Vascular Endothelial Growth Factor-C Upregulates Cortactin and Promotes Metastasis of Esophageal Squamous Cell Carcinoma

Su, Chih-Ming; Su, Yea-Huey; Chiu, Ching-Feng; Chang, Yi Wen; Hong, Chih Chen; Yu, Yang; Ho, Yuan Soon; Wu, Chih Hsiung; Yen, Chia Sheng; Su, Jen Liang

doi:10.1245/s10434-014-4009-7

Cited by 18 publications

(10 citation statements)

References 34 publications

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“…Furthermore, in our previous study it was demonstrated that SIX1, a developmental transcription factor predicted to represent a potential target gene of miR-23b-3p, may enhance the expression of VEGF-C in OS (2). VEGF-C promotes cervical cancer cell invasion and migration (48), and enhances the metastatic ability of esophageal carcinoma (49), whereas knocking down VEGF-C suppresses gastric cancer cell migration (50). Therefore, VEGF-C was investigated in the present study, and the results demonstrated that miR-23b-3p is associated with decreased expression levels of VEGF-C in U2OS cells.…”

Section: Discussionmentioning

confidence: 85%

miR‑23b‑3p promotes the apoptosis and inhibits the proliferation and invasion of osteosarcoma cells by targeting SIX1

et al. 2018

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Osteosarcoma (OS) is the most common primary malignant bone tumor and the third most common cancer that occurs during childhood and adolescence. Increasing evidence has suggested that microRNA (miR)-23b-3p has an important role in OS tumorigenesis; however, the underlying molecular mechanisms remain unknown. The aim of the present study was to investigate the expression levels of miR-23b-3p and sine oculis homeobox homolog 1 (SIX1) in OS tissues and cell lines (MG-63, SaOS-2 and U2OS), as well as to observe the effects of miR-23b-3p on U2OS cell viability, cell cycle, apoptosis and invasive ability. The results revealed that the expression levels of miR-23b-3p were significantly decreased in OS tissues and cell lines compared with tumor-adjacent normal tissues and a non-cancerous human fetal osteoblastic cell line (hFOB1.19). To investigate the underlying mechanisms of miR-23b-3p in OS tumorigenesis and progression, human U2OS cell lines over-or under expressing miR-23b-3p were established. The effects of miR-23b-3p on U2OS cell viability, cell cycle, apoptosis and invasion properties were determined by performing Cell Counting Kit-8, flow cytometry and Transwell invasion assays. miR-23b-3p was revealed to suppress cell viability, proliferation and invasion, and to enhance the levels of cell apoptosis. Furthermore, SIX1 mRNA and protein expression levels in OS tissues and cell lines were significantly upregulated when compared with tumor-adjacent normal tissues and hFOB 1.19 cells, which suggested that SIX1 expression levels may be inversely associated with miR-23b-3p levels in OS. Luciferase reporter system analysis demonstrated that miR-23b-3p binds to the SIX1 3'-untranslated region. miR-23b-3p downregulation contributed to SIX1 upregulation, which facilitated the potentiation of cyclin D1 and vascular endothelial growth factor-C expression levels, as well as the inhibition of caspase-3 expression. Collectively, these results suggested that miR-23b-3p is downregulated and SIX1 is upregulated in OS cells, and that miR-23b-3p inhibition may suppress the proliferation and invasion of OS cells, and contribute to cell apoptosis via negative regulation of SIX1. miR-23b-3p/SIX1 may therefore represent a potential target for the treatment of OS.

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Section: Discussionmentioning

confidence: 85%

miR‑23b‑3p promotes the apoptosis and inhibits the proliferation and invasion of osteosarcoma cells by targeting SIX1

et al. 2018

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“…Tumour angiogenesis involves not only the overexpression of angiogenic factors, but also the low expression of angiogenic inhibitors and an imbalance between the two (118). VEGF is an important pro-angiogenic factor and the most powerful pro-vascular endothelial growth cytokine that promotes cell division and vascular construction from esophageal cancer and ovarian cancer, increases microvascular permeability and promotes endothelial cell migration (119)(120)(121).…”

