Overexpression of Long Non-Coding RNA HOTAIR Promotes Tumor Growth and Metastasis in Human Osteosarcoma

Wang, Bo; Su, Yun; Yang, Qun; Lv, Decheng; Zhang, Weiguo; Tang, Kai; Wang, Hong; Zhang, Rui; Liu, Yang

doi:10.14348/molcells.2015.2327

Cited by 72 publications

(64 citation statements)

References 54 publications

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“…Furthermore, Hotair seemed to be required for repression of HoxD genes and several imprinted loci such as Dlk1-Meg3 and Igf2-H19 , without affecting imprinting choice (61). In analogy to our study, it has been shown that knockdown of HOTAIR impairs proliferation (62). The results of our study support the notion that HOTAIR is also important to modulate proliferation and differentiation of MSCs.…”

Section: Discussionsupporting

confidence: 82%

The lncRNA HOTAIR impacts on mesenchymal stem cellsviatriple helix formation

et al. 2016

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There is a growing perception that long non-coding RNAs (lncRNAs) modulate cellular function. In this study, we analyzed the role of the lncRNA HOTAIR in mesenchymal stem cells (MSCs) with particular focus on senescence-associated changes in gene expression and DNA-methylation (DNAm). HOTAIR binding sites were enriched at genomic regions that become hypermethylated with increasing cell culture passage. Overexpression and knockdown of HOTAIR inhibited or stimulated adipogenic differentiation of MSCs, respectively. Modification of HOTAIR expression evoked only very moderate effects on gene expression, particularly of polycomb group target genes. Furthermore, overexpression and knockdown of HOTAIR resulted in DNAm changes at HOTAIR binding sites. Five potential triple helix forming domains were predicted within the HOTAIR sequence based on reverse Hoogsteen hydrogen bonds. Notably, the predicted triple helix target sites for these HOTAIR domains were also enriched in differentially expressed genes and close to DNAm changes upon modulation of HOTAIR. Electrophoretic mobility shift assays provided further evidence that HOTAIR domains form RNA–DNA–DNA triplexes with predicted target sites. Our results demonstrate that HOTAIR impacts on differentiation of MSCs and that it is associated with senescence-associated DNAm. Targeting of epigenetic modifiers to relevant loci in the genome may involve triple helix formation with HOTAIR.

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Section: Discussionsupporting

confidence: 82%

The lncRNA HOTAIR impacts on mesenchymal stem cellsviatriple helix formation

et al. 2016

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“…LncRNAs have been employed as biomarkers and therapeutic targets in various skeletal diseases including osteoarthritis and osteoporosis, as well as in cancers related to the skeletal system [23], among which the lncRNA DANCR has been observed to act as a regulatory element in patients suffering from osteoporosis [9]. Elevated expression of the lncRNA MyoD has been detected in skeletal muscle cells, and elevated lncRNA HOTAIR expression has been observed in osteosarcoma tissues [24,25]. DLL3 is a spondylocostal dysplasia/pudgy gene whose mutation may lead to axial skeletal defects and spondylocostal dysostosis [26][27][28].…”

