Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K2

Yamamoto, Toshijiro; Nakamura, Hitomi; Liu, Weidong; Cao, Ke; Yoshikawa, Shohei; Enomoto, Hirayuki; Iwata, Yoshinori; Koh, Naoki; Saito, Masaki; Imanishi, Hiroyasu; Shimomura, Soji; Iijima, Hiroko; Hada, Toshikazu; Nishiguchi, Shuhei

doi:10.1007/s00535-008-2304-4

Cited by 32 publications

(31 citation statements)

References 32 publications

(52 reference statements)

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“…In various malignant cancers, HDGF expression is highly elevated and has been demonstrated to be a pleiotropic growth factor with motogenic, mitogenic, and angiogenic properties. This may be mediated by an abnormal cell cycle regulation, antiapoptosis pathway, and alternative extracellular matrix activity [18][19][20]. However, little is known about how this upregulation occurs.…”

Section: Discussionmentioning

confidence: 94%

“…HDGF participates in many cellular processes including endothelial angiogenesis [15], cardiovascular differentiation [16], and renal and liver development [17]. Although HDGF is expressed ubiquitously in normal tissue and cell lines, including HuH-7, COS-7, aortic vascular smooth muscle cells, endothelial cells, fibroblasts, and fetal hepatocytes, its expression is dramatically increased in fetal tissues and cancers [18][19][20]. It has been shown that HDGF increases the tumorigenic potential and mitogenic and angiogenic activity of a variety of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Tumorigenesis and prognostic role of hepatoma-derived growth factor in human gliomas

et al. 2011

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Hepatoma-derived growth factor (HDGF) is a neurotrophic factor found in mouse spinal cord and hippocampal neurons. In various malignant tumors, the role of HDGF in tumor progression and its use as a diagnostic biomarker or therapeutic target have been extensively explored. However, the prognostic function and mitogenic role of HDGF in gliomagenesis are yet to be verified. In this study, we found a significant incidence of HDGF prevalence between the different pathological types and stages of glioma in 105 patients. We also found a prognostic significance in 41 glioblastoma multiforme (GBM) patients, with prevalence of nuclear HDGF predicting short survival of patients with GBM after surgery. To delineate the mitogenic role of HDGF in gliomagenesis, an adenoviral-expressed HDGF small interfering RNA (Ad-HDGF siRNA) was used to knock down expression of nuclear HDGF. After knocking down nuclear HDGF expression in human GBM cells, cell growth and cell invasion and induction on apoptosis by caspase-3 activation were significantly inhibited. We conclude that HDGF is a mitogenic growth factor in glioma progression and can be a useful prognostic marker for GBM and therapeutic target for clinical management of glioma in the future.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Tumorigenesis and prognostic role of hepatoma-derived growth factor in human gliomas

et al. 2011

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“…For promoter activity assay, cells were cotransfected with 1 mg HDGF-driven luciferase vector (32) or E-cadherin-driven luciferase vector (generous gift from Dr. Yu-Sun Chang, Chang Gen University, Taipei, Taiwan; ref. 33) and the 0.2 mg Renilla reniformis luciferase reporter vector (Promega).…”

Section: Transfection and Luciferase Measurementmentioning

confidence: 99%

Downregulation of Hepatoma-Derived Growth Factor Contributes to Retarded Lung Metastasis via Inhibition of Epithelial–Mesenchymal Transition by Systemic POMC Gene Delivery in Melanoma

