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Abstract Disintegrin-metalloproteinase 15(ADAM15), a member of disintegrin metalloproteinases (ADAMs), plays important roles in various cancer types. However, the underlying ADAM15 functioning in lung cancer is still unclear. In the present study, we find that ADAM15 regulates the epidermal growth factor receptor/focal adhesion kinase (EGFR/FAK) signalling pathway by interactions with integrins. Integrin αV is involved in ADAM15-mediated FAK signalling. Further, we find that ADAM15 and CD151 were co-expressed, and the presence of ADAM15 affected the integrin α3/α6-related EGFR signalling pathway by cooperating with CD151. In addition, we also prove the effect of ADAM15 on proliferation in nude mice. Finally, we show that ADAM15 is a direct target of miR-204-5p by luciferase reporter assays, qRT-PCR and western blot analyses. Our findings provide molecular and cellular evidence that ADAM15 promotes cell proliferation and metastasis in NSCLC, which might provide a potential target for NSCLC treatment.

Abstract Lung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics.

Abstract Neovascularization is a key factor that contributes to tumor metastasis, and vasculogenic mimicry (VM) is an important form of neovascularization found in highly invasive tumors, including lung cancer. Despite the increasing number of studies focusing on VM, the mechanisms underlying VM formation remain unclear. Herein, our study explored the role of the HIF-1α/NRP1 axis in mediating lung adenocarcinoma metastasis and VM formation. HIF-1α, NRP1 expression, and VM in lung adenocarcinoma (LUAD) patient samples were examined by immunohistochemical staining. Quantitative real-time (qRT-PCR), western blot, transwell assay, wound healing assay, and tube formation assay were performed to verify the role of HIF-1α/NRP1 axis in LUAD metastasis and VM formation. ChIP and luciferase reporter assay were used to confirm whether NRP1 is a direct target of HIF-1α. In LUAD tissues, we confirmed a positive relationship between HIF-1α and NRP1 expression. Importantly, high HIF-1α and NRP1 expression and the presence of VM were correlated with poor prognosis. We also found that HIF-1α could induce LUAD cell migration, invasion, and VM formation by regulating NRP1. Moreover, we demonstrated that HIF-1α can directly bind to the NRP1 promoter located between −2009 and −2017 of the promoter. Mechanistically, MMP2, VE-cadherin, and Vimentin expression were affected. HIF-1α plays an important role in inducing lung adenocarcinoma cell metastasis and VM formation via upregulation of NRP1. This study highlights the potential therapeutic value of targeting NRP1 for suppressing lung adenocarcinoma metastasis and progression.