High levels of urinary midkine in various cancer patients

Ikematsu, Shinya; Okamoto, Kohji; Yoshida, Yasuhiko; Oda, Munehiro; Sugano-Nagano, Hitomi; Ashida, Kouzou; Kumai, Hideshi; Kadomatsu, Kenji; Muramatsu, Hisako; Muramatsu, Takashi; Sakuma, Sadatoshi

doi:10.1016/s0006-291x(03)00984-7

Cited by 29 publications

(28 citation statements)

References 22 publications

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“…Moreover, MK is expressed higher in human gastrointestinal cancers than in the corresponding non-cancerous tissues and normal tissue [3,4]. Urinal-MK [5] and serum-MK levels increased in gastric cancer patients [6,7], and serum-MK levels decreased after surgical resection of the tumor in several carcinomas, including gastric cancer [8]. MK may act as a prognostic marker for gastriointestinal stromal tumors [9].…”

Section: Introductionmentioning

confidence: 99%

siRNA targeting midkine inhibits gastric cancer cells growth and induces apoptosis involved caspase-3,8,9 activation and mitochondrial depolarization

Wang

Huang

et al. 2007

J Biomed Sci

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Midkine (MK), a heparin-binding growth factor, is expressed highly in various malignant tumors, so it acts as attractive therapeutic target. In the present study, we used siRNA targeting MK to downregulate human MK expression in human gastric cancer cell line BGC823 and SGC7901 so as to determine the advantages of this anticancer therapeutic. The cell proliferation was evaluated by a WST-8 (4-[3-(2-methoxy-4-nitrophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1, 3-benzene disulfonate sodium salt) assay and colony formation assay. Apoptosis was determined by flow cytometer analysis and colorimetric assay. Our results showed that the BGC823 and SGC7901 cell growth were significantly inhibited by knockdown of MK gene. The loss of mitochondrial membrane potential, release of cytochrome c from the mitochondria into cytosol and increased activity of caspase-3, 8 and 9 occurred concomitantly with inhibition of MK gene. These results indicated that siRNA targeting MK gene can inhibit gastric cancer cells growth and induce apoptosis via mitochondrial depolarization and caspase-3 activation. MK siRNA may be a promising novel and potential therapeutic strategy for the treatment of gastric cancers.

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Section: Introductionmentioning

confidence: 99%

siRNA targeting midkine inhibits gastric cancer cells growth and induces apoptosis involved caspase-3,8,9 activation and mitochondrial depolarization

Wang

Huang

et al. 2007

J Biomed Sci

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“…MDK was detectable at early stages (48), and the plasma level has been reported to be correlated with poor outcome (23,24). Interestingly, MDK was also detectable in urine samples of patients with cancer (25). Although significant, the increase in serum concentration observed between healthy patients and patients with cancer remains limited (48).…”

Section: Discussionmentioning

confidence: 99%

“…Its expression in tumors can be detected early (13), and it was therefore considered as a relevant biomarker of disease progression. Its expression in tumors can be determined by blood (23,24) and urinary analysis (25). Because of its functions, its wide expression in tumors, and its biomarker status, we have investigated whether MDK can induce a cellular cytotoxic response in humans.…”

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confidence: 99%

The Angiogenic Growth Factor and Biomarker Midkine Is a Tumor-Shared Antigen

Kerzerho

Adotévi

Castelli

et al. 2010

The Journal of Immunology

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The angiogenic factor Midkine (MDK) is overexpressed in various human malignant tumors, although its expression is low or undetectable in normal adult tissues. Its expression in tumors and its detection in plasma have been associated with poor disease outcome, whereas its blockade was found to contribute to tumor regression. By weekly stimulation of T lymphocytes harvested in HLA-A2 healthy donors, we derived CD8 T cell lines specific for several MDK peptides. The T cell response was mostly dominated by two nonamer peptides localized in the signal peptide and in the C-terminal part of the protein, as assessed by IFN-γ ELISPOT and HLA-A2 tetramer labeling. Peptide-specific T cell lines recognized cells transfected with an MDK-encoded plasmid and tumor cell lines naturally expressing the MDK protein, but not untransfected cells. T cell presentation of the two MDK epitopes was found to be TAP dependent. Experiments performed in HLA-A2 transgenic mice demonstrated the capacity of the two identified CD8 T cell epitopes to elicit a cytotoxic response. Altogether, our data show that the secreted MDK protein is a candidate vaccine for multiple cancers.

