Tissue factor pathway inhibitor-2 inhibits the growth and invasion of hepatocellular carcinoma cells and is inactivated in human hepatocellular carcinoma

Xu, Yong; Qin, Xiaoli; Jin-jing, Zhou; Tu, Zhiguang; Bi, Xiao; Li, Wuxian; Fan, Xiaoxuan; Zhang, Yi

doi:10.3892/ol.2011.340

Cited by 15 publications

(13 citation statements)

References 37 publications

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“…Also, a role for DKK1 as a tumor suppressor by Wnt-signaling inhibition was documented (53). Tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated serine protease inhibitor, which has been previously described as a tumor suppressor gene in several types of cancer (54, 55). Our results therefore support the notion that FLASH represses the expression of numerous genes that support the epithelial phenotype and therefore is a critical determinant of the mesenchymal phenotype.…”

Section: Discussionmentioning

confidence: 99%

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Dragoi¹,

Swiss²,

Gao³

et al. 2014

Cancer Research

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E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definion of several known regulators of E-cadherin expression, including ZEB1, HDAC1 and MMP14. We identified three new regulators (FLASH, CASP7 and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. Additionally, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a post-transcriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through post-transcriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT.

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Section: Discussionmentioning

confidence: 99%

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Dragoi¹,

Swiss²,

Gao³

et al. 2014

Cancer Research

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“…A number of studies have reported that TFPI-2 is produced and secreted into the extracellular medium where it acts as a serine proteinase inhibitor 7 , 9 , 13 . To determine the secretion levels of TFPI-2, we employed ELISA experiments.…”

Section: Resultsmentioning

confidence: 99%

“…TFPI-2 has been recently recognized as a tumor suppressor, playing a suppressive role in tumor cell proliferation, apoptosis, invasion and angiogenesis 7 – 9 . Down-regulation of TFPI-2 expression, due to hypermethylation of its promoter, was seen in some highly aggressive tumors such as glioma, non-small cell lung cancer and breast cancers 8 , 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

“…Down-regulation of TFPI-2 expression, due to hypermethylation of its promoter, was seen in some highly aggressive tumors such as glioma, non-small cell lung cancer and breast cancers 8 , 10 , 11 . Decreased expression of TFPI-2 in cancer cells resulted in aberrant proliferation and invasion 1 , 7 , 12 . Immunohistochemical staining showed that the low levels of TFPI-2 were associated with breast cancer progression, recurrence and poor survival outcome after surgery 13 .…”

Section: Introductionmentioning

confidence: 99%

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Localization of TFPI-2 in the nucleus modulates MMP-2 gene expression in breast cancer cells

Wang

Zeng

Chen

et al. 2017

Sci Rep

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TFPI-2 has recently been recognized as a tumor suppressor, which not only plays a fundamental role in modulation of ECM integrity, but also involves the regulation of many oncogenes. In this study, we investigated the potential mechanism of TFPI-2 in the suppression of breast cancer growth and invasion. We showed that, with either over-expression of TFPI-2 or after treatment with exogenous rTFPI-2, breast cancer cells exhibited reduced proliferation and invasion. We demonstrated that in addition to being secreted, TFPI-2 was also distributed throughout the cytoplasm and nucleus. Nuclear localization of TFPI-2 contributed to inhibition of MMP-2 mRNA expression, which could be reversed after the nuclear localization signal was deleted. In the nucleus, interaction of TFPI-2 with Ap-2α attenuated the binding of AP-2α to the MMP-2 promoter, therefore reducing the transcriptional activity of the gene. Our results suggest that one of the mechanisms by which TFPI-2 inhibits breast cancer cell invasion could be via the regulation of MMP-2 gene transcription.

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“…Autophagy and apoptosis synergistically affect each other [7] . Hepatocellular carcinoma (HCC) is a common primary tumor [9,10] . With the development of diagnostic imaging and advanced treatments in recent years, clinicians have adopted radical treatment strategies, such as surgical resection, liver transplantation, and radiofrequency ablation therapy.…”

Section: Original Articlementioning

confidence: 99%

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

Sun

et al. 2017

Acta Pharmacol Sin

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Bisindolylmaleimides, a series of derivatives of a PKC inhibitor staurosporine, exhibit potential as anti-cancer drugs and have received considerable attention in clinical trials. This study aims to investigate the effects of a bisindolylmaleimide alkaloid 155Cl (BMA-155Cl) with a novel structure on autophagy and apoptosis in human hepatocarcinoma HepG-2 cells in vitro and in vivo. The cell poliferation was assessed with a MTT assay. Autophagy was evaluated by MDC staining and TEM analysis. Apoptosis was investigated using Annexin V-FITC/PI and DAPI staining. The antitumor effects were further evaluated in nude mice bearing HepG-2 xenografts, which received BMA-155Cl (10, 20 mg/kg, ip) for 18 days. Autophagy-and apoptosis-associated proteins and their mRNA levels were examined with Western blotting, immunohistochemistry, and RT-PCR. BMA-155Cl (2.5-20 μmol/L) inhibited the growth of HepG-2 cells with IC 50 values of 16.62±1.34, 12.21±0.83, and 8.44±1.82 μmol/L at 24, 48, and 72 h, respectively. Furthermore, BMA155Cl (5-20 μmol/L) dose-dependently induced autophagy and apoptosis in HepG-2 cells. The formation of autophagic vacuoles was induced by BMA-155Cl (10 μmol/L) at approximately 6 h and peaked at approximately 15 h. Pretreatment with 3-MA potentiated BMA-155Cl-mediated apoptotic cell death. This compound dose-dependently increased the mRNA and protein levels of Beclin-1, NF-κB p65, p53, and Bax, but decreased the expression of IκB and Bcl-2. Pretreatment with BAY 11-7082, a specific inhibitor of NF-κB p65, blocked BMA-155Cl-induced expression of autophagy-and apoptosis-associated proteins. BMA-155Cl administration effectively suppressed the growth of HepG-2 xenografts in vivo, and increased the protein expression levels of LC3B, Beclin-1, NF-κB p65, and Bax in vivo. We conclude that the NF-κB p65 pathway is involved in BMA-155Cl-triggered autophagy, followed by apoptosis in HepG-2 cells in vitro and in vivo. Hence, BMA-155Cl could be a promising pro-apoptotic candidate for developing as a novel anti-cancer drug.

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Tissue factor pathway inhibitor-2 inhibits the growth and invasion of hepatocellular carcinoma cells and is inactivated in human hepatocellular carcinoma

Cited by 15 publications

References 37 publications

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Localization of TFPI-2 in the nucleus modulates MMP-2 gene expression in breast cancer cells

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

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