LncRNA AWPPH promotes osteosarcoma progression via activation of Wnt/β-catenin pathway through modulating miR-93-3p/FZD7 axis

https://doi.org/10.1016/j.bbrc.2019.04.203Get rights and content

Highlights

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    AWPPH up-regulation is associated with poor prognosis in OS.

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    AWPPH sponges miR-93-3p in OS.

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    AWPPH promotes OS progression through suppressing miR-93-3p.

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    FZD7 up-regulation by AWPPH-caused miR-93-3p suppression induces activation of Wnt/β-catenin signaling.

Abstract

Long noncoding RNAs (lncRNAs) have important regulatory roles in osteosarcoma (OS) progression. Recent researches have shown lncRNA AWPPH promotes lung cancer progression and bladder cancer development. Yet, the function of AWPPH in OS is unknown. In this research, results indicated AWPPH levels were increased in OS tissues in contrast to paracancerous controls. Up-regulated AWPPH was associated with advanced stage, tumor size and metastasis. Besides, AWPPH up-regulation indicated a low survival rate in OS patients. Silencing of AWPPH suppressed proliferation, migration and invasion of OS cells. Mechanistically, AWPPH was demonstrated to sponge miR-93-3p and promote FZD7 expression, causing activation of Wnt/β-catenin. Inhibition of miR-93-3p effectively reversed the effects of AWPPH knockdown on OS cells. Collectively, our findings suggested AWPPH may be a prognostic biomarker and potential therapeutic target. AWPPH enhances FZD7-mediated activation of Wnt/β-catenin by sponging miR-93-3p to promote OS progression.

Introduction

Osteosarcoma (OS) is an aggressive bone cancer and usually occurs among adolescents [1]. High rate of metastasis contributes to rapid progression of OS and leads to large numbers of deaths [2]. The 5-year survival rate in OS patients is quite low [3]. To date, no effective strategy is developed for radical cure of OS. Especially, the mechanism of OS development remains obscure. Today, there is an urgent need to investigate novel targets for OS therapy and improve patients’ outcomes.

Long noncoding RNA (lncRNA) has been defined as a new member of noncoding RNA as miRNA [4]. LncRNA is featured by a length of over 200 nucleotides and limited protein-coding potential [5]. Growing studies show lncRNAs play crucial regulatory functions in various pathological processes, including cancer [6]. Reports have indicated that cell-cycle, metastasis, differentiation or stemness of tumor cells is regulated by lncRNAs [7,8]. For example, Guo et al. showed that lncRNA AB073614 regulates growth and apoptosis in cervical cancer [9]. Sun et al. reported that SNHG12 promotes proliferation and invasiveness in ovarian cancer by up-regulating SOX4 [10]. Wang et al. found that lncRNA IUR regulates tumorigenesis by modulating STAT5-CD71 signaling [11]. Additionally, Huang et al. proved that lncRNA ADPGK-AS1 promotes gastric cancer development and may be a therapeutic target [12]. Thus, functional lncRNAs may be important for OS prognosis and potential therapeutic target.

AWPPH was first reported to regulate hepatocellular carcinoma progression [13]. Recent studies also indicated that AWPPH participates in regulation of bladder cancer, breast cancer and lung cancer [[14], [15], [16]]. Nevertheless, its function in OS remains obscure. In our study, we found AWPPH expression was upregulated in OS tissues. AWPPH level was correlated with advanced stage, tumor size and metastasis. Moreover, AWPPH is a prognostic biomarker of OS patients. AWPPH knockdown caused inhibition on proliferation, migration and invasion. Mechanistically, AWPPH could sponge miR-93-3p to upregulate FZD7 and trigger activation of Wnt/β-catenin signaling. Collectively, our data provides a novel insight on the function and mechanism of AWPPH in OS development.

Section snippets

Human samples

OS tissues and normal tissues were collected from our hospital and stored in liquid nitrogen after surgery. No patient was treated by chemotherapy or radiotherapy before surgery. Singed inform content was obtained from each involved patient. This study was approved by the Ethic Committee of our hospital.

Cell culture and transfection

OS cell lines and normal cell line hFOB 1.19 were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA). Cells were cultured with DMEM medium containing 10% FBS (Gibco,

AWPPH up-regulation is associated with poor prognosis in OS

To determine potential roles of AWPPH in OS, its levels were analyzed by qRT-PCR in collected OS tissues and corresponding normal controls. AWPPH expression was up-regulated in OS tissues (Fig. 1A). Notably, AWPPH levels were higher in OS tissues with advanced stages (Fig. 1B) and metastasis (Fig. 1C). We further analyzed the correlation between AWPPH and clinical features. As shown in Table 1, AWPPH expression was positively correlated with tumor size, advance stage and metastasis. There was

Discussion

Elucidating the molecular mechanism of OS development is still urgently required. In this study, we showed AWPPH was up-regulated in OS tissues and correlated with tumor size, advanced stage and metastasis. Moreover, AWPPH high expression indicated a low survival rate. Knockdown of AWPPH inhibited proliferation, migration and invasion of OS cells. We demonstrated AWPPH activated Wnt/β-catenin pathway through modulating miR-93-3p/FZD7 axis. Thus, our findings revealed a novel mechanism

Conflicts of interest

None.

Acknowledgements

None.

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