Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker

Abstract

Midkine (MDK) is a multifunctional secreted protein that can act as a cytokine or growth factor regulating multiple signaling pathways and being implicated in fundamental cellular processes, such as survival, proliferation, and migration. Although its expression in normal adult tissues is barely detectable, MDK serum levels are found to be elevated in several types of cancer, including hepatocellular carcinoma (HCC). In this review, we summarize the findings of recent studies on the role of MDK in HCC diagnosis and progression. Overall, studies show that MDK is a powerful biomarker for HCC early diagnosis, as it can differentiate not only between HCC patients and normal individuals but also between HCC patients and patients with other liver pathologies. It is correlated with high recurrence rates and was shown to be valuable for the diagnosis of early-stage HCC, even in patients negative for α-fetoprotein (AFP), the most commonly used biomarker for HCC diagnosis. A comparison with AFP reveals that MDK is inferior to AFP with regard to specificity but significantly superior with regard to sensitivity, which further indicates the need for using both biomarkers for more effective HCC diagnosis.

Midkine: A Cancer Biomarker Candidate and Innovative Therapeutic Approaches

“…Syndecanes, glipican-2, PG-M/versican, and neuroglycan C are a few such protein glycans that interact with MDK (6,(25)(26)(27)(28). MDK consists of two domains and three antiparallel β-strands containing heparin-binding sites (3,29,30). This structure allows MDK to form molecular complexes with proteoglycans (3,29,30).…”

“…MDK consists of two domains and three antiparallel β-strands containing heparin-binding sites (3,29,30). This structure allows MDK to form molecular complexes with proteoglycans (3,29,30). MDK binding to sulfated glycosaminoglycans interacts with a large number of crucial receptors, initiating a variety of signaling pathways (3, 29, 30) (Figure 2).…”

“…MDK binding to sulfated glycosaminoglycans interacts with a large number of crucial receptors, initiating a variety of signaling pathways (3, 29, 30) (Figure 2). While MDK is involved in critical processes such as development, reproduction, repair, inflammation, innate immunity, blood pressure regulation, neurite outgrowth, and angiogenesis, it also plays an important role in cancer formation and progression by stimulating cellular activity (1,3,25).MDK expression has been shown to be regulated by several kinds of transcription factors (30). The hormone estradiol (E2) has been shown to increase MDK mRNA levels in lung cancer cells (30).…”

“…The Midkine (MDK) gene, which has a retinoic acid (RA) receptor in its promoter, is a heparin-binding growth factor or cytokine (1). MDK, a 13-kDa cysteine-rich protein, is activated by retinoic acid and generated in large quantities throughout development, especially in the nervous system (2,3). It is generally overexpressed in adult tissues after injury, disease, and healing (2).…”