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

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.

Ras suppressor 1 long form (RSU1L) silencing promotes apoptosis in invasive breast cancer cells.

Ras Suppressor-1 (RSU1) is a cell-extracellular matrix (ECM) adhesion protein implicated in breast cancer (BC) cell metastasis. Nevertheless, its role in apoptosis is yet unknown. In the present study, we used bioinformatics tools to evaluate the association of RSU1 expression and BC patient survival, the expression of basic pro- and anti-apoptotic genes in metastatic BC samples and their correlation with the expression of RSU1. Then, we specifically depleted RSU1 long form (RSU1L) using a short hairpin RNA (shRNA) silencing approach in two BC cell lines, the non-invasive MCF-7 and the highly invasive MDA-MB-231-LM2 cells and assessed gene expression of pro-and anti-apoptotic genes, as well as cell survival and apoptosis. Our results showed that high RSU1 expression was correlated with poor survival and significant changes were found in the expression of apoptosis-related genes (PUMA, TP53, BCL-2 and BCL-XL) in metastatic BC. Moreover, silencing of the long and most common isoform of RSU1 (RSU1L) resulted in the upregulation of PUMA and TP53 and concomitant downregulation of anti-apoptotic BCL-2 and BCL-XL, with the effect being more prominent in invasive MDA-MB-231-LM2 cells. Finally, RSU1L depletion leads to a dramatic increase in apoptosis of MDA-MB-231-LM2 cells, while no change was observed in the apoptotic rate of MCF-7 cells. This is the first study linking RSU1L with apoptosis and provides evidence for its differential role in cell lines of different invasive potential. This indicates that RSU1L represses apoptosis in aggressive BC cells helping them evade cell death and survive.