Neuropilin 1 modulates TGF-β1-induced epithelial–mesenchymal transition in non-small cell lung cancer

Ding, Zongli; Du, Wenwen; Li, Zhe; Zhang, Yang; Zhu, Jianjie; Zeng, Yuanyuan; Wang, Shengjie; Zheng, Yulong; Liu, Zeyi; Huang, Jianan

doi:10.21203/rs.2.10348/v1

Cited by 5 publications

(5 citation statements)

References 38 publications

(45 reference statements)

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“…In support, it has been reported that NRP-1 serving as a highaffinity receptor for TGF-bcan activate the TGF-b signaling in MDA-MB-231 cells (8,31). Interestingly, NRP-1 has also been reported to contribute to TGF−b−induced EMT and metastasis of non−small cell lung cancer cells by binding with TGFbRII (40). In the TGF−b signaling pathway, TGF−b binds to TGFbRII on the cell membrane to recruit TGFbRI and form a complex, leading to the phosphorylation of TGFbRI (41).…”

Section: Discussionmentioning

confidence: 77%

The miR-124-3p/Neuropilin-1 Axis Contributes to the Proliferation and Metastasis of Triple-Negative Breast Cancer Cells and Co-Activates the TGF-β Pathway

Zhang

Wang

et al. 2021

Front. Oncol.

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Triple-negative breast cancer (TNBC) accounts for 90% of breast cancer-associated mortality. Neuropilin-1 (NRP-1) acts as a non-tyrosine kinase receptor for several cellular signaling pathways involved in the proliferation and metastasis of cancer cells. However, the miRNAs that regulate NRP-1 expression and the underlying mechanisms in TNBC cells remain unclear. In the present study, we found that TNBC cells expressed higher levels of NRP-1 than non-TNBC cells. Stable transfectants depleted of NRP-1 were generated from two TNBC cell lines, human MDA-MB-231 and mouse 4T1 cells. NRP-1 depletion significantly suppressed the proliferation of TNBC cells by arresting the cell cycle at phase G0/G1 by upregulating p27 and downregulating cyclin E and cyclin-dependent kinase 2. NRP-1 depletion also repressed cell migration and epithelial-mesenchymal transition (EMT) by inducing the upregulation of E-cadherin and the downregulation of N-cadherin, matrix metalloproteinase (MMP)-2 and MMP-9, and reducing MMP-2 and MMP-9 activities as detected by gelatin zymography assay. By applying multiple miRNA-target prediction tools, we screened potential miRNAs with binding sites with the 3’-untranslated region of the NRP-1 gene and selected 12 miRNA candidates, among which miR-124-3p displayed the most vigorous activity to downregulate NRP-1 as validated by luciferase assay and miRNA transfection assay. By downregulating NRP-1, miR-124-3p mimics inhibited the proliferation, migration, and invasion of TNBC cells, and antagomiR-124-3p could partially abolish the effects of NRP-1 depletion. In the animal experiments, NRP-1 depletion inhibited tumorigenesis and liver metastasis of TNBC cells, while miR-124-3p mimics inhibited the growth of established TNBC tumors. In the mechanistic exploration, we revealed that NRP-1 co-interacted with transforming growth factor (TGF)-β to activate the TGF-β pathway, which regulates EMT-related molecules. In summary, the present results indicate that the miR-124-3p/NRP-1 axis contributes to the proliferation and metastasis of TNBC cells and co-activates the TGF-β pathway, suggesting that these molecules may present as potential therapeutic targets and valuable biomarkers for TNBC.

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Section: Discussionmentioning

confidence: 77%

The miR-124-3p/Neuropilin-1 Axis Contributes to the Proliferation and Metastasis of Triple-Negative Breast Cancer Cells and Co-Activates the TGF-β Pathway

Zhang

Wang

et al. 2021

Front. Oncol.

