proliferation by decreasing FOXF2, RECK and MTSS1 genes in human prostate cancer [8]. Xue et al. found that STAT3 activation induced miR-182-5p to repress PCDH8 expression, which leading to glioma cell growth, migration, and invasion [9]. While, Xu et al. showed that miR-182-5p suppressed renal cell carcinoma proliferation via activating the AKT/FOXO3a signaling pathway [10]. However, its function in OC remains unclear.

In the present study, we found that ADAMTS9-AS2 was downregulated in OC tissues and cell lines. Low ADAMTS9-AS2 expression was correlated with advanced clinical features and poor overall survival of OC patients. Mechanistic investigations showed that ADAMTS9-AS2 could decrease OC cells proliferation and invasion by regulating miR-182-5p/FOXF2 axis. Therefore, our results suggested that ADAMTS9-AS2 might be used as a potential target in OC treatment.

Section snippets

Patient samples and cell culture

47 OC tissue samples were obtained from patients who underwent surgical resection of OC. Normal ovarian tissue samples were collected from cervical cancer surgery patients. All tissues were collected from the Third Affiliated Hospital of Zhengzhou University and Gynecology Oncology laboratory of Zhengzhou from 2012 to 2013. The specimens were frozen immediately in liquid nitrogen and stored at −80 °C until used. Patient follow-up was performed every 3 months during the first year post-surgery

ADAMTS9-AS2 was down-regulated in OC

To explore the role of ADAMTS9-AS2 in OC progression, we first determined ADAMTS9-AS2 expression in OC cell lines by qRT-PCR. Results showed that ADAMTS9-AS2 expression was significantly decreased in OC cell lines (SKOV3, HO8910, A2780, OVCAR, and HOSEpiC) compared to human ovarian surface epithelial cell line (IOSE80) (Fig. 1A, p < 0.05). QRT-PCR revealed that ADAMTS9-AS2 expression was also significantly reduced in OC tissues (Fig. 1B, p < 0.05). Moreover, correlation analysis revealed that

Discussion

With the fast-development of basic medical research, the molecular mechanisms underlying OC tumorigenesis have been disclosed gradually over the past years. Growing evidence indicated that lncRNAs could play critical roles in OC progression [12]. For example, Qiu et al. showed that lncRNA HOTAIR promoted the proliferation of ovarian cancer cells through the regulation of cell cycle arrest and apoptosis [13]. Gao et al. showed that lncRNA-HOST2 regulated cell biological behaviors in epithelial

Conclusions

In the present study, we showed that ADAMTS9-AS2 suppressed OC cells progression by functioning as a miR-182-5p sponge and modulating the expression of FOXF2. Thus, our data shed light on utilizing ADAMTS9-AS2 as a potential novel therapeutic target for OC treatment.

Acknowledgement

None.

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