A promoter region of the midkine gene that is frequently expressed in human hepatocellular carcinoma can activate a suicide gene as effectively as the α-fetoprotein promoter

Tomizawa, M.; Yu, Ling; Wada, Akihiko; Tamaoki, Taiki; Kadomatsu, Kenji; Muramatsu, Takashi; Matsubara, Shigeo; Watanabe, Kazuko; Ebara, Masaaki; Saisho, Hiromitsu; Sato, Shigeru; Tagawa, Masatoshi

doi:10.1038/sj.bjc.6601246

Cited by 24 publications

(10 citation statements)

References 21 publications

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“…Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung, esophageal, stomach, colon, hepatocellular, breast, renal and pancreatic carcinoma [10]–[15]. MDK binds to multiple membrane receptors, ALK, syndecans, PTP and LRP, and subsequently activates the PI3 kinase (PI3K) and MAP kinase pathways.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer

et al. 2013

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Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.

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Section: Introductionmentioning

confidence: 99%

Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer

et al. 2013

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“…[27][28][29][30][31][32][33][34] The activity of this promoter might be down-regulated by p53-dependent pathways but further evidence is needed to elucidate the mechanism of this phenomenon. 32 In the case of glioma, midkine promoter activity was shown to be two times higher in midkine-positive cells than in midkine-negative primary normal brain cells.…”

Section: Discussionmentioning

confidence: 99%

Comparative evaluation of survivin, midkine, and CXCR4 promoters for transcriptional targeting of glioma gene therapy

Ulasov¹,

Rivera²,

Sonabend³

et al. 2007

Cancer Biology & Therapy

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Objective: Transcriptional targeting is a key strategy to enhance therapeutic efficacy of gene therapy applications. In the context of oncolytic virotherapy, transcriptional promoter elements are used from genes that are over expressed in a variety of malignant cancers. In the present study, we examined the feasibility of transcriptional targeting to glioma cells by comparing the activity of survivin, midkine, and CXCR4 tumor-specific promoters.Methods: To evaluate the expression level of several glioma related genes, we performed quantitative RT-PCR analyses on samples obtained from cell lines and patients. To determine specific level of gene expression mediated by selective promoter elements, we measured luciferase expression in glioma samples transduced with replication deficient adenoviral vectors. Finally, we incorporated the optimal promoters into a conditionally replicative adenoviral vector, CRAd-5/3, and examined the cytopathic effect in vitro.Results: The survivin promoter demonstrated the highest level of mRNA expression in primary tumor samples and cell lines. Transcriptional targeting was confirmed by infection of glioma cells with an adenovirus expression vector containing a survivin-driven luciferase reporter gene. Of the tested promoters, minimal level of survivin activity was detected in normal human liver and brain. A novel vector, CRAd-survivin5/3, with E1a under the control of the survivin promoter, exhibited enhanced cytopathic effect in vitro.Conclusions: Our data demonstrate that the survivin promoter element is very active in glioma samples and has low activity in normal human brain and liver. A novel oncolytic virus, CRAd-survivin-5/3, was effective against a panel of glioma cell lines in vitro. Our results suggest that employing the survivin promoter element in the context of CRAd-5/3 may present a new opportunity for the development of glioma specific oncolytic vectors.

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“…In addition, the MK promoter‐driven thymidine kinase gene, a suicide gene, effectively induced Wilms' tumor cell death in response to ganciclovir. The MK promoter also works as effectively as the AFP promoter in hepatocellular carcinoma and the c‐erbB‐2 promoter in breast cancer 81,82 . Therefore, suicide‐gene transfer under the control of the MK promoter is a promising therapeutic strategy for treating cancer.…”

Section: Biological Activities Of Mk and Its Implication In Human Dismentioning

confidence: 99%

“…The MK promoter also works as effectively as the AFP promoter in hepatocellular carcinoma and the c-erbB-2 promoter in breast cancer. 81,82 Therefore, suicide-gene transfer under the control of the MK promoter is a promising therapeutic strategy for treating cancer.…”

Section: Cancermentioning

confidence: 99%

Midkine in the pathology of cancer, neural disease, and inflammation

Sakamoto

Kadomatsu

2012

Pathology International

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Midkine (MK) is a heparin-binding growth factor involved in various cellular processes such as cellular proliferation, survival, and migration. In addition to these typical growth factor activities, MK exhibits several other activities related to fibrinolysis, blood pressure, host defense and other processes. Many cell-surface receptors have been identified to account for the multiple biological activities of MK. The expression of MK is frequently upregulated in many types of human carcinoma. Moreover, blood MK levels are closely correlated with patient outcome. Knockdown and blockade of MK suppress tumorigenesis and tumor development. Thus, MK serves as a tumor marker and a molecular target for cancer therapy. Furthermore, there is growing evidence that MK plays pivotal roles in neural and inflammatory diseases. Understanding of the mechanisms of action of MK is expected to create new therapeutic options for several human diseases.

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A promoter region of the midkine gene that is frequently expressed in human hepatocellular carcinoma can activate a suicide gene as effectively as the α-fetoprotein promoter

Cited by 24 publications

References 21 publications

Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer

Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer

Comparative evaluation of survivin, midkine, and CXCR4 promoters for transcriptional targeting of glioma gene therapy

Midkine in the pathology of cancer, neural disease, and inflammation

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