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“…NRP1 could promote tumor metastasis through several mechanisms, such as facilitate endothelial cell migration induced by VEGF [22][23][24], boost the migration and proliferation of tumor cells through autocrine Semaphorin 3A (Sema 3A) [25] and HGF/SF signaling [26], stimulate tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment [27], uphold dedifferentiation and propagation phenotypes of cancer cells [28], maintain the properties of cancer stem cells [29], and induce tumor immunosuppression signaling [8,30]. Furthermore, NRP1 had been shown to enhance EMT in oral squamous cell carcinoma and non-small cell lung cancer, thereby promoting cancer cell invasion and metastasis [31,32].…”

Section: Discussionmentioning

confidence: 99%

Neuropilin-1 predicts poor prognosis and promotes tumor metastasis through epithelial-mesenchymal transition in gastric cancer

Jin¹,

Ren²,

Chang³

et al. 2021

J. Cancer

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We aimed to determine whether Neuropilin-1 (NRP1) promotes gastric cancer (GC) metastasis by inducing epithelial-mesenchymal transition (EMT), and to clarify its regulatory mechanism. Using the data of GC patients in The Cancer Genome Atlas (TCGA) and Gene Tissue Expression (GTEx) databases, combined with the data of GC patients in our medical center, the effect of NRP1 on the prognosis of GC patients were analyzed. Then, we investigated the role of NRP1 in GC metastasis and its potential mechanism. The level of NRP1 was up-regulated in GC tissues and associated with poor prognosis of GC patients. The expression of NRP1 was closely related to maximum tumor diameter, invasion depth, lymphnode metastasis, distant metastasis, and advanced TNM stage, and was an independent prognostic factor for overall survival (OS) in GC patients. Besides, the results of in vitro indicated that NRP1 could induce EMT to promote the migration and invasion of GC cells by activating PI3K/Akt signaling pathway, and the HGF/c-Met axis was involved in this process. This study determined that NRP1 was a gene that promotes gastric cancer. NRP1 induced EMT to enhance the migration and invasion ability of GC cells by activating PI3K/Akt signaling pathway. NRP1 was an independent prognostic marker for OS in GC patients and expected to be a therapeutic target for GC patients.

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“…High stromal expression of Versican correlates with poor tumor differentiation, disease recurrence, advanced tumor stage, and lymph node metastases [44]. Neuropilin 1 (NRP1) modulates TGF-β1-induced epithelial-mesenchymal transition in NSCLC [45], and dual-targeting of EGFR and NRP1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant NSCLC [46]. NRP1 expression correlates with radio-resistance [47], and NRP1 antagonism in human cancer cells inhibits migration and enhances chemosensitivity [48,49].…”

Section: Discussionmentioning

confidence: 99%

Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer

Lohinai

Khazamipour

et al. 2021

Cancers

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Broad-spectrum therapeutics in non-small cell lung cancer (NSCLC) are in demand. Most human solid tumors express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that can be detected and targeted with recombinant VAR2CSA (rVAR2) proteins and rVAR2-derived therapeutics. Here, we investigated expression and targetability of oncofetal CS expression in human NSCLC. High oncofetal CS expression is associated with shorter disease-free survival and poor overall survival of clinically annotated stage I and II NSCLC patients (n = 493). Oncofetal CS qualifies as an independent prognosticator of NSCLC in males and smokers, and high oncofetal CS levels are more prevalent in EGFR/KRAS wild-type cases, as compared to mutation cases. NSCLC cell lines express oncofetal CS-modified proteoglycans that can be specifically detected and targeted by rVAR2 proteins in a CSA-dependent manner. Importantly, a novel VAR2-drug conjugate (VDC-MMAE) efficiently eliminates NSCLC cells in vitro and in vivo. In summary, oncofetal CS is a prognostic biomarker and an actionable glycosaminoglycan target in NSCLC.

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Neuropilin 1 modulates TGF-β1-induced epithelial–mesenchymal transition in non-small cell lung cancer

Cited by 5 publications

References 38 publications

The miR-124-3p/Neuropilin-1 Axis Contributes to the Proliferation and Metastasis of Triple-Negative Breast Cancer Cells and Co-Activates the TGF-β Pathway

The miR-124-3p/Neuropilin-1 Axis Contributes to the Proliferation and Metastasis of Triple-Negative Breast Cancer Cells and Co-Activates the TGF-β Pathway

Neuropilin-1 predicts poor prognosis and promotes tumor metastasis through epithelial-mesenchymal transition in gastric cancer

Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer

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