Section: Figure 14mentioning

confidence: 99%

LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3

Wang¹,

Luo²,

Liu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoporosis is a commonly occurring condition marked by a loss of bone density. Previous evidence has highlighted the roles played by microRNAs as potential treatment tools for the disease. At present, the influence of long non-coding RNAs (lncRNAs) on the progression of osteoporosis remains largely unclear. Thus, an investigation was conducted into the target relationship between LINC00311, which has been reported to be highly expressed in osteoporosis, and delta-like 3 (DLL3), which is involved in the Notch signaling pathway, in connection with a series of bioinformatic methods. An osteoporotic rat model was established by means of ovariectomy (OVX) to evaluate the influence exerted by DLL3-binding LINC00311 on osteoclasts through the Notch signaling pathway. Methods: Osteoclasts were extracted from osteoporotic rats and transfected with the LINC00311-vector, shRNA-LINC00311, Notch activator, or a combination of the Notch activator and LINC00311-vector. Western blotting and RT-qPCR techniques were applied to determine the expression levels of LINC00311, DLL3, Notch1, Notch2, Jagged1, Hes-1 and TRAP in tissues and cells, while cell activity was detected by MTT assay. The cell cycle as well as the rate of apoptosis was detected by flow cytometry. The successfully established osteoporotic rats were designated into the OVX-siRNA, OVX-LINC00311 and OVX-control groups to observe the effects of LINC00311 on the proliferation and differentiation of osteoclasts. Results: Cells transfected with the LINC00311-vector exhibited increased expression levels of Notch2 and TRPA as well as increased cell activity, while decreased expression levels of DLL3, Notch1, Jagged1 and Hes-1, along with a decreased cell apoptosis rate, were observed. The opposite tendencies of these parameters were observed in the cells treated with shRNA-LINC00311. A key observation was made when the Notch signaling pathway was activated, in that the cell activity was decreased while the rate of apoptosis increased. In comparison with the OVX-control group, the expression levels of LINC00311, Notch2 and TRAP as well as the positive expression rate of TRAP all exhibited reductions, while those of DLL3, Jagged1 and Notch1 were elevated in the OVX-siRNA group. Compared with those in the sham group, in the OVX-control and OVX-LINC00311 groups, LINC00311 and the expression levels of Notch2 and TRAP were increased; however, decreased levels of DLL3, Jagged1 and Notch1 were noted. Conclusions: Taken together, the key findings of the present study suggest that LINC00311 induces proliferation and inhibits apoptosis of osteoclasts via the regulation of the Notch signaling pathway by inhibiting DLL3 expression, ultimately demonstrating that LINC00311 and its target gene DLL3 may serve as independent factors in cases of osteoporosis.

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“…7 The important epigenetic modification modes of DNA methylation and histone methylation are known to directly regulate the expression of various tumor-related genes. 8, 9 Aberrant DNA methylation and histone methylation, mediated by HOTAIR, have been found in many types of tumors.…”

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confidence: 99%

Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth

et al. 2017

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Current practices for the therapy of chondrosarcoma, including wide-margin surgical resection and chemotherapy, are less than satisfactory. Recently, emerging evidence has demonstrated that long non-coding RNAs (lncRNAs) have an essential role in the initiation and progression of tumors. As a typical lncRNA, HOTAIR is significantly overexpressed in various tumors. However, the function and potential biological mechanisms of HOTAIR in human chondrosarcoma remain unknown. Quantitative RT-PCR demonstrated that HOTAIR expression was upregulated in chondrosarcoma tissues and cell lines. High HOTAIR expression is correlated with tumor stage and poor prognosis. Functional experiments reveal that HOTAIR knockdown leads to growth inhibition of human chondrosarcoma cells in vitro and in vivo. In addition to cycle arrest and apoptosis, knockdown of HOTAIR inhibits autophagy, which favors cell death. Mechanistically, we demonstrated that HOTAIR induced DNA methylation of miR-454-3p by recruiting EZH2 and DNMT1 to the miR-454-3p promoter regions, which markedly silences miR-454-3p expression. Further analysis revealed that STAT3 and ATG12 are targets of miR-454-3p, initiate HOTAIR deficiency-induced apoptosis and reduce autophagy. Collectively, our data reveal the roles and functional mechanisms of HOTAIR in human chondrosarcoma and suggest that HOTAIR may act as a prognostic biomarker and potential therapeutic target for chondrosarcoma.

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Overexpression of Long Non-Coding RNA HOTAIR Promotes Tumor Growth and Metastasis in Human Osteosarcoma

Cited by 72 publications

References 54 publications

The lncRNA HOTAIR impacts on mesenchymal stem cellsviatriple helix formation

The lncRNA HOTAIR impacts on mesenchymal stem cellsviatriple helix formation

LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3

Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth

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