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

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. 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. 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. 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.

Fei D ，Zhang X ，Liu J ，Tan L ，Xing J ，Zhao D ，Zhang Y ... -  《-》

LncRNA FER1L4 induces apoptosis and suppresses EMT and the activation of PI3K/AKT pathway in osteosarcoma cells via inhibiting miR-18a-5p to promote SOCS5.

Previous studies have determined that long non-coding RNA (lncRNA) Fer-1-like protein 4 (FER1L4) is suppressed in osteosarcoma (OS) and inhibits the tumorigenesis in a variety of cancer. However, the precise biological of FER1L4 in OS has not been cleared. The aim of this study is to investigate the roles and potential mechanisms of FER1L4 in apoptosis and epithelial-mesenchymal transition (EMT) in OS. In the present study, the levels of FER1L4 were decreased significantly in OS tissues and cell lines compared with non-tumorous tissues or hFOB1.19. Knockdown of FER1L4 in OS cells decreased the apoptosis rate, but increased the OS cell proliferation, upregulated the expression levels of CD133 and Nanog, as well as promoted Twist1 expression, increased the N-cadherin and Vimentin expression. In turn, the opposite trends were observed upon overexpression of FER1L4. In addition, the expression of PI3K, p-AKT (Ser470) and p-AKT (Thr308) was upregulated by siFER1L4, while decreased upon overexpression of FER1L4. MicroRNA (miRNA) -18a-5p, an osteosarcoma-promoting miRNA which was suggested a target of FER1L4 in osteosarcoma, was identified to be a functional target of FER1L4 on the regulating of cell apoptosis and EMT, presently. The effects of FER1L4 overexpression on the markers of cell apoptosis, proliferation, EMT, and stemness and PI3K/AKT signaling were all reversed by miR-18a-5p upregulation. Furthermore, the suppressor of cytokine signaling 5 (SOCS5) was confirmed a target gene of miR-18a-5p by luciferase gene reporter assay and SOCS5 suppression by miR-18a-5p attenuated the effects of FER1L4 overexpression on the OS cells apoptosis and the expressed levels of PI3K, AKT, Twist1, N-cadherin and Vimentin. In conclusion, our data indicated thatthe overexpression of FER1L4 promoted apoptosis and inhibited the EMT markers expression and PI3K/AKT signaling pathway activation in OS cells via downregulating miR-18a-5p to promote SOCS5.

Ye F ，Tian L ，Zhou Q ，Feng D ... -  《-》

Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma.

Wang Y ，Zeng X ，Wang N ，Zhao W ，Zhang X ，Teng S ，Zhang Y ，Lu Z ... -  《Molecular Cancer》

Long non-coding RNA Fer-1-like protein 4 suppresses oncogenesis and exhibits prognostic value by associating with miR-106a-5p in colon cancer.

Novel long non-coding RNA Fer-1-like protein 4 (FER1L4) has been confirmed to play crucial regulatory roles in tumor progression. It exerts an impact on tumor suppression and functions as a competing endogenous RNA (ceRNA) by sponging miR-106a-5p in gastric cancer. However, its clinical significance in colon cancer is completely unknown. The aim of the present study was to annotate the role of FER1L4 and its clinical value in colon cancer. The results showed the aberrant expression of FER1L4 and miR-106a-5p in colon cancer tissues. In addition, significant negative correlation between FER1L4 and miR-106a-5p expression levels was observed. Among the colon cancer cell lines, FER1L4 levels were relatively lower, with concurrent high levels of miR-106a-5p. Restoration of FER1L4 decreased the expression of miR-106a-5p, and had a significant influence on colon cancer cell proliferation, migration and invasion. The FER1L4 expression was correlated with depth of tumor invasion, lymph node metastasis, vascular invasion and clinical stage. Moreover, striking differences in overall survival and disease-free survival were observed for the cases with both low FER1L4 expression and high miR-106a-5p expression compared with cases with high FER1L4 expression and low miR-106a-5p expression. Circulating FER1L4 and miR-106a-5p levels were decreased and increased, respectively, in colon cancer patients after surgery. Our findings indicated that FER1L4 could exert a tumor suppressive impact on colon cancer, which at least, in part, through suppressing miR-106a-5p expression, and depletion of FER1L4, alone or combined with overexpression of miR-106a-5p, is predictive of poor prognosis in colon cancer and may play a crucial role in cancer prevention and treatment.

Yue B ，Sun B ，Liu C ，Zhao S ，Zhang D ，Yu F ，Yan D ... -  《-》

Linc00460 promotes osteosarcoma progression via miR-1224-5p/FADS1 axis.

Previous studies have demonstrated that long non-coding RNAs (lncRNAs) were involved in tumorigenesis in various human neoplasms, including osteosarcoma (OS). However, the expression and specific role of lncRNA linc00460 in OS remain unknown. Bioinformatics analysis, Quantitative real-time polymerase chain reaction (qRT-PCR), CCK-8 assay, Colony formation assay, Wound healing assay, Transwell assay, Dual luciferase reporter assay, RNA immunoprecipitation and Western blot were utilized to analyze or detect survival, gene expression, cell proliferation, cell migration, cell invasion and interest protein levels, respectively. In this study, we found high linc00460 expression predicted poor prognosis of pan-cancer patients. Linc00460 was up-regulated in OS tissues and cells. High linc00460 expression was positively correlated with distant metastasis and poor overall survival of OS patients. Knockdown of linc00460 suppressed OS cells proliferation and metastasis in vitro. In addition, an inverse correlation between linc00460/miR-1224-5p and miR-1224-5p/FADS1 was observed in OS. Mechanistically, linc00460 functioned as a competitively endogenous RNA (ceRNA) to up-regulate FADS1 expression via sponging miR-1224-5p in OS, thereby promoting OS progression. In conclusion, this study recognized linc00460 as a new oncogenic lncRNA in OS and suggests that the linc00460/miR-1224-5p/FADS1 axis might be a potential therapeutic target for OS.

Lian H ，Xie P ，Yin N ，Zhang J ，Zhang X ，Li J ，Zhang C ... -  《-》