Exosomal LncRNA LBX1-AS1 Derived From RBPJ Overexpressed-Macrophages Inhibits Oral Squamous Cell Carcinoma Progress via miR-182-5p/FOXO3

Abstract

ObjectivesMacrophage-derived exosomes (Mφ-Exos) are involved in tumor onset, progression, and metastasis, but their regulation in oral squamous cell carcinoma (OSCC) is not fully understood. RBPJ is implicated in macrophage activation and plasticity. In this study, we assessed the role of Mφ-Exos with RBPJ overexpression (RBPJ-OE Mφ-Exos) in OSCC.Materials and MethodsThe long non-coding RNA (lncRNA) profiles in RBPJ-OE Mφ-Exos and THP-1-like macrophages (WT Mφ)-Exos were evaluated using lncRNA microarray. Then the functions of Mφ-Exo-lncRNA in OSCC cells were assessed via CCK-8, EdU, and Transwell invasion assays. Besides, luciferase reporter assay, RNA immunoprecipitation, and Pearson’s correlation analysis were adopted to confirm interactions. Ultimately, a nude mouse model of xenografts was used to further analyze the function of Mφ-Exo-lncRNAs in vivo.ResultsIt was uncovered that lncRNA LBX1-AS1 was upregulated in RBPJ-OE Mφ-Exos relative to that in WT Mφ-Exos. RBPJ-OE Mφ-Exos and LBX1-AS1 overexpression inhibited OSCC cells to proliferate and invade. Meanwhile, LBX1-AS1 knockdown boosted the tumor to grow in vivo. The effects of RBPJ-OE Mφ-Exos on OSCC cells can be reversed by the LBX1-AS1 knockdown. Additionally, mechanistic investigations revealed that LBX1-AS1 acted as a competing endogenous RNA of miR-182-5p to regulate the expression of FOXO3.ConclusionExo-LBX1-AS1 secreted from RBPJ-OE Mφ inhibits tumor progression through the LBX1-AS1/miR-182-5p/FOXO3 pathway, and LBX1-AS1 is probably a diagnostic biomarker and potential target for OSCC therapy.

A micro‑peptide encoded by HOXB‑AS3 promotes the proliferation and viability of oral squamous cell carcinoma cell lines by directly binding with IGF2BP2 to stabilize c‑Myc

“…LncRNAs serve crucial roles in the tumourigenesis and progression of OSCCs (19)(20)(21)(22)(23)(24). PDGF-BB regulates the transformation of fibroblasts into cancer-associated fibroblasts via modulating the expression of lncRNA LURAP1L-AS1 and this is mostly accomplished by affecting the NF-κB signaling pathway (19).…”

“…lncRNA LINC01929 promotes the expression of Forkhead box protein C1 by sponging the microRNA(miR)-137-3p and serves oncogenic roles ( 20 ). Tumor associated macrophages secrete LncRNA LBX1-AS1 via the exosome, inhibiting OSCC progression by targeting miR-182-5p/Forkhead box protein O3 ( 21 ). LncRNA PART1 directly binds with the E2-ubiquitin ligating enzyme of EZH2 and promotes cell proliferation ( 22 ).…”

Long Non-Coding RNA (lncRNA) in Oral Squamous Cell Carcinoma: Biological Function and Clinical Application

“…Notably, lncRNA LBX1-AS1 was significantly upregulated in the exosomes, which are derived from RBPJ overexpressed-macrophages in OSCC, and lncRNA LBX-AS1 inhibits tumor growth and invasion. Furthermore, this effect can be attenuated by lncRNA LBX1-AS1 knockdown [ 58 ]. In addition, lncRNAs can impact the function and cytotoxicity of T cells via regulation of the expression of molecules on the surface of the tumor cells and directly inducing cell death or enhancing T cell exhaustion in the TME [ 124 ].…”

“…For instance, in the studies of OSCC, FLJ22447 and LBX1-AS1 were representative exosome-associated lncRNAs that were derived from CAFs and macrophages, respectively. Both of these are strongly associated with OSCC progression, recurrence, and poor prognosis [ 42 , 58 ]. Analysis of FLJ22447 derived from CAFs revealed it as a medium in which to interact with surrounding stromal fibroblasts to exert the modulatory function in activating CAFs via IL-33, thus inducing the proliferation of OSCC cells [ 42 ].…”

“…Analysis of FLJ22447 derived from CAFs revealed it as a medium in which to interact with surrounding stromal fibroblasts to exert the modulatory function in activating CAFs via IL-33, thus inducing the proliferation of OSCC cells [ 42 ]. In contrast, combined analysis of LBX1-AS1, which is secreted from RBPJ overexpressed macrophages in OSCC patients, the overexpression of exosome-associated lncRNA LBX1-AS1 upregulated tumor suppressor gene FOXO3 to inhibit the proliferation and invasion of OSCC cells [ 58 ]. These studies suggested that exosomes, especially exosome-associated lncRNA, probably exert modulation functions in OSCC development and could be a potential biomarker for OSCC diagnosis and therapy.…”