Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.
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, wound-healing 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 tissues. 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 polymerization 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 expression was associated with poor prognosis in PNET patients. Conclusion Vascular NRP2 promotes PNET angiogenesis by activating the SSH1/cofilin/actin axis. Our findings demonstrate that NRP2 is an important regulator of angiogenesis and a potential therapeutic target of anti-angiogenesis therapy for PNET.
BackgroundThe poor immunogenicity of solid tumors limits the efficacy ofanti-programmed cell death protein 1 (anti-PD1)-based immune checkpoint blockade (ICB); thus, less than 30% of patients with cancer exhibit a response. Currently, there is still a lack of effective strategies for improving tumor immunogenicity.MethodsThe antitumor effect of ultrasound-stimulated nanobubbles (USNBs) alone and in combination with an anti-PD1 antibody was evaluated in RM1 (prostate cancer), MC38 (colon cancer) and B16 (melanoma) xenograft mouse models. The phenotypes of antigen-presenting cells and CD8+ T cells were evaluated by flow cytometry. Damage-associated molecular pattern (DAMP) release, antigen release and tumor cell necrosis were assessed via western blot, flow cytometry, transmission electron microscopy and confocal microscopy.ResultsUSNB promoted the infiltration and antitumor activity of CD8+ T cells. The combination of USNB and anti-PD1 blockade improved systemic antitumor immunity and resulted in an abscopal effect and long-term immune memory protection after complete tumor remission. Mechanistically, tumor-targeting USNB induced tumor cell necrosis through an ultrasound-mediated cavitation effect, which significantly increased DAMP release and tumor antigen presentation, consequently sensitizing tumors to ICB treatment.ConclusionThe administration of USNB increased tumor immunogenicity by remodeling the tumor-immune microenvironment, providing a promising strategy for sensitizing poorly immunogenic solid tumors to immunotherapy in the clinic.
Genes involved in the neuronal biological process are enriched in nasopharyngeal carcinoma. Overexpression of NgR3 correlates with poor prognosis of nasopharyngeal carcinoma. NgR3 promotes NPC cell migration by downregulating E-cadherin. NgR3 promotes NPC cell polarity and enhances the formation of NPC cell pseudopodia by activating FAK/Src pathway.
Background Angiogenesis is a critical step in pancreatic neuroendocrine tumour (PNET) growth and may be a selective target for PNET therapy. However, PNET is robustly resistant to current antiangiogenic therapies which primarily target the VEGFR pathway. Thus, PNET angiogenesis mechanism was urgently to be clarified. Methods Dataset analysis was used to identify PNET angiogenesis related genes. Immunohistochemistry was performed to determine relation among Neuropilin 2 (NRP2), VEGFR2 and CD31. Cell proliferation, wound-healing and tube formation assay were investigated to clarify the function of NRP2 in angiogenesis. The mechanism involved in NRP2 inducing angiogenesis was detected by mutant construction, Western blot, and immunofluorescence assay. In vivo, mice model was performed to evaluate the effect of NRP2 antibody, and clinical data was recruited to verify association between NRP2 and patients prognosis. Results NRP2, a VEGFR2 co-receptor, positively correlated with vascularity rather than with VEGFR2 in PNET tissues. NRP2 promoted PNET cell medium-treated HUVEC cell migration via a VEGF/VEGFR2-independent pathway. Moreover, NRP2 induced F-actin polymerization by activating the actin-binding protein cofilin. Mechanistically, cofilin phosphatase slingshot-1 (SSH1) was highly expressed involved in NRP2-activating cofilin. Silencing SSH1 rescued NRP2-activated HUVEC cell migration and F-actin polymerization. Furthermore, blocking NRP2 in vivo suppressed PNET angiogenesis and tumour growth. High NRP2 expression was associated with poor prognosis in PNET patients. Conclusion Vascular NRP2 promotes PNET angiogenesis via activating SSH1/cofilin/actin axis. Our findings demonstrate NRP2 to be an important regulator of angiogenesis and potential therapeutic target of anti-angiogenesis therapy for PNET.
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