Long Noncoding RNA FER1L4 Suppresses Tumorigenesis by Regulating the Expression of PTEN Targeting miR-18a-5p in Osteosarcoma

Abstract

Background/Aims: Novel long non-coding RNA Fer-1-like protein 4 (FER1L4) has been reported to play crucial regulatory roles in tumor progression. However, its clinical significance and biological role in osteosarcoma (OS) is completely unknown. The aim of the present study was to investigate the role of FER1L4 in OS progression and the underlying mechanism. Methods: We analyzed the expression levels of FER1L4 in tissues of OS patients and cell lines via quantitative RT-PCR (qRT-PCR). The effect of FER1L4 on cell proliferation, colony formation, migration and invasion was analyzed by cell counting kit-8 (CCK-8), colony formation, wound healing and transwell invasion assay, respectively. Novel targets of FER1L4 were selected through a bioinformatics soft and confirmed using a dual-luciferase reporter system and qRT-PCR. To detect the role of FER1L4 in vivo tumorigenesis, tumor xenografts were created. Results: We found that the expression of FER1L4 was significantly downregulated in OS tissues and cell lines; moreover, low expression of FER1L4 was associated with advanced tumor-nude-metastasis (TNM) stage, lymph node metastases, and poor overall survival. Functional assays showed that upregulation of FER1L4 significantly inhibited OS cell proliferation, colony formation, migration, and invasion in vitro, as well as suppressed tumor growth in vivo. Assays performed to determine the underlying mechanism, indicated that FER1L4 interacted directly with miR-18a-5p. Subsequently, we found that FER1L4 significantly increased PTEN expression, a known target of miR-18a-5p, in OS cells. Furthermore, PTEN was found to be down-regulated, and positively correlated with FER1L4 in OS tissues. Conclusion: These findings suggest that FER1L4, acting as a competing endogenous RNA (ceRNA) of miR-18a-5p, exerts its anti-cancer role by modulating the expression of PTEN. Thus, FER1L4 may be a novel target for the prevention and treatment of OS.

Functions of Vertebrate Ferlins

“…The exception is a report about the Fer1L4 possible role in glioma progression, where high expression of Fer1L4 was associated with a poor disease prognosis [162]. Fer1L4 exerts its function via the PTEN/PI3K/AKT signaling pathway [161,163,164]. The role of this pathway in tumorigenesis was described in detail [165].…”

“…PTEN is known as a tumor suppressor inhibiting PI3K/AKT proliferation signaling. Downregulation of Fer1L4 expression correlated with decrease of the level of PTEN [164,166], while Fer1L4 overexpression inhibited the PI3K/AKT signaling pathway [67,163]. Thus, the Fer1L4 RNA may serve as a competing endogenous RNA and regulate the expression of PTEN via miRNA-mediated mechanisms inhibiting cancer cell proliferation and metastasis [164,166].…”

Long non-coding RNA FER1L4 inhibits prostate cancer progression via sponging miR-92a-3p and upregulation of FBXW7

“…Studies on FER1L4 suggested that FER1L4 mainly exerted its function via sponging miRNAs in cancer cells [18,28]. We predicted that FER1L4 sequence harbored binding site for miR-92a-3p.…”

“…The most well-characterized role of FER1L4 is its tumor suppressor function as a negative regulator of AKT signaling in cancers [30,31]. Many studies showed that FER1L4 inactivated AKT signaling to suppress cancer progression including osteosarcoma, lung cancer, hepatocellular carcinoma and endometrial carcinoma [28,38,39]. FER1L4 also repressed esophageal squamous cell carcinoma proliferation [37].…”

“…Studies showed that FER1L4 functioned as a ceRNA to regulate gene expression and disease progression [18,28]. Using RegRNA 2.0, miR-92a-3p was predicted as a potential binding miRNA for FER1L4 with the highest score.…”