HMGA2 promotes vasculogenic mimicry and tumor aggressiveness by upregulating Twist1 in gastric carcinoma

Sun, Junying; Sun, Baocun; Sun, Ryan; Zhu, Dongwang; Zhao, Xiulan; Zhang, Yanhui; Dong, Xueyi; Che, Na; Li, Jing; Liu, Fang; Zhao, Nan; Wang, Yong; Zhang, Danfang

doi:10.1038/s41598-017-02494-6

Cited by 41 publications

(35 citation statements)

References 43 publications

(52 reference statements)

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“…The present results confirmed TNC upregulation in glioma tissues, especially in GBM tissues and show that 34% of samples were VM-positive, as reported previously 32 . We assessed VM formation in glioma cell lines and low-passaged primary cultured glioma cells, and found that TNC expression levels correlated with VM formation ability.…”

Section: Discussionsupporting

confidence: 93%

Tenascin-c mediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma

Cai

Wang

et al. 2019

Cell Death Dis

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Vasculogenic mimicry (VM), the formation of vessel-like structures by highly invasive tumor cells, has been considered one of several mechanisms responsible for the failure of anti-angiogenesis therapy in glioma patients. Therefore, inhibiting VM formation might be an effective therapeutic method to antagonize the angiogenesis resistance. This study aimed to show that an extracellular protein called Tenascin-c (TNC) is involved in VM formation and that TNC knockdown inhibits VM in glioma. TNC was upregulated with an increase in glioma grade. TNC and VM formation are potential independent predictors of survival of glioma patients. TNC upregulation was correlated with VM formation, and exogenous TNC stimulated VM formation. Furthermore, TNC knockdown significantly suppressed VM formation and proliferation in glioma cells in vitro and in vivo, with a reduction in cellular invasiveness and migration. Mechanistically, TNC knockdown decreased Akt phosphorylation at Ser 473 and Thr 308 and subsequently downregulated matrix metalloproteinase 2 and 9, both of which are important proteins associated with VM formation and migration. Our results indicate that TNC plays an important role in VM formation in glioma, suggesting that TNC is a potential therapeutic target for anti-angiogenesis therapy for glioma.

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Section: Discussionsupporting

confidence: 93%

Tenascin-c mediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma

Cai

Wang

et al. 2019

Cell Death Dis

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“…miRNA-320a has been shown to be crucial for intestinal barrier integrity through modulation of the regulatory subunit PPP2R5B of phosphatase PP2A (38). In addition, miRNA-320a was found to both target ␤-catenin directly (39) and VE-cadherin through inhibition of the transcriptional repressor TWIST1 (40,41). miRNA-34a-5p has been shown to serve as an inhibitor for the zinc finger transcription factor Snail (42,43), which in turn functions as a transcriptional repressor of the adherens and tight junction proteins E-cadherin, claudin, and occludin (44)(45)(46).…”

Section: Resultsmentioning

confidence: 99%

Hypoxic Environment Promotes Barrier Formation in Human Intestinal Epithelial Cells through Regulation of MicroRNA 320a Expression

Muenchau

Deutsch

Castro

et al. 2019

Molecular and Cellular Biology

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Intestinal epithelial cells (IECs) are exposed to the low-oxygen environment present in the lumen of the gut. These hypoxic conditions on one hand are fundamental for the survival of the commensal microbiota and, on the other hand, favor the formation of a selective semipermeable barrier, allowing IECs to transport essential nutrients/water while keeping the sterile internal compartments separated from the lumen containing commensals. The hypoxia-inducible factor (HIF) complex, which allows cells to respond and adapt to fluctuations in oxygen levels, has been described as a key regulator in maintaining IEC barrier function by regulating their tight junction integrity. In this study, we sought to better evaluate the mechanisms by which low oxygen conditions impact the barrier function of human IECs. By profiling miRNA expression in IECs under hypoxia, we identified microRNA 320a (miRNA-320a) as a novel barrier formation regulator. Using pharmacological inhibitors and short hairpin RNA-mediated silencing, we could demonstrate that expression of this microRNA (miRNA) was HIF dependent. Importantly, using overexpression and knockdown approaches of miRNA-320a, we could confirm its direct role in the regulation of barrier function in human IECs. These results reveal an important link between miRNA expression and barrier integrity, providing a novel insight into mechanisms of hypoxia-driven epithelial homeostasis.

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“…a and b ). Previously, reported results showed that the VM incidence in gastric carcinomas, cutaneous melanoma, esophageal stromal cancer, colorectal cancer and osteosarcoma were 28.5%, 34%, 33.3%, 19.2% and 22.7%, respectively . Intriguingly, the presence of VM is less than 50% in almost all cancer types examined to date; researchers suspect that VM may only exist in aggressive malignant sub‐phenotypes of cancers .…”

Section: Discussionmentioning

confidence: 99%

The role of sema4D in vasculogenic mimicry formation in non‐small cell lung cancer and the underlying mechanisms

Xia

Cai

Fan

et al. 2018

Intl Journal of Cancer

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Vasculogenic mimicry (VM) is a special vascular pattern in malignant tumors, which is composed of highly aggressive tumor cells. This tumor cell-mediated blood supply pattern is closely associated with a poor prognosis in cancer patients. The interaction of axon guidance factor Sema4D and its high affinity receptor plexinB1 could activate small GTPase RhoA and its downstream ROCKs; this process has an active role in the migration of endothelial cells and tumor angiogenesis. Here, we have begun to uncover the role of this pathway in VM formation in non-small cell lung cancer (NSCLC). First, we confirmed this special form of vasculature in NSCLC tissues and found the existence of VM channels in tumor tissues was correlated with Sema4D expression. Further, we found that inhibition of Sema4D in the human NSCLC cells H1299 and HCC827 reduces VM formation both in vitro and in vivo. Moreover, we demonstrated that downregulating the expression of plexinB1 by siRNA expressing vectors and inhibiting the RhoA/ROCK signaling pathway using fasudil can reduce VM formation of H1299 and HCC827 cells. Finally, we found that suppression of Sema4D leads to less stress fibers and depleted the motility of H1299 and HCC827 cells. Collectively, our study implicates Sema4D plays an important role in the process of VM formation in NSCLC through activating the RhoA/ROCK pathway and regulating tumor cell plasticity and migration. Modulation of the Sema4D/ plexinB1 and downstream RhoA/ROCK pathway may prevent the tumor blood supply through the VM pattern, which may eventually halt growth and metastasis of NSCLC. Role of sema4D in vasculogenic mimicry formationInt.

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HMGA2 promotes vasculogenic mimicry and tumor aggressiveness by upregulating Twist1 in gastric carcinoma

Cited by 41 publications

References 43 publications

Tenascin-c mediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma

Tenascin-c mediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma

Hypoxic Environment Promotes Barrier Formation in Human Intestinal Epithelial Cells through Regulation of MicroRNA 320a Expression

The role of sema4D in vasculogenic mimicry formation in non‐small cell lung cancer and the underlying mechanisms

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