Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis
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Cell & Bioscience Open Access
RESEARCH
Vascular NRP2 triggers PNET angiogenesis by activating the SSH1‑cofilin axis Xi Luo1*†, Jiang‑yi He1†, Jie Xu2, Shao‑yi Hu3, Bang‑hui Mo1, Qiu‑xia Shu1, Can Chen1, Yu‑zhu Gong1, Xiao‑long Zhao4, Gan‑feng Xie1* and Song‑tao Yu1*
Abstract Background: Angiogenesis is a critical step in the growth of pancreatic neuroendocrine tumors (PNETs) and may be a selective target for PNET therapy. However, PNETs are robustly resistant to current anti-angiogenic therapies that primarily target the VEGFR pathway. Thus, the mechanism of PNET angiogenesis urgently needs to be clarified. Methods: Dataset analysis was used to identify angiogenesis-related genes in PNETs. Immunohistochemistry was performed to determine the relationship among Neuropilin 2 (NRP2), VEGFR2 and CD31. Cell proliferation, woundhealing and tube formation assays were performed to clarify the function of NRP2 in angiogenesis. The mechanism involved in NRP2-induced angiogenesis was detected by constructing plasmids with mutant variants and performing Western blot, and immunofluorescence assays. A mouse model was used to evaluate the effect of the NRP2 antibody in vivo, and clinical data were collected from patient records to verify the association between NRP2 and patient prognosis. Results: NRP2, a VEGFR2 co-receptor, was positively correlated with vascularity but not with VEGFR2 in PNET tis‑ sues. NRP2 promoted the migration of human umbilical vein endothelial cells (HUVECs) cultured in the presence of conditioned medium PNET cells via a VEGF/VEGFR2-independent pathway. Moreover, NRP2 induced F-actin polymeri‑ zation by activating the actin-binding protein cofilin. Cofilin phosphatase slingshot-1 (SSH1) was highly expressed in NRP2-activating cofilin, and silencing SSH1 ameliorated NRP2-activated HUVEC migration and F-actin polymerization. Furthermore, blocking NRP2 in vivo suppressed PNET angiogenesis and tumor growth. Finally, elevated NRP2 expres‑ sion was associated with poor prognosis in PNET patients. Conclusion: Vascular NRP2 promotes PNET angiogenesis by activating the SSH1/cofilin/actin axis. Our findings dem‑ onstrate that NRP2 is an important regulator of angiogenesis and a potential therapeutic target of anti-angiogenesis therapy for PNET. Keywords: Neuropilin 2, Angiogenesis, SSH1, Cofilin, Pancreatic neuroendocrine tumor
*Correspondence: [email protected]; [email protected]; [email protected] † Xi Luo and Jiang-yi He contributed equally to this work. 1 Department of Oncology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China Full list of author information is available at the end of the article
Background Pancreatic neuroendocrine tumors (PNETs) are a rare cancer with an incidence of less than 1 per 100,000 persons per year and represent 1–2% of all pancreatic neoplasms [1]. In recent years, the incidence of PNETs has increased due to improvements in the pathologic and diagnostic techniques used to identify these tumors [2]. Sur
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