Emerging evidence has demonstrated that circular RNAs (circRNA) are involved in cancer metastasis. Further elucidation of the role of circRNAs in oral squamous cell carcinoma (OSCC) could provide insights into mechanisms driving metastasis and potential therapeutic targets. Here, we identify a circRNA, circFNDC3B, that is significantly upregulated in OSCC and is positively associated with lymph node (LN) metastasis. In vitro and in vivo functional assays showed that circFNDC3B accelerated the migration and invasion of OSCC cells and the tube-forming capacity of human umbilical vein endothelial cells and human lymphatic endothelial cells. Mechanistically, circFNDC3B regulated ubiquitylation of the RNA-binding protein FUS and the deubiquitylation of HIF1A through the E3 ligase MDM2 to promote VEGFA transcription, thereby enhancing angiogenesis. Meanwhile, circFNDC3B sequestered miR-181c-5p to upregulate SERPINE1 and PROX1, which drove epithelial–mesenchymal transition (EMT) or partial-EMT (p-EMT) in OSCC cells and promoted lymphangiogenesis to accelerate LN metastasis. Overall, these findings uncovered the mechanistic role of circFNDC3B in orchestrating cancer cell metastatic properties and vasculature formation, suggesting circFNDC3B could be a potential target to reduce OSCC metastasis. Significance: Dual functions of circFNDC3B in enhancing the metastatic ability of cancer cells and promoting vasculature formation through regulation of multiple pro-oncogenic signaling pathways drive lymph node metastasis of OSCC.

Dysregulation of miRNAs is associated with aberrant migration and invasion by suppressing relevant target genes in multiple cancers, including oral squamous cell carcinoma (OSCC). Accumulating evidence suggests that microRNA-155-5p is involved in carcinogenesis and tumor progression. However, the exact function and molecular mechanism of miR-155-5p in OSCC remain unclear. This study aimed to investigate the function of miR-155-5p and the molecular mechanisms underlying the influencing progression of OSCC. The miR-155-5p expression level in the OSCC tissues and oral cancer cell lines were determined by the qRT-PCR. Gain-of-function and knockdown approach were used to examine the effect of miR-155-5p on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of OSCC. The luciferase reporter assay was applied to confirm the AT-rich interactive domain 2 (ARID2) as a potential target of miR-155-5p, and the rescue experiment was employed to verify the roles of the miRNA-155-5p-ARID2 axis in OSCC progression. Immunohistochemical staining was used to detect ARID2 expression in another cohort sample tissues from OSCC patients. MiR-155-5p was significantly upregulated in OSCC tissues and cell lines. The miR-155-5p expression level was positively correlated with tumor size, TNM stage, histological grade and lymph node metastasis of OSCC patients. Functional assays demonstrated that miR-155-5p enhanced OSCC cell proliferation, migration and invasion. Mechanistically, ARID2 was identified as a direct target and functional effector of miR-155-5p in OSCC. Furthermore, ARID2 overexpression could rescue the aberrant biological function by overexpressed miR-155-5p in OSCC cells. Notably, we showed that ARID2 could be used as an independent prognosis factor in OSCC. Our results suggest that miR-155-5p facilitates tumor progression of OSCC by targeting ARID2, and miR-155-5p-ARID2 axis may be a potential therapeutic target of OSCC.

Adenosine deaminases acting on RNA (ADARs) are involved in adenosine-to-inosine (A-to-I) editing and implicated in tumorigenesis and prognosis. Emerging evidence has indicated that ADAR1, an ADAR family member, participates in the regulation of various cancers; however, its biological function in oral squamous cell carcinoma (OSCC) remains unclear. This study aimed to determine the role of ADAR1 in OSCC progression. ADAR1 expression in both normal tissues and carcinoma tissues and in OSCC cell lines was examined by real-time PCR and western blotting. Gain-of-function and loss-of-function approaches were used to examine the effect of ADAR1 on the migration, invasion, epithelial-mesenchymal transition (EMT) and stemness of OSCC. Furthermore, the relationship between ADAR1 and Dicer was determined by co-immunoprecipitation, and the expression of OSCC-associated oncogenic miRNAs was evaluated by real-time PCR. For in vivo experiments, a xenograft model where OSCC cells stably expressing ADAR1 were implanted was used to investigate the effect of ADAR1 on tumor growth and progression, and the expression of ADAR1, PCNA, SOX2 and POU5F1 was further detected by immunohistochemistry. The impact of ADAR1 expression on the survival status of OSCC patients was determined by survival analysis. ADAR1 was overexpressed in OSCC and significantly associated with poor patient survival. There was a positive correlation between ADAR1 and the migration, invasion, EMT and stemness of OSCC. Mechanistically, ADAR1 was physically associated with Dicer, and six OSCC-associated oncogenic miRNAs were increased in OSCC cells with ADAR1 overexpression. In the mouse xenograft model of OSCC, ADAR1 overexpression promoted tumor growth and progression. Moreover, ADAR1 was highly expressed in OSCC patients with low survival rates. Our findings demonstrated that ADAR1 may play a significant role in OSCC progression via combining with Dicer to regulate oncogenic miRNA maturation and further affect cell migration and invasion.

