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WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression.

ABSTRACT: Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by poor prognosis and a low survival rate. VEGF-A is the most established angiogenic factor involved in the angiogenic-regulated tumor progression. WISP-1/CCN4 is an extracellular matrix-related protein that belongs to the Cyr61, CTGF, Nov (CCN) family and regulates many biological functions, such as angiogenesis. Previous studies indicated the role of WISP-1 in tumor progression. However, the angiogenic property of WISP-1 in the cancer microenvironment has never been discussed. Here, we provide novel insights regarding the role of WISP-1 in the angiogenesis through promoting VEGF-A expression. In this study, the correlation of WISP-1 and VEGF-A was confirmed by IHC staining of specimens from patients with OSCC. In vitro results indicated that WISP-1 induced VEGF-A expression via the integrin ?v?3/FAK/c-Src pathway, which transactivates the EGFR/ERK/HIF1-? signaling pathway in OSCC. This pathway in turn induces the recruitment of endothelial progenitor cells and triggers the neovascularization in the tumor microenvironment. Our in vivo data revealed that tumor-secreted WISP-1 promoted the angiogenesis through VRGF expression and increased angiogenesis-related tumor growth. Our study offers new information that highlights WISP-1 as a potential novel therapeutic target for OSCC.

SUBMITTER: Chuang JY

PROVIDER: S-EPMC4414186 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression.

Chuang Jing-Yuan JY Chen Po-Chun PC Tsao Ching-Wen CW Chang An-Chen AC Lein Ming-Yu MY Lin Ching-Chia CC Wang Shih-Wei SW Lin Chiao-Wen CW Tang Chih-Hsin CH

Oncotarget 20150201 6

Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by poor prognosis and a low survival rate. VEGF-A is the most established angiogenic factor involved in the angiogenic-regulated tumor progression. WISP-1/CCN4 is an extracellular matrix-related protein that belongs to the Cyr61, CTGF, Nov (CCN) family and regulates many biological functions, such as angiogenesis. Previous studies indicated the role of WISP-1 in tumor progression. Howeve ...[more]

PMID: 25738362

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Project description:Non‑small cell lung cancer (NSCLC) accounts for over 80% of all diagnosed lung cancer cases. Lung cancer is the leading cause of cancer‑related deaths worldwide. Most NSCLC cells overexpress vascular endothelial growth factor‑A (VEGF‑A) which plays a pivotal role in tumour angiogenesis. Anti‑angiogenic therapies including VEGF‑A neutralisation have significantly improved the response rates, progression‑free survival and overall survival of patients with NSCLC. However, the median survival of these patients is shorter than 18 months, suggesting that NSCLC cells secrete VEGF‑independent angiogenic factors, which remain unknown. We aimed to explore these factors in human NSCLC cell lines, A549, Lu99 and EBC‑1 using serum‑free culture, to which only EBC‑1 cells could adapt. By mass spectrometry, we identified 1,007 proteins in the culture supernatant derived from EBC‑1 cells. Among the identified proteins, interleukin‑8 (IL‑8), macrophage migration inhibitory factor (MIF), galectin‑1, midkine (MK), IL‑18, galectin‑3, VEGF‑A, hepatoma‑derived growth factor (HDGF), osteopontin (OPN), connective tissue growth factor (CTGF) and granulin (GRN) are known to be involved in angiogenesis. Tube formation, neutralisation and RNA interference assays revealed that VEGF‑A and HDGF function as angiogenic factors in EBC‑1 cells. To confirm whether VEGF‑A and HDGF also regulate angiogenesis in the other NSCLC cell lines, we established a novel culture method. NSCLC cells were embedded in collagen gel and cultured three‑dimensionally. Tube formation, neutralisation and RNA interference assays using the three‑dimensional (3D) culture supernatant showed that VEGF‑A and HDGF were not angiogenic factors in Lu99 cells. By gene microarray in EBC‑1 and Lu99 cells, we identified 61 mRNAs expressed only in Lu99 cells. Among these mRNAs, brain‑derived neurotrophic factor (BDNF), fibroblast growth factor‑2 (FGF‑2) and FGF‑5 are known to be involved in angiogenesis. Tube formation and neutralisation assays clarified that FGF‑2 functions as an angiogenic factor in Lu99 cells. These results indicate that HDGF enhances VEGF‑dependent angiogenesis and that FGF‑2 is a VEGF‑independent angiogenic factor in human NSCLC cells.

Dataset Information

WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression.

Publications

WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression.

Similar Datasets

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