Long noncoding RNA LSINCT5 acts as an oncogene via increasing EZH2-induced inhibition of APC expression in osteosarcoma

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Abstract

Long noncoding RNAs (lncRNAs) are recognized as a class of critical regulators in various tumors. Recently, lncRNA LSINCT5 has been reported to promote the progression of bladder cancer, ovarian cancer, gastric cancer, and breast cancer. However, the biological function of LSINCT5 remains elusive in osteosarcoma (OS). In our study, we found that LSINCT5 was significantly upregulated in OS tissues than in adjacent normal tissues. Additionally, the expression of LSINCT5 was inversely associated with the prognosis of patients with OS. LSINCT5 knockdown dramatically inhibited OS cell proliferation in vitro and tumor growth in vivo. Mechanistic exploration revealed that LSINCT5 interacted with EZH2 to suppress the expression of APC, a negative regulator of the Wnt/β-catenin pathway. Moreover, rescue assays suggested that LSINCT5 exerted oncogenic roles by partially inhibiting APC expression in OS. In summary, our study demonstrated that LSINCT5 was a promising candidate for OS prognosis and therapy.

Introduction

Osteosarcoma (OS) is the most frequent aggressive bone cancer among adolescents, whose incidence and mortality are very high [1]. In the past, surgical techniques together with radiotherapy and chemotherapy were developed as the major therapeutic strategies for patients with OS [2]. However, the five-year survival rate of patients with OS remains unsatisfactory [3]. Thus, the development of effective clinical methods for OS therapy is urgently required. To achieve this goal, the molecular mechanism underlying OS progression should be understood.

Long noncoding RNAs (lncRNAs) are noncoding transcripts with more than 200 nucleotides [4]. Over 90% of transcripts are noncoding RNAs [5]. LncRNAs were recently identified as functional noncoding RNAs. An increasing number of studies verified that lncRNAs are implicated in various pathophysiological processes, especially tumorigenesis [6]. LncRNA dysregulation is usually observed in tumor tissues. The proliferation, cell cycle, survival, migration, and invasion of tumor cells can be regulated by lncRNAs [7]. The important functions of lncRNAs in OS are also widely acknowledged. For instance, lncRNA THOR promotes OS cell survival and proliferation in vitro and in vivo [8]. LncRNA SNHG6 regulates p21 and KLF2 expression, leading to increased proliferation of OS cells [9]. LncRNA H19 regulates the NF-κB pathway to promote OS cell migration and invasion [10].

LSINCT5 has been shown to be overexpressed in many cancers, such as breast cancer [11], gastric cancer [12], ovarian cancer [13], and bladder cancer [14]. Yet, the potential roles of LSINCT5 remain largely unknown in OS. In our study, we showed that LSINCT5 was upregulated in OS tissues compared to normal tissues. The expression level of LSINCT5 was also negatively correlated with patients’ survival. LSINCT5 knockdown significantly inhibited the proliferation, migration, and invasion of OS cells in vitro. LSINCT5 knockdown also suppressed tumor growth in vivo. In terms of the underlying mechanism, we found that LSINCT5 inhibited APC expression by binding to EZH2. Our study suggested that LSINCT5 might be a promising target for OS therapy.

Section snippets

Patient samples

42 OS tissues and paired normal tissues were obtained from China-Japan Union Hospital of Jilin University. The patients received no chemotherapy before surgery. Tissues were stored in liquid nitrogen until use. This work was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University. Written informed consent was received from all participants.

Cell culture

OS cell lines (Saos-2, U2OS, MG-63, and 143B) and normal osteoblasts (hFOB 1.19) were from the American Type Culture Collection

LSINCT5 overexpression was associated with decreased survival

To explore the function of LSINCT5 in OS progression, we assessed the relative expression of LSINCT5 in 42 pairs of OS tissues and adjacent normal tissues by qRT-PCR. The results showed that LSINCT5 expression was significantly upregulated in OS tissues compared with adjacent normal tissues (Fig. 1A). LSINCT5 expression was also determined in OS cell lines. LSINCT5 expression was higher in OS cell lines than in normal human osteoblasts (hFOB 1.19; Fig. 1B). We then investigated the correlation

Discussion

The cure for OS is challenging due to the complicated molecular mechanism underlying OS development [19]. At present, the mechanism of OS progression remains unclear. In our study, we investigated the function and regulatory mechanism of LSINCT5 in OS progression.

LncRNAs are important regulatory molecules in multiple tumors, including OS [20]. Accumulating evidence demonstrated the increasing important roles of lncRNAs in OS tumorigenesis. For instance, overexpressing lncRNA Xist increases OS

Conflicts of interest

The authors declare no competing financial interests.

Abbreviations

OS, osteosarcoma; lncRNAs, long noncoding RNAs.

Acknowledgements

None.

References (27)

  • R. Jiang et al.

    MicroRNA-107 promotes proliferation, migration, and invasion of osteosarcoma cells by targeting tropomyosin 1

    Oncol. Res.

    (2017)
  • G.Y. Lv et al.

    Long non-coding RNA XIST promotes osteosarcoma progression by targeting ras-related protein RAP2B via miR-320b

    Oncol. Res.

    (2018 Jul 5)
  • Y.L. Gao et al.

    Long noncoding RNA PVT1 facilitates cervical cancer progression via negative regulating of miR-424

    Oncol. Res.

    (2017)
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