LncRNA LBX2-AS1 impacts osteosarcoma sensitivity to JQ-1 by sequestering miR-597-3p away from BRD4

Jiayu Li; Xuhui Yuan; Cong Ma; Junhong Li; Gaoyang Qu; Bo Yu; Feng Cai; Yuanxiang Peng; Lang Liu; Duo Zeng; QuanHui Jiao; Jiongfeng Zhang; Xiaohui Luo; Qi Liao; Xiao-Bin Lv

doi:10.3389/fonc.2023.1139588

LncRNA LBX2-AS1 impacts osteosarcoma sensitivity to JQ-1 by sequestering miR-597-3p away from BRD4

Front Oncol. 2023 Mar 24:13:1139588. doi: 10.3389/fonc.2023.1139588. eCollection 2023.

Authors

Jiayu Li^{1

2}, Xuhui Yuan^{1

2}, Cong Ma³, Junhong Li³, Gaoyang Qu^{1

2}, Bo Yu^{1

2}, Feng Cai^{1

2}, Yuanxiang Peng^{1

2}, Lang Liu^{1

2}, Duo Zeng^{1

2}, QuanHui Jiao¹, Jiongfeng Zhang^{1

2}, Xiaohui Luo^{1

2}, Qi Liao^{1

2}, Xiao-Bin Lv¹

Affiliations

¹ Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Central Laboratory, The First Hospital of Nanchang, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
² Department of Orthopedics, The First Hospital of Nanchang, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
³ Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Abstract

Objective: Recent knowledge concerning the significance of long non-coding RNA (lncRNA)-mediated ceRNA networks provides new insight into their possible roles as specific biomarkers for the treatment of osteosarcoma (OS). Thus, this study aims to clarify the functional relevance and mechanistic actions of lncRNA LBX2-AS1 in OS.

Methods: Differential analysis was performed by integrating the TCGA and GTEx databases. Cox regression analysis was then employed to assess the prognostic value of the model. The expression of lncRNA LBX2-AS1 and miR-597-3p was quantified in OS cell lines by qRT-PCR. The proliferation, migration, invasion, and apoptosis of OS cell lines in response to manipulated lncRNA LBX2-AS1 were evaluated by MTT, colony formation, transwell, Western blot, and flow cytometry assays. Luciferase activity was assayed to validate the reciprocal regulation between lncRNA LBX2-AS1 and miR-597-3p. The protein levels of BRD4 and EMT-related factors were examined by Western blot assay. Finally, tumor growth in response to LBX2-AS1 knockdown was evaluated in xenograft-bearing nude mice.

Results: By integrating the GTEx and TCGA databases, we identified 153 differentially expressed lncRNAs. Among them, 5 lncRNAs, RP11-535M15.1, AC002398.12, RP3-355L5.4, LBX2-AS1, and RP11.47A8.5, were selected to establish a model, which predicted the prognosis of OS. Higher lncRNA LBX2-AS1 expression was noted in OS tissues relative to that in normal tissues. Silencing lncRNA LBX2-AS1 facilitated apoptosis and curtailed proliferative, migratory, and invasive capacities of OS cells. Mechanistically, lncRNA LBX2-AS1 could elevate the expression of BRD4, an oncogene, by competitively binding to miR-597-3p. More importantly, knockdown of lncRNA LBX2-AS1 increased the sensitivity of OS cells to the BRD4 inhibitor JQ-1. Finally, the tumor growth of OS cell xenografts was constrained in vivo in the presence of lncRNA LBX2-AS1 knockdown.

Conclusion: In conclusion, lncRNA LBX2-AS1 promotes the growth of OS and represses the sensitivity to JQ-1 by sponging miR-597-3p to elevate the expression of BRD4.

Keywords: BRD4; JQ-1; lncRNA LBX2-AS1; miR-597-3p; osteosarcoma.

Grants and funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81960501); “Double-Hundred Talents Project” from Nanchang science and Technology Bureau (grant numbers 2021-156 to X.B.L.); the Natural Science Foundation of Jiangxi Province (grant numbers 20212ACB206028 and 20202BAB206041 to X.B.L.); Nanchang science and Technology Bureau (grant numbers 2022-146 and 2020-133 to X.B. L.); the Foundation of Jiangxi Province Health Commission (grant numbers 20202003 to X.B.L.); General Project of Science and Technology Research of Jiangxi Provincial Education Department (grant numbers GJJ190104 to QL). Key scientific and technological research projects of Jiangxi Provincial Department of Education. (Grant No. GJJ200132 to YXP).