The prognostic significance of vasohibin 1–associated angiogenesis in patients with hepatocellular carcinoma

Murakami, Keigo; Kasajima, Atsuko; Kawagishi, Naoki; Sekiguchi, Satoshi; Fujishima, Fumiyoshi; Watanabe, Mika; Sato, Yasufumi; Ohuchi, Noriaki; Sasano, Hironobu

doi:10.1016/j.humpath.2013.10.028

Cited by 33 publications

(34 citation statements)

References 30 publications

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“…VASH1 is a negative feedback regulator of angiogenesis, whereas VASH2 promotes angiogenesis [25, 26]. Several studies have shown that VASH1 expression in HCC is associated with vascular invasion and poor prognosis [27, 28]. VASH may have different functions in HCC, and it is necessary to analyse its organ-specific functions.…”

Section: Discussionmentioning

confidence: 99%

Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesis

et al. 2016

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BackgroundKeratin (K) 19-positive hepatocellular carcinoma (HCC) is well known to have a higher malignant potential than K19-negative HCC: However, the molecular mechanisms involved in K19-mediated progression of HCC remain unclear. We attempted to clarify whether K19 directly affects cell survival and invasiveness in association with cellular senescence or epithelial-mesenchymal transition (EMT) in K19-positive HCC.MethodsK19 expression was analysed in 136 HCC surgical specimens. The relationship of K19 with clinicopathological factors and survival was analysed. Further, the effect of K19 on cell proliferation, invasion, and angiogenesis was examined by silencing K19 in the human HCC cell lines, HepG2, HuH-7, and PLC/PRF/5. Finally, we investigated HCC invasion, proliferation, and angiogenesis using K19-positive HCC specimens.ResultsAnalysis of HCC surgical specimens revealed that K19-positive HCC exhibited higher invasiveness, metastatic potential, and poorer prognosis. In vitro experiments using the human HCC cell lines revealed that K19 silencing suppressed cell growth by inducting apoptosis or upregulating p16 and p27, resulting in cellular senescence. In addition, transfection with K19 siRNA upregulated E-cadherin gene expression, significantly inhibited the invasive capacity of the cells, downregulated angiogenesis-related molecules such as vasohibin-1 (VASH1) and fibroblast growth factor 1 (FGFR1), and upregulated vasohibin-2 (VASH2). K19-positive HCC specimens exhibited a high MIB-1 labelling index, decreased E-cadherin expression, and high microvessel density around cancer foci.ConclusionK19 directly promotes cancer cell survival, invasion, and angiogenesis, resulting in HCC progression and poor clinical outcome. K19 may therefore be a novel drug target for the treatment of K19-positive HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2949-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesis

et al. 2016

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“…Kitajima and colleagues [17] found that overexpression of Vasohibin-1 in colon cancer cells increased malignant potential and promoted metastasis. There were also reports about high Vasohibin-1 expression presented worse tumor clinicopathological characteristics in lung cancer [18], renal cancer [19], hepatocellular cancer [20], and prostate cancer [21]. Therefore, Vasohibin-1 might be a molecular marker of Fig.…”

Section: Discussionmentioning

confidence: 95%

The effect of Vasohibin-1 expression and tumor-associated macrophages on the angiogenesis in vitro and in vivo

Shen

Yan

et al. 2015

Tumor Biol.

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Vasohibin-1 is an intrinsic inhibitor of angiogenesis induced by VEGF-A. However, there little is known about the relationship between Vasohibin-1 expression, angiogenesis, and tumor-associated macrophages (TAMs). Vasohibin-1 expression, VEGF-A expression, microvessel density (MVD) marked with CD34, and density of cells marked with CD68 were measured in 111 paraffin-embedded tissues of gastric cancer by immunohistochemistry. The length of tube forming structures of endothelial cells and mobility rate of gastric cancer cells in Matrigel were tested by three-dimensional live cell imaging system. The effect of TAMs on the tumor growth, MVD, and Vasohibin-1 expression was measured by nude mice tumor genesis assay in vivo. We found that high Vasohibin-1 protein expression correlated significantly with worse TNM stage (P=0.002), metastatic lymph node (P= 0.014), distant metastasis (P = 0.022), overall survival (P<0.001), and progression-free survival (P<0.001) compared to those with low Vasohibin-1 expression. Vasohibin-1 protein expression had statistical correlation with the MVD (r = 0.860, P < 0.001), density of CD68 + cells (r = 0.882, P<0.001), and VEGF-A expression (r=0.719, P<0.001) in the gastric cancer tissues. Decreasing Vasohibin-1 expression with siRNA increased the length of tube forming structures of endothelial cells in co-culture with endothelial cells (EAhy923), macrophages, and gastric cancers (Hs746T). Tumor volume (P=0.001), Vasohibin-1 (P<0.001), and VEGF-A (P <0.001) expression in mice inoculated with AGS and THP (10:1) was significantly higher than that with AGS alone (P=0.001). Vasohibin-1 protein expression had statistical correlation with VEGF expression (r=0.786, P<0.001) and MVD (r=0.496, P= 0.014) in gastric xenografted tumor. Therefore, Vasohibin-1 might be a potential marker of worse prognosis and therapeutic target in gastric cancer. Vasohibin-1 might play an important role in the process of angiogenesis regulated by TAMs.

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“…Recently, associations have been reported between VASH1 expression and prognosis of patients with various types of cancer (8)(9)(10)(11)(12)(13)(14)(15). For example, in prostate cancer and non-small cell lung cancer, VASH1 expression was associated with tumour progression, and high VASH1 expression was a negative predictor, with specific VASH1 expression in tumour-associated endothelial cells being reported (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that VASH1 expression in tumour blood vessels is associated with VEGF and FGF2 expression in tumour cells (7). VASH1 expression in tumour blood vessels is associated with the clinical outcomes of various types of cancers, such as breast cancer, hepatocellular carcinoma, non-small cell lung cancer, prostate cancer, renal cell carcinoma and upper urinary tract urothelial carcinoma (8)(9)(10)(11)(12)(13)(14)(15). Conversely, VASH1 expression in tumour cells, but not in tumour blood vessels, is associated with clinical outcomes of colorectal cancer (16).…”

mentioning

confidence: 99%

Vasohibin-1 as a Novel Prognostic Factor for Head and Neck Squamous Cell Carcinoma

Torii

Hida

Shindoh

et al. 2017

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The prognostic significance of vasohibin 1–associated angiogenesis in patients with hepatocellular carcinoma

Cited by 33 publications

References 30 publications

Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesis

Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesis

The effect of Vasohibin-1 expression and tumor-associated macrophages on the angiogenesis in vitro and in vivo

Vasohibin-1 as a Novel Prognostic Factor for Head and Neck Squamous Cell Carcinoma

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