Midkine translocated to nucleoli and involved in carcinogenesis

Abstract

Midkine (MK) is a heparin-binding growth factor with its gene first identified in embryonal carcinoma cells at early stages of retinoic acid-induced differentiation. MK is frequently and highly expressed in a variety of human carcinomas. Furthermore, the blood MK level is frequently elevated with advance of human carcinomas, decreased after surgical removal of the tumors. Thus, it is expected to become a promising marker for evaluating the progress of carcinomas. There is mounting evidence that MK plays a significant role in carcinogenesis-related activities, such as proliferation, migration, anti-apoptosis, mitogenesis, transforming, and angiogenesis. In addition, siRNA and anti-sense oligonucleotides for MK have yielded great effects in anti-tumor activities. Therefore, MK appears to be a potential candidate molecular target of therapy for human carcinomas. In this paper, we review MK targeting at nucleoli in different tumor cells and its role in carcinogenesis to deepen our understanding of the mechanism of MK involved in carcinogenesis.

Figure 1

Subcellular localization analysis of MKS-GFP and MKN-GFP fusion proteins in carcinoma cell lines. MKS-GFP and MKN-GFP fusion proteins were localized to nuclei and accumulated in nucleoli, but rarely localized to cytoplasm. The high light “spots” in the center of nuclei are nucleoli. HepG2 cells (upper panel) and DU145 cells (bottom panel) are transfected with pEGFP-N2, and diffuse freely in the whole cell except in nucleoli.

Figure 2

Nuclear targeting by growth factor MK. MK was endocytosed into cell cytosol through binding to the receptor of LRP, and then tanslocated to nuclei in the presence of nucleulin or LBP. At the same time, the internalized MK is degraded by proteasome to “off” the signals from the cell surface receptors.

Figure 3

Biological function and medical application of MK. The most attractive feature of MK is its involvement in carcinogenesis, which plays a great role in proliferation, migration, anti-apoptosis, mitogenesis, transformation, and angiogenesis. Furthermore, MK is expected to be a target molecule of diagnosis of and therapy for tumor.