Midkine confers Adriamycin resistance in human gastric cancer cells

Department of Breast Surgery, Department of Surgical Oncology, Research Unit of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, 110001, People's Republic of China.
Tumor Biology (Impact Factor: 3.61). 05/2012; 33(5):1543-8. DOI: 10.1007/s13277-012-0406-3
Source: PubMed


Midkine (MDK) is a heparin-binding molecule involved in the regulation of growth and differentiation during embryogenesis, which is overexpressed in most of human malignant tumors and may act as an oncoprotein. The aim of the current study was to investigate the mechanism of MDK involved in the Adriamycin (ADR) resistance in human gastric cancer cells in vitro. We found that Adriamycin-resistant SGC7901 (SGC7901/ADR) exhibited 58.6-fold greater resistance to ADR compared with Adriamycin-sensitive SGC7901 cell line. MDK mRNA and protein expression levels were significantly higher in SGC7901/ADR than in SGC7901. To gain a deeper insight into the role of MDK in SGC7901/ADR, we stably transfected Adriamycin-sensitive SGC7901 with viral vector expressing MDK. Our result showed that multidrug resistance type I (MDR1) was found in SGC7901/ADR, not in SGC7901 by RT-PCR regardless of MDK transfection. P-Glycoprotein, which is the MDR1-coded protein, was found in SGC7901/ADR, not in SGC7901 by Western blot regardless of MDK transfection. We investigated whether an activation of the tyrosine kinase pathway would change the drug resistance phenotype with MDK transfection. Western blot results showed the upregulation of phosphorylated protein kinase B (AKT) and phosphorylated extracellular signal-regulated protein kinase (ERK) in Adriamycin-sensitive SGC7901 cell by MDK transfection accompanied with drug resistance to ADR, although the level of AKT and ERK protein expression did not change, so our results suggested that MDK, which can activate AKT and ERK by phosphorylation, induced the Adriamycin resistance in gastric cancer cells. Understanding the molecular mechanisms, driving MDK-induced ADR resistance, will provide benefits in developing new therapies for gastric cancer.

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    ABSTRACT: Midkine is highly expressed in various cancers, including neuroblastoma, one of the most malignant paediatric solid tumours known. Also, it has been shown to be useful as a tumour marker, a prognosis factor and a target of molecular therapy. Several molecular tools (e.g. siRNA, antibodies and RNA aptamer) have been used to establish a midkine-targeted therapy. The involvement of midkine in tumourigenesis has been demonstrated in vivo in a mouse neuroblastoma model, where targeting it with an RNA aptamer was shown to be an effective treatment for xenografted tumours. Chemoresistance is one of the notable phenotypes regulated by midkine in various cancer cell types. In pancreatic tumours and glioma cells, midkine is expressed in chemoresistant cells and is involved in the survival of these cells in the presence of anticancer drugs. In contrast to these tumours, midkine was found to be expressed in every neuroblastoma cell line tested and the knockdown of midkine alone was sufficient to suppress their growth. These results indicate that neuroblastoma cells are highly dependent on midkine and that a midkine-targeted therapy could exert a significant effect in these cells. However, to achieve a midkine-targeted therapy for high-risk neuroblastoma patients, the further refinement of the RNA aptamer or antibody as tools and the elucidation of midkine signalling are immediate issues that need to be resolved. Regarding the latter, although it has been shown that Notch2 functions as a receptor in neuroblastoma cells, it is likely that other receptors (e.g. anaplastic lymphoma kinase) are also involved in midkine signalling. This article is part of a themed section on Midkine. To view the other articles in this section visit
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    ABSTRACT: CRKL encodes an adaptor protein that has been recently reported to be overexpressed in various cancers and associate with the malignant behavior of cancer cells. However, the expression pattern of CRKL protein and its clinical significance in human bladder cancer have not been well characterized to date. In the present study, CRKL expression was analyzed in 82 archived bladder cancer specimens using immunohistochemistry, and the correlations between CRKL expression and clinicopathological parameters were evaluated. We found that CRKL was overexpressed in 31 of 82 (37.8 %) bladder cancer specimens. A significant association was observed between CRKL overexpression and tumor status (p = 0.019). To further explore the biological functions of CRKL in bladder cancer, we overexpressed CRKL in BIU-87 and 5637 cell lines. Using CCK8 assay and colony formation assay, we showed that CRKL upregulation increased cell proliferation. In addition, transwell assay showed that CRKL could also facilitate invasion. Further study demonstrated that CRKL upregulation increased cyclin D1 expression and ERK phosphorylation. In conclusion, CRKL is overexpressed in bladder cancer and regulates malignant cell growth and invasion, which makes CRKL a candidate therapeutic target for bladder cancer.
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    ABSTRACT: The present study aimed to determine whether the expression levels of midkine (MK) and syndecan‑1 correlate with the malignant progression and poor prognosis of gastric cardiac adenocarcinoma (GCA). GCA tissue samples (n=72) were obtained from the Department of Pathology of the First Affiliated Hospital of Henan University of Science and Technology (Luoyang, China). The paraffin‑embedded samples had been surgically resected and pathologically diagnosed between 2007 and 2009. Normal gastric cardiac biopsy specimens (n=40) were also collected as the control. The expression levels of MK and syndecan‑1 were assessed by immunohistochemistry using the high‑sensitivity streptavidin‑peroxidase method. Statistical analysis was performed on the data obtained using the SPSS 17.0 statistics package. MK expression was detected in 76.4% of GCA samples and 5% of normal gastric cardiac mucosa specimens. A significant positive correlation was observed between the expression levels of MK and the infiltrative depth of the tumor, the presence of lymph node metastasis and the prognosis of the patients (P<0.05). Syndecan‑1 expression was detected in 38.9% of GCA samples and 100% of normal gastric cardiac mucosa samples. The expression levels of syndecan‑1 were negatively correlated with the grade of differentiation, serosal membrane invasion, lymph node metastasis and the patient's prognosis (P<0.05). Notably, the expression levels of MK and syndecan‑1 were inversely correlated (r=‑0.352, P<0.01) in the GCA tissue samples. These results suggest that high expression levels of MK in GCA tissues may indicate a differentiation stage that is characteristic of malignancy, a late clinical stage and a poor prognosis, whereas increased syndecan‑1 levels may indicate a high degree of differentiation, an early clinical stage and a favorable prognosis. MK and syndecan‑1 may serve as important biomarkers for monitoring the development and progression of GCA.
    Preview · Article · Jul 2014 · Molecular Medicine Reports
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