Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway

Zhang, Jingtao; Sun, Wei; Zhang, Wenzhong; Ge, Chao; Liu, Zhongyan; Zhao, Zhenze; Lu, Xing-Sui; Fan, Yonggang

doi:10.1186/1471-2407-14-193

Cited by 45 publications

(46 citation statements)

References 46 publications

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“…NCTD is the demethylated analog of cantharidin isolated from blister beetles, and it is reported to possess anticancer activity but less nephrotoxicity than cantharidin (10). There is increasing evidence that NCTD inhibits the proliferation, induces apoptosis (19,20,(22)(23)(24)(25)(26)(27)(28)30), blocks the cell cycle (20,21,26), suppresses invasion, metastasis (27,29), angiogenesis (27), and possess anticancer activity via MAPK, TnR3, VEGFR2/MEK/ERK, PI3-K/MMPs/Ln-5γ2 signaling, DNA replication, or ROS-mediated mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Norcantharidin blocks Wnt/β-catenin signaling via promoter demethylation of WIF-1 in glioma

Xie

Wan

et al. 2016

Oncology Reports

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Glioma is one of the most common primary intracranial tumors, and the prognosis is poor even though much treatment management is employed. Wnt/β-catenin signaling has been reported to be associated with glioma. Norcantharidin (NCTD) is the demethylated analog of cantharidin isolated from blister beetles, and it is reported to possess anticancer activity but less nephrotoxicity than cantharidin. Accordingly, we aimed to investigate NCTD as an anti-neoplastic drug that inhibits the Wnt/β‑catenin pathway via promoter demethylation of Wnt inhibitory factor-1 (WIF-1) in glioma growth in vitro. In the present study, we report that NCTD inhibited cell proliferation, induced apoptosis and cell cycle arrest, and suppressed cell migration and invasion in vitro. Moreover, we observed that the expression levels of WIF-1 mRNA and protein in the NCTD-treated cells were increased significantly compared with these levels in the negative control (NC) cells. Promoter demethylation was observed in the NCTD‑treated cells. In contrast, aberrant methylation was observed in the NC cells. Additionally, more investigation revealed that NCTD suppressed activity of Wnt/β-catenin signaling and transcription of β-catenin/TCF-4. Furthermore, the expression of apoptosis-related proteins Bcl-2 and cleaved caspase-3 indicated significant cell apoptosis. We provide initial evidence that NCTD reactivates WIF-1 from a methylation state, and downregulates canonical Wnt/β-catenin signaling. Our findings revealed that NCTD is effective for glioma in vitro and may be a new therapeutic option in vivo.

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Section: Discussionmentioning

confidence: 99%

Norcantharidin blocks Wnt/β-catenin signaling via promoter demethylation of WIF-1 in glioma

Xie

Wan

et al. 2016

Oncology Reports

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“…It has been shown that NCTD inhibits angiogenesis [29,30], induces DNA damage and ROS-mediated mitochondrial dysfunction [31,32], suppresses proliferation [33][34][35], invasion and migration [36], increases apoptosis [37][38][39], possesses anticancer activity via TR3, PKC, PI3-K/MMPs/ Ln-5c2, MAPK [40], VEGFR2/MEK/ERK [41] signal pathways and so on.…”

Section: Discussionmentioning

confidence: 99%

Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer

Xie

Zhang

et al. 2015

Med Oncol

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Wingless-type (Wnt) family of secreted glycoproteins is a group of signal molecules implicated in oncogenesis. Abnormal activation of Wnt signal pathway is associated with a variety of human cancers, including non-small cell lung cancer (NSCLC). Wnt antagonists, such as the secreted frizzled-related protein (SFRP) family, Wnt inhibitory factor-1 (WIF-1) and cerberus, inhibit Wnt signal pathway by directly binding to Wnt molecules. Norcantharidin (NCTD) is known to possess anticancer activity but less nephrotoxicity than cantharidin. In this study, we found that NCTD inhibited cell proliferation, induced apoptosis, arrested cell cycle and suppressed cell invasion/migration in vitro. Additionally, Wnt signal pathway transcription was also suppressed. NCTD treatment blocked cytoplasmic translocation of beta-catenin into the nucleus. Alterations of apoptosis-related proteins, such as Bax, cleaved caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic), had been detected. Furthermore, the expression levels of WIF-1 and SFRP1 were significantly increased in NCTD-treated groups compared with negative control (NC) groups. Abnormal methylation was observed in NC groups, while NCTD treatment promoted WIF-1 demethylation. The present study revealed that NCTD activated WIF-1 via promoter demethylation, inhibiting the canonical Wnt signal pathway in NSCLC, which may present a new therapeutic target in vivo.

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“…In recent years, studies have found a novel tumor blood supply pattern, called vasculogenic mimicry (VM), which occurs in certain highly aggressive malignancies, and is closely related to poor clinical results and poor prognosis [13][14][15][16]. It has become one of the potential targets for anticancer therapy [17][18][19][20]. We previously reported that VM exists in GBC and is associated with the patient's poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported that VM exists in GBC and is associated with the patient's poor prognosis. The mechanism of VM formation in GBC may be closely related to the activation of PI3K/MMPs/Ln-5γ2 and/or EphA2/FAK/Paxillin signaling pathways [14][15][16][17][18][19]. Recently, it was reported that CAFs can promote VM formation in hepatocellular cancer (HCC) [21].…”

Section: Introductionmentioning

confidence: 99%

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth of gallbladder cancers via upregulating the expression of NOX4, a poor prognosis factor, through activating IL-6-JAK-STAT3 signal pathway

Pan

Wang

Ansari

et al. 2020

Preprint

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Background Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism.Methods A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (-) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored.Results GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the up-regulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway.Conclusions GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is over-expressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

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Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway

Cited by 45 publications

References 46 publications

Norcantharidin blocks Wnt/β-catenin signaling via promoter demethylation of WIF-1 in glioma

Norcantharidin blocks Wnt/β-catenin signaling via promoter demethylation of WIF-1 in glioma

Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth of gallbladder cancers via upregulating the expression of NOX4, a poor prognosis factor, through activating IL-6-JAK-STAT3 signal pathway

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