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“…By contrast, in a genome-wide search for abundantly expressed genes in cancerous vs. normal tissue, midkine was identified as the second highest expressed gene in the most common types of human cancer (14). Consistently, midkine protein was demonstrated to be highly expressed in various malignancies, including neuroblastoma, breast cancer, hepatocellular carcinoma, colorectal cancer and BCa (15,16). Although the expression of midkine protein in BCa and its correlation with a poor outcome in patients with invasive cancers has been previously reported (16), to the best of our knowledge there are only three studies reporting the measurement of midkine protein in urine specimens from BCa patients (15,17,18).…”

Section: Introductionmentioning

confidence: 91%

“…Consistently, midkine protein was demonstrated to be highly expressed in various malignancies, including neuroblastoma, breast cancer, hepatocellular carcinoma, colorectal cancer and BCa (15,16). Although the expression of midkine protein in BCa and its correlation with a poor outcome in patients with invasive cancers has been previously reported (16), to the best of our knowledge there are only three studies reporting the measurement of midkine protein in urine specimens from BCa patients (15,17,18). Only one study investigated whether there is a correlation between midkine protein concentration in urine and disease progression in terms of tumor stage and grade (17).…”

Section: Introductionmentioning

confidence: 91%

Validation of the diagnostic utility of urinary midkine for the detection of bladder cancer

et al. 2016

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As it has been demonstrated previously that midkine (also known as neurite growth-promoting factor 2) protein levels in urine of bladder cancer (BCa) patients are increased compared to healthy controls, the present study validated the diagnostic utility of midkine in an independent patient cohort and compared the observed values with voided urine cytology (VUC), which is the current reference standard for non-invasive diagnosis of BCa. Voided urine samples were prospectively collected from 92 BCa patients and 70 control subjects. Protein levels of midkine were assessed using a commercially available enzyme-linked immunosorbent assay and normalized to urinary creatinine. The diagnostic performance of urinary midkine was evaluated by receiver operating characteristic curves. The best combinations of sensitivities and specificities were determined by Youden's Index. Midkine concentrations were significantly elevated in urine samples from BCa patients compared to controls (P<0.001; Mann-Whitney U Test). The level of midkine was associated with disease progression, with the highest concentrations in urine specimens of patients with pT1 and ≥pT2a, as well as high-grade tumors (P<0.001; Mann-Whitney U test). Sensitivities of urinary midkine and VUC were 69.7 and 87.6%, respectively. The corresponding specificities for midkine and VUC were 77.9 and 87.7%, respectively. The combined use of VUC and midkine improved the sensitivity to 93.3%, but reduced the specificity to 66.2%. Despite its reduced discriminatory power for low-grade and low-stage BCa, urinary midkine can be utilized for the identification of high-grade pT1 and ≥pT2a tumors. This means that midkine may potentially be suitable for the identification of patients with high risk BCa.

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High levels of urinary midkine in various cancer patients

Cited by 29 publications

References 22 publications

siRNA targeting midkine inhibits gastric cancer cells growth and induces apoptosis involved caspase-3,8,9 activation and mitochondrial depolarization

siRNA targeting midkine inhibits gastric cancer cells growth and induces apoptosis involved caspase-3,8,9 activation and mitochondrial depolarization

The Angiogenic Growth Factor and Biomarker Midkine Is a Tumor-Shared Antigen

Validation of the diagnostic utility of urinary midkine for the detection of bladder cancer

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