Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1‐mediated EMT

Zhang, Nan; Zhang, Shao-Qin; Wu, Wenda; Lu, Wen; Jiang, Mingting; Zheng, Ning; Huang, Jing; Wang, Long; Liu, Hekun; Zheng, Min; Wang, Jichuang

doi:10.1002/mc.23279

Cited by 16 publications

(12 citation statements)

References 44 publications

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“…The multi-targeted tyrosine kinase inhibitors like sorafenib and regorafenib have an established place in the systemic treatment for advanced HCC. It was reported that sorafenib (39) and regorafenib (40) could suppress the EMT of HCC cells. The expression levels of various molecules also change during EMT.…”

Section: Discussionmentioning

confidence: 99%

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

Fang

et al. 2021

J Gastrointest Oncol

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Background: The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness.However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC).Methods: Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative realtime PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules.Results: MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing.Conclusions: Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.

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Section: Discussionmentioning

confidence: 99%

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

Fang

et al. 2021

J Gastrointest Oncol

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“…Since DCA is an important risk factor for promoting VM formation in intestinal tumors, it is necessary to investigate the specific molecular mechanism of this strong stimulation effect. The mechanisms promoting VM formation are very complex, among which EMT is the most studied 21,50 . EMT is a dynamic dedifferentiation process, where epithelial cells lose their typical epithelial features, such as apical‐basal polarity and cell adhesion, and acquire mesenchymal cell traits, such as motility and invasion, by downregulating epithelial genes and upregulating mesenchymal genes 51,52 .…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms promoting VM formation are very complex, among which EMT is the most studied. 21 , 50 EMT is a dynamic dedifferentiation process, where epithelial cells lose their typical epithelial features, such as apical‐basal polarity and cell adhesion, and acquire mesenchymal cell traits, such as motility and invasion, by downregulating epithelial genes and upregulating mesenchymal genes. 51 , 52 EMT, which is involved in biological processes such as embryonic development, organ formation, and tissue regeneration in adults, has received more attention in the past two decades due to its potential role in the development of cancer.…”

Section: Discussionmentioning

confidence: 99%

“…The various molecular mechanisms are closely related to the VM formation of tumors, mainly involving vascular endothelial growth factor receptor 1/2 (VEGFR1/2), vascular endothelial (VE)‐cadherin, and matrix metalloproteinases (MMPs) 18,19 . Furthermore, epithelial‐mesenchymal transition (EMT) is considered a potential mechanism in VM formation and tumor metastasis 20,21 . VM formation is associated with tumor progression, invasion, and poor prognosis in CRC patients 22,23 .…”

Section: Introductionmentioning

confidence: 99%

“… 18 , 19 Furthermore, epithelial‐mesenchymal transition (EMT) is considered a potential mechanism in VM formation and tumor metastasis. 20 , 21 VM formation is associated with tumor progression, invasion, and poor prognosis in CRC patients. 22 , 23 However, the relationship between microbial metabolite DCA and VM in intestinal carcinogenesis has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Microbial metabolite deoxycholic acid promotes vasculogenic mimicry formation in intestinal carcinogenesis

Song

Chen

et al. 2021

Cancer Science

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A high‐fat diet (HFD) leads to long‐term exposure to gut microbial metabolite secondary bile acids, such as deoxycholic acid (DCA), in the intestine, which is closely linked to colorectal cancer (CRC). Evidence reveals that vasculogenic mimicry (VM) is a critical event for the malignant transformation of cancer. Therefore, this study investigated the crucial roles of DCA in the regulation of VM and the progression of intestinal carcinogenesis. The effects of an HFD on VM formation and epithelial‐mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in HFD‐treated Apcmin/+ mice. Then the effects of DCA on VM formation, EMT, and vascular endothelial growth factor receptor 2 (VEGFR2) signaling were evaluated in vitro and in vivo. Here we demonstrated that compared with a normal diet, an HFD exacerbated VM formation and EMT in CRC patients. An HFD could alter the composition of the gut microbiota and significantly increase the fecal DCA level in Apcmin/+ mice. More importantly, DCA promoted tumor cell proliferation, induced EMT, increased VM formation, and activated VEGFR2, which led to intestinal carcinogenesis. In addition, DCA enhanced the proliferation and migration of HCT‐116 cells, and induced EMT process and vitro tube formation. Furthermore, the silence of VEGFR2 reduced DCA‐induced EMT, VM formation, and migration. Collectively, our results indicated that microbial metabolite DCA promoted VM formation and EMT through VEGFR2 activation, which further exacerbated intestinal carcinogenesis.

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The cumulative antitumor effects of regorafenib and radiotherapy in hepatocellular carcinoma

Kuang,

Zhang,

Huang

et al. 2024

Molecular Carcinogenesis

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Regorafenib is a second‐line standard treatment for hepatocellular carcinoma (HCC). However, the efficacy of regorafenib is often limited due to drug resistance, individual differences among patients, and irrational drug use. Radiotherapy (RT) is an important method of localized HCC treatment, and combining RT with other therapies may exert a synergetic antitumor effect. Platelet‐derived growth factor receptor‐like (PDGFRL) is a tumor suppressor in various solid tumors. However, the function of PDGFRL in HCC is still unknown. In this study, we explored whether regorafenib and RT exert a synergetic effect on the treatment of HCC. The antitumor effect and mechanisms of the combination of regorafenib and RT were verified in a xenograft mouse model in vivo and in HCC cells in vitro. The combination treatment significantly inhibited cell proliferation and promoted apoptosis both in vitro and in vivo. PDGFRL, a potential target of regorafenib, was increased after cumulative treatment in HCC cells, and PDGFRL suppressed HCC cell proliferation and promoted apoptosis by inhibiting STAT3 pathway activation. Furthermore, the cumulative antitumor effect was dependent on the upregulated expression of PDGFRL and inhibition of STAT3 signaling pathway activation in HCC cells. This study increased the understanding of the molecular mechanism underlying the effect of regorafenib plus RT on HCC and provided a theoretical basis for the clinical practice of HCC.

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Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1‐mediated EMT

Cited by 16 publications

References 44 publications

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway

Microbial metabolite deoxycholic acid promotes vasculogenic mimicry formation in intestinal carcinogenesis

The cumulative antitumor effects of regorafenib and radiotherapy in hepatocellular carcinoma

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