Vasohibin‐2 is required for epithelial–mesenchymal transition of ovarian cancer cells by modulating transforming growth factor‐β signaling

Rie, Norita; Suzuki, Yasuhiro; Furutani, Yutaka; Takahashi, Kuniyuki; Yoshimatsu, Yasuhiro; Podyma‐Inoue, Katarzyna Α.; Watabe, Tetsuro; Sato, Yasufumi

doi:10.1111/cas.13157

Cited by 29 publications

(35 citation statements)

References 32 publications

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“…Our previous study showed that VASH2 modulates the metastatic potential of tumor cells through EMT by regulation of transforming growth factor beta (TGF‐β) signaling in ovarian cancer cells . We confirmed EMT markers in KPC cell lines and PDAC in KPC mice.…”

Section: Resultssupporting

confidence: 65%

“…Whereas VASH1 is expressed in endothelial cells, VASH2, which is more similar to the ancestral VASH, is not expressed in normal tissues except in the testis after birth . However, VASH2 is overexpressed in various cancer cells, and promotes tumor angiogenesis, accumulation of CAF and EMT of cancer cells . VASH2 knockdown or blockade in cancer cells including human ovarian cancer and hepatocellular carcinoma showed significant anticancer effects, and VASH2 has consequently been identified as a potential molecular target for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…9 However, VASH2 is overexpressed in various cancer cells, and promotes tumor angiogenesis, accumulation of CAF and EMT of cancer cells. [10][11][12][13][14] VASH2 knockdown or blockade in cancer cells including human ovarian cancer and hepatocellular carcinoma showed significant anticancer effects, 10,11,15,16 and VASH2 has consequently been identified as a potential molecular target for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

et al. 2019

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Vasohibin‐2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL‐KrasG12D; LSL‐Trp53R172H; Pdx‐1‐Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2‐knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2‐deficient mice, metastasis was significantly decreased in Vash2‐deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2‐induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2‐deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.

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Section: Resultssupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

et al. 2019

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“…Our results also demonstrated that VASH2 promotes tumor angiogenesis in hepatocellular carcinoma (HCC) cells . Subsequently, VASH2 was discovered as a promoter of EMT in human malignancies . VASH2 is localized in both cytosol and nucleus and is abnormally expressed in various types of cancer cells.…”

Section: Introductionsupporting

confidence: 57%

Vasohibin 2 promotes malignant behaviors of pancreatic cancer cells by inducing epithelial‐mesenchymal transition via Hedgehog signaling pathway

Zhang

Xue²,

Zhao

et al. 2018

Cancer Medicine

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BackgroundBased on previous findings, we hypothesized that Vasohibin 2 (VASH2) protein may induce epithelial‐mesenchymal transition (EMT) of pancreatic cancer (PC) cells by promoting the malignant behaviors of these cells. The present study aimed to test this hypothesis and explore the possible mechanisms involved.MethodsThe expression of VASH2 in PC tissues and cell lines was detected by quantitative real‐time PCR and Western blot. PC cells with overexpression or knockdown of VASH2 were used to examine the involvement of VASH2 in EMT by detecting the expression of epithelial (E‐cadherin) and mesenchymal (vimentin) markers and EMT‐related transcription factor ZEB1/2, in gemcitabine resistance and tumor cell invasion by apoptosis and invasion assays, and in cancer stem cell‐like phenotypes by detecting the proportion of CD24+CD44+ and side population (SP) cells in PC cells with flow cytometry. The impact of VASH2 overexpression and knockdown on components of the Hedgehog signaling pathway was also assessed.ResultsWe found that VASH2 was highly expressed in PC tissues and cells. It promoted the EMT of PC cells by altering ZEB1/2 expression. VASH2 also stimulated invasion and chemotherapeutic resistance of PC cells and increased the proportion of cancer stem‐like cells in PC cells. VASH2 did so by upregulating the expression of multiple molecules in the Hedgehog signaling pathway of PC cells.ConclusionVASH2 promotes malignant behaviors of PC cells by inducing EMT via activation of the Hedgehog signaling pathway.

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“…Transforming growth factor‐β (TGF‐β) signal is one of the most important pathways for CAF activation as well as tumor metastasis. VASH2 has been recently reported to be involved in epithelial–mesenchymal transition and the chemoprevention ability of cancer cells . We earlier found that VASH2 might accelerate TGF‐β‐induced epithelial–mesenchymal transition and invasiveness of ovarian cancer cells by modulating TGF‐β type I receptor expression, suggesting functional links between TGF‐β signal and VASH2 action in tumor progression …”

Section: Discussionmentioning

confidence: 93%

Requisite role of vasohibin‐2 in spontaneous gastric cancer formation and accumulation of cancer‐associated fibroblasts

et al. 2017

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The vasohibin (VASH) family consists of two genes, VASH1 and VASH2. VASH1 is mainly expressed in vascular endothelial cells and suppresses angiogenesis in an autocrine manner, whereas VASH2 is mainly expressed in cancer cells and exhibits pro‐angiogenic activity. Employing adenomatous polyposis coli gene mutant mice, we recently reported on the role of Vash2 in the spontaneous formation of intestinal tumors. In this study, we used K19‐Wnt1/C2mE (Gan) mice and examined the role of Vash2 in spontaneous gastric cancer formation. Gan mice spontaneously develop gastric tumors by activation of Wnt and prostaglandin E2 signaling pathways in gastric mucosa after 30 weeks of age. Expression of Vash2 mRNA was significantly increased in gastric tumor tissues compared with normal stomach tissues. When Gan mice were crossed with the Vash2‐deficient (Vash2 LacZ/LacZ) strain, gastric cancer formation was significantly suppressed in Vash2 LacZ/LacZ Gan mice. Normal composition of gastric mucosa was partially maintained in Vash2 LacZ/LacZ Gan mice. Knockout of Vash2 caused minimal reduction of tumor angiogenesis but a significant decrease in cancer‐associated fibroblasts (CAF) in tumor stroma. DNA microarray analysis and real‐time RT‐PCR showed that mRNA levels of epiregulin (Ereg) and interleukin‐11 (Il11) were significantly downregulated in gastric tumors of Vash2 LacZ/LacZ Gan mice. Furthermore, conditioned medium of gastric cancer cells stimulated migration of and α‐smooth muscle actin expression in fibroblasts, whereas conditioned medium of VASH2 knockdown cells attenuated these effects in vitro. These results suggest that VASH2 plays an important role in gastric tumor progression via the accumulation of CAF accompanying upregulation of EREG and IL‐11 expression.

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Vasohibin‐2 is required for epithelial–mesenchymal transition of ovarian cancer cells by modulating transforming growth factor‐β signaling

Cited by 29 publications

References 32 publications

Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Vasohibin 2 promotes malignant behaviors of pancreatic cancer cells by inducing epithelial‐mesenchymal transition via Hedgehog signaling pathway

Requisite role of vasohibin‐2 in spontaneous gastric cancer formation and accumulation of cancer‐associated fibroblasts

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