PUBLICATION
Pharmacological Targeting of Midkine (MDK) Reveals Stiffness-Dependent Control of Hepatocellular Carcinoma Invasiveness
- Authors
- Christou, C., Agathangelou, K., Dietis, N., Stylianou, A., Gkretsi, V.
- ID
- ZDB-PUB-260227-46
- Date
- 2026
- Source
- International Journal of Molecular Sciences 27: (Journal)
- Registered Authors
- Dietis, Nikolas
- Keywords
- cell adhesion, lamellipodia, liver cancer, matrix stiffness, tumor spheroids, zebrafish xenograft
- MeSH Terms
-
- Animals
- Carcinoma, Hepatocellular*/drug therapy
- Carcinoma, Hepatocellular*/genetics
- Carcinoma, Hepatocellular*/metabolism
- Carcinoma, Hepatocellular*/pathology
- Cell Adhesion/drug effects
- Cell Line, Tumor
- Cell Movement/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Liver Neoplasms*/drug therapy
- Liver Neoplasms*/genetics
- Liver Neoplasms*/metabolism
- Liver Neoplasms*/pathology
- Midkine*/antagonists & inhibitors
- Midkine*/genetics
- Midkine*/metabolism
- Neoplasm Invasiveness
- Zebrafish
- PubMed
- 41751909 Full text @ Int. J. Mol. Sci.
Citation
Christou, C., Agathangelou, K., Dietis, N., Stylianou, A., Gkretsi, V. (2026) Pharmacological Targeting of Midkine (MDK) Reveals Stiffness-Dependent Control of Hepatocellular Carcinoma Invasiveness. International Journal of Molecular Sciences. 27:.
Abstract
Metastasis accounts for most cancer-related deaths and hepatocellular carcinoma (HCC) is no exception. Midkine (MDK) is a multifunctional secreted protein elevated in HCC with a vague role in HCC. In this study, we used bioinformatics to verify MDK expression in HCC tumors, and next, we inhibited the MDK protein in invasive Hep3B cells using an MDK inhibitor (iMDK) both in vitro and in vivo. Our results showed that iMDK promoted cell migration and enhanced lamellipodia formation while at the same time downregulating the expression of cell-matrix adhesion genes. In order to also consider forces exerted by the surrounding matrix, we performed cell adhesion, transwell invasion, and 3D tumor spheroid invasion assays in two different stiffness conditions. Adhesion and invasion always exhibited opposite patterns, with adhesion being inhibited in soft matrix environments, accompanied by increased invasion, and a reverse effect in stiff environments. In vivo experiments where cells pre-treated with iMDK were implanted to zebrafish embryos showed overall reduced metastasis, verifying that MDK is a central mechanotransduction regulator that enables HCC cells to adapt their metastatic strategies to ECM stiffness. Thus, MDK inhibition effectively disrupts mechanosensitive coordination during metastasis, highlighting its potential as a therapeutic target.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping