Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling

Yeh, Yu Wen; Cheng, Chien‐Chuan; Yang, Shu; Tseng, Chi Feng; Chang, Ting; Tsai, Sin Ying; Fu, Earl; Chiang, Chien Ping; Liao, Li Chuan; Tsai, Pei Wen; Yu, Yung Luen; Su, Jen Liang

doi:10.18632/oncotarget.13629

Cited by 41 publications

(44 citation statements)

References 67 publications

(75 reference statements)

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“…However, we and others did not detect VEGF receptors on the different RCC cell lines 56. VEGFC signaling in RCC depends on the VEGFR3 co-receptor neuropilin 2 57, and this autocrine loop probably maintains stemness as already described in skin cancers, and consequently, a low ability to proliferate 58. α 9 β 1 integrin was described as a VEGFC receptor mediating the migration of breast cancer cells 59, 60.…”

Section: Discussionmentioning

confidence: 47%

VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness

Ndiaye¹,

Dufies²,

Giuliano³

et al. 2019

Theranostics

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Hypoxic zones are common features of metastatic tumors. Due to inactivation of the von Hippel-Lindau gene ( VHL ), renal cell carcinomas (RCC) show constitutive stabilization of the alpha subunit of the hypoxia-inducible factor (HIF). Thus, RCC represents a model of chronic hypoxia. Development of the lymphatic network is dependent on vascular endothelial growth factor C (VEGFC) and lies at the front line of metastatic spreading. Here, we addressed the role of VEGFC in RCC aggressiveness and the regulation of its expression in hypoxia. Methods: Transcriptional and post transcriptional regulation of VEGFC expression was evaluated by qPCR and with reporter genes. The involvement of HIF was evaluated using a siRNA approach. Experimental RCC were performed with immuno-competent/deficient mice using human and mouse cells knocked-out for the VEGFC gene by a CRISPR/Cas9 method. The VEGFC axis was analyzed with an online available data base (TCGA) and using an independent cohort of patients. Results: Hypoxia induced VEGFC protein expression but down-regulated VEGFC gene transcription and mRNA stability. Increased proliferation, migration, over-activation of the AKT signaling pathway and enhanced expression of mesenchymal markers characterized VEGFC-/- cells. VEGFC-/- cells did not form tumors in immuno-deficient mice but developed aggressive tumors in immuno-competent mice. These tumors showed down-regulation of markers of activated lymphocytes and M1 macrophages, and up-regulation of M2 macrophages markers and programmed death ligand 1 (PDL1). Over-expression of lymphangiogenic genes including VEGFC was linked to increased disease-free and overall survival in patients with non-metastatic tumors, whereas its over-expression correlated with decreased progression-free and overall survival of metastatic patients. Conclusion: Our study revisited the admitted dogma linking VEGFC to tumor aggressiveness. We conclude that targeting VEGFC for therapy must be considered with caution.

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Section: Discussionmentioning

confidence: 47%

VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness

Ndiaye¹,

Dufies²,

Giuliano³

et al. 2019

Theranostics

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“…LAMA1, an extracellular glycoprotein of the laminin family, is an essential component of basement membranes, being involved in tumorigenesis and other biological processes [ 17 ]. VEGFC results in the promotion of angiogenesis and/or lymphangiogenesis [ 18 ]. Moreover, it has been reported that FLT4 significantly correlate with the different stages of cervical carcinogenesis [ 19 ]; the ligand of FLT4 might effecting tumor cells directly to affect cancer development and progression [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance in human breast cancer

Men

Jun

et al. 2017

Oncotarget

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was applied to analyze the association of ER signal pathway with the 10 DEGs. 3 significant genes (GFRA3, NPY1R and PTPRN2) were closely related to ER related pathway. These significant DEGs regulated many biological activities such as cell proliferation and survival, motility and migration, and tumor cell invasion. The interactions between these DEGs and drug resistance phenomenon need to be further elucidated at a functional level in further studies. Based on our findings, we believed that these DEGs could be therapeutic targets, which can be explored to develop new treatment options.

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“…A previous study revealed that the vascular endothelial growth factor receptor (VEGFR) signaling pathway plays a major role in angiogenesis (20) and that KRAS plays a key role in VEGF signaling (21). To ascertain these results, we knocked down KRAS using shRNA and determined the expression level of VEGFA in HCT116 cells.…”

Section: Kras Is a Key Regulator In Vegf-related Angiogenesismentioning

confidence: 98%

Overexpression of miR-19a inhibits colorectal cancer angiogenesis by suppressing KRAS expression

2017

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The microRNA miR-19a is closely related to tumor formation and development and is a key oncogene. Previous studies have demonstrated that miR-19a is upregulated in multiple cancer types, including colorectal cancer (CRC). However, most of these experiments were performed in vitro, and consequently, the mechanisms underlying the effects of miR-19a on CRC are still unclear. Therefore, in the present study, we investigated the role of miR-19a in the development of solid CRC tumors. We generated KRAS 3'UTR-Mut by deleting the predicted binding site for miR-19a in KRAS, and observed that the expression of a reporter gene containing the KRAS 3'UTR in HCT116 cells was suppressed by miR-19a, while that of a reporter gene with mutant KRAS 3'UTR was unaffected by miR-19a. We observed that high miR-19a levels reduced KRAS expression. In the tube formation assay, overexpression of miR-19a exhibited anti-angiogenesis effects, which were rescued by KRAS expression. We established a nude mouse xenograft model to investigate the specific role of miR-19a in solid tumors. The results revealed that the sizes of xenograft tumors and density of blood vessels developed from HCT116 cells expressing miR-19a were smaller/lower compared with those of the control. KRAS and VEGFA levels were also reduced. In conclusion, our results revealed that miR-19a overexpression supressed KRAS expression and angiogenesis in CRC, indicating possibilities of using miR-19a in future therapeutic applications.

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Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling

Cited by 41 publications

References 67 publications

VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness

VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness

Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance in human breast cancer

Overexpression of miR-19a inhibits colorectal cancer angiogenesis by suppressing KRAS expression

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