Section: Erk/mapk Signalling In Tumour Invasion and Metastasismentioning

confidence: 99%

ERK/MAPK signalling pathway and tumorigenesis (Review)

et al. 2020

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Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised. signalling elements that regulate basic processes including cell proliferation, differentiation and stress responses (1-3). These cascades transmit signals through sequential activation of three to five layers of protein kinases known as MAPK kinase kinase kinase (MAP4K), MAPK kinase kinase (MAP3K), MAPK kinase (MAPKK), MAPK and MAPK-activated protein kinases (MAPKAPK). The first three central layers are considered as a basic core unit, while the last two layers appear in some cascades and can vary among cells and stimuli. Four MAPK cascades have been defined based on the components in the MAPK layer: ERK1/2, c-Jun N-terminal kinase (JNK), p38 MAPK and ERK5. This review focuses on the ERK cascade (4-6) which involves several kinases in the MAP3K layer (mainly Rafs), including Ras/Raf/MAPK (MEK) 1/2 at the MAPKK layer, ERK1/2 at the MAPK layer and several MAPKAPKs in the next layer (ribosomal s6 kinases, MAP kinase-interacting serine/threonine-protein kinases, mitogen-and stress-activated protein kinases and cytosolic phospholipase A2). ERK cascades are highly regulated cascades that are responsible for basic cellular processes, including cell proliferation and differentiation. These regulatory factors affect bispecific phosphatases (7-10), scaffold proteins (11-14), signal duration and intensity (15), and the dynamic subcellular localization of cascade components (16,17). Due to the importance of the ERK cascade, ERK disorders are harmful to cells and ultimately to the body. Excessive activation of upstream proteins and kinases in the ERK pathway has been shown to induce various diseases, including cancer, inflammation, developmental disorders and neurological disorders (18-22). Since ERK1 and ERK2 are very similar, the singular form of ERK is used in this review, although two subtypes exist. Dysfunction in the Ras-ERK pat...

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“…Among these VEGF-VEGFR complexes, VEGF-C binds to both VEGFR2 and VEGFR3 and further enhances diverse biological effects, such as cell growth, proliferation, mobility and invasiveness, to promote angiogenesis, metastasis and tumor progression [12–14]. Previous studies reported that activation of the VEGF-C/VEGFR3 signaling pathway increases cell migration and invasion to promote cancer metastasis, and a high expression level of VEGF-C has been correlated with the shortest survival time in lung cancer [10, 15] and esophageal squamous cell carcinoma [16, 17]. Elevated VEGF-C expression is also found in the lymph nodes of patients with metastatic melanoma [18].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Vascular endothelial growth factor-C (VEGF-C) has been implicated in epithelial-mesenchymal transition (EMT) processes and various human cancers, including skin cancer. Skin cancer is an aggressive human malignancy with increasing incidence worldwide; however, the underlying mechanisms involved in VEGF-C-induced skin cancer stemness and metastasis remain unclear. Here, we report that VEGF-C enhances skin cancer migration, invasion and stemness through Slug up-regulation. Oncomine database analysis indicated that the KRAS/MAPK (mitogen-activated protein kinases) pathway and YAP1 (yes-associated protein 1) expression are positively correlated with metastatic skin cancer. We show that VEGF-C triggers the activation of KRAS/MAPK signaling to increase YAP1 and downstream Slug expression, which are suppressed by an anti-VEGFR3 (VEGF receptor 3) peptide, a specific peptide targeting VEGFR3. The VEGF-C-induced migration, invasion and stemness of skin cancer cells are also abrogated by the anti-VEGFR3 peptide. Based on these data, we reveal the role of the VEGF-C/VEGFR3-mediated KRAS/MAPK-YAP1/Slug pathway in skin cancer progression and propose that the VEGF-C/VEGFR3 axis is a promising target for the anti-VEGFR3 peptide.

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Vascular Endothelial Growth Factor-C Upregulates Cortactin and Promotes Metastasis of Esophageal Squamous Cell Carcinoma

Cited by 18 publications

References 34 publications

miR‑23b‑3p promotes the apoptosis and inhibits the proliferation and invasion of osteosarcoma cells by targeting SIX1

miR‑23b‑3p promotes the apoptosis and inhibits the proliferation and invasion of osteosarcoma cells by targeting SIX1

ERK/MAPK signalling pathway and tumorigenesis (Review)

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

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