Tsai

Liu

Kung

et al. 2013

Molecular Cancer Therapeutics

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The prognosis of malignant melanoma is poor due to high incidence of metastasis, underscoring the demand for development of novel therapeutic strategies. Stress hormone pro-opiomelanocortin (POMC) is the precursor for several anti-inflammatory peptides that hold promise for management of cancer-related diseases. The present study evaluated the antimetastatic potential and mechanism of POMC therapy for metastatic melanoma. Adenovirus-mediated POMC gene delivery potently inhibited the invasiveness of human and mouse melanoma cells. Moreover, after induction of lung metastasis, systemic POMC expression significantly reduced the foci formation and neovascularization in lungs. Mechanistic studies revealed that POMC therapy inhibited the epithelial-mesenchymal transition (EMT) of melanoma cells by upregulation of E-cadherin and downregulation of vimentin and a-smooth muscle actin (a-SMA). In addition, microarray analysis unveiled POMC gene transfer reduced the mRNA level of multiple prometastatic factors, including hepatoma-derived growth factor (HDGF). Cell culture and immunohistochemical studies further confirmed that POMC gene delivery significantly decreased the expression of HDGF in melanoma cells and tissues. Despite stimulating the invasion and EMT, exogenous HDGF supply only partially attenuated the POMC-mediated invasion inhibition and EMT change in melanoma cells. Finally, we delineated the contribution of melanocortins to POMC-induced inhibition of invasion, HDGF downregulation, and E-cadherin upregulation. Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma. Mol Cancer Ther; 12(6); 1016-25. Ó2013 AACR.

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“…Yamamoto et al suggested that regulation of the expression of the hepatoma-derived growth factor gene is one of the crucial mechanisms of MK-4-induced cell growth suppression in HCC. Hepatomaderived growth factor stimulates the proliferation of HCC cells after its translocation to the nucleus by use of bipartite nuclear localization signals [16]. Azuma et al [17] suggested that activation of steroid and xenobiotic receptors (SXR) by MK-4 contributes to the tumor suppressive effects on HCC cells.…”

Section: Mechanisms Of Growth Inhibition Of Hcc Cells By Mk-4mentioning

confidence: 99%

Enhanced Intracellular Delivery and Improved Antitumor Efficacy of Menaquinone-4

Matsunaga¹,

Enjoji²,

Karube³

et al. 2017

Vitamin K2 - Vital for Health and Wellbeing

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Hepatocellular carcinoma (HCC) is a major malignant tumor type that occurs globally. HCC incidence is increasing, especially in Asian countries. Despite many therapeutic approaches, the long-term prognosis of HCC remains poor because of frequent recurrence due to intrahepatic metastasis or multicentric carcinogenesis. Therefore, it is necessary to develop effective and safe chemopreventive agents to improve the prognosis of HCC. Menaquinone-4 (MK-4) has a suppressive effect on HCC, but cellular delivery is poor. We hypothesized that effective cellular delivery of menahydroquinone-4 (MKH), a fully reduced form of MK-4, would regulate HCC growth and metastasis. We developed a bioreductive activation-independent delivery system with the N,N-dimethylglycine ester of MKH (MKH-bis-DMG) to deliver MKH to HCC cells without any bioreductive processing of MK-4. MKH-bis-DMG inhibited the proliferation of both DCP-positive and DCP-negative HCC cell lines in a time-and dose-dependent manner via G1/S cell-cycle arrest. We assessed the effect of MKH-derivatives on HCC metastasis using a mouse model of spleen-liver metastasis. The mean tumor hepatic replacement area of MKH-bis-DMG treated mice was significantly less than that of untreated mice. In conclusion, MKH-bis-DMG may be beneficial as a chemopreventive agent for recurrent HCC.

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Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K2

Abstract: These findings suggested that regulation of the HDGF gene expression is one of the crucial mechanisms of vitamin K(2)-induced cell growth suppression for HCC.

Cited by 32 publications

References 32 publications

Tumorigenesis and prognostic role of hepatoma-derived growth factor in human gliomas

Tumorigenesis and prognostic role of hepatoma-derived growth factor in human gliomas

Downregulation of Hepatoma-Derived Growth Factor Contributes to Retarded Lung Metastasis via Inhibition of Epithelial–Mesenchymal Transition by Systemic POMC Gene Delivery in Melanoma

Enhanced Intracellular Delivery and Improved Antitumor Efficacy of Menaquinone-4

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