Bisphosphonate-related (BP-related) osteonecrosis of the jaw (BRONJ) is one of the severe side effects of administration of BPs, such as zoledronic acid (ZA), which can disrupt the patient’s quality of life. Although the direct target of skeletal vasculature and bone resorption activity by BPs has been phenomenally observed, the underlying mechanism in BRONJ remains largely elusive. Thus, it is urgently necessary to discover effective therapeutic targets based on the multifaceted underlying mechanisms in the development of BRONJ. Here, we determined the inhibitory role of ZA-treated macrophages on osteoclast differentiation and type H vessel formation during tooth extraction socket (TES) healing. Mechanistically, ZA activated the NF-κB signaling pathway and then induced p65 nuclear translocation in macrophages to promote miR-149-5p transcription, resulting in impaired osteoclast differentiation via directly binding to the Traf6 3′-UTR region. Moreover, we identified that miR-149-5p–loaded extracellular vesicles derived from ZA-treated bone marrow–derived macrophages could regulate biological functions of endothelial cells via the Rap1a/Rap1b/VEGFR2 pathway. Furthermore, local administration of chemically modified antagomiR-149-5p was proven to be therapeutically effective in BRONJ mice. In conclusion, our findings illuminate the dual effects of miR-149-5p on skeletal angiogenesis and bone remolding, suggesting it as a promising preventive and therapeutic target for BRONJ.

Background: We aimed to compare the relationship between the buccal and lingual positions of the inferior alveolar nerve canal (IAC) relative to the lower third molar (LM3) and the rate of the inferior alveolar nerve (IAN) injury. Methods: A systematic search was performed in the following databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Journals@Ovid. No language or publication status restrictions were set. The publication year was set from 2009 to 2021. The process of meta-analysis was performed by Review Manager software (Cochrane Collaboration). Results: A total of 1063 articles were initially searched and full texts of 53 articles were read, and 11 satisfactory articles were found. There was a statistical difference between the rate of IAN injury and the lingual position and buccal position of the IAC relative to the LM3 roots (OR, 4.96; 95% CI, 2.11 to 11.62; p = 0.0002), with high heterogeneity (p = 0.001, I² = 65%). Conclusion: A statistical difference was found in the rate of IAN injury between cases where the IAC was positioned buccally and lingually of the LM3 roots. The IAC was at a relatively higher risk of damage in third molar extraction when it was located on the lingual position of the LM3 roots.

Background: Venous malformations (VMs), most of which associated with activating mutations in the endothelial cells (ECs) tyrosine kinase receptor TIE2, are characterized by dilated and immature veins with scarce smooth muscle cells (SMCs) coverage. However, the underlying mechanism of interaction between ECs and SMCs responsible for VMs has not been fully understood.Methods: Here, we screened 5 patients with TIE2-L914F mutation who were diagnosed with VMs by SNP sequencing, and we compared the expression of platelet-derived growth factor beta (PDGFB) and α-SMA in TIE2 mutant veins and normal veins by immunohistochemistry. In vitro, we generated TIE2-L914F-expressing human umbilical vein endothelial cells (HUVECs) and performed BrdU, CCK-8, transwell and tube formation experiments on none-transfected and transfected ECs. Then we investigated the effects of rapamycin (RAPA) on cellular characteristics. Next we established a co-culture system and investigated the role of AKT/FOXO1/PDGFB in regulating cross-talking of mutant ECs and SMCs.Results: VMs with TIE2-L914F mutation showed lower expression of PDGFB and α-SMA than normal veins. TIE2 mutant ECs revealed enhanced cell viability and motility, and decreased tube formation, whereas these phenotypes could be reversed by rapamycin. Mechanically, RAPA ameliorated the physiological function of mutant ECs by inhibiting AKT-mTOR pathway, but also facilitated the nuclear location of FOXO1 and the expression of PDGFB in mutant ECs, and then improved paracrine interactions between ECs and SMCs. Moreover, TIE2 mutant ECs strongly accelerated the transition of SMCs from contractile phenotype to synthetic phenotype, whereas RAPA could prevent the phenotype transition of SMCs.Conclusions: Our data demonstrate a previously unknown mechanistic linkage of AKT-mTOR/FOXO1 pathway between mutant ECs and SMCs in modulating venous dysmorphogenesis, and AKT/FOXO1 axis might be a potential therapeutic target for the recovery of TIE2-mutation causing VMs.Graphical