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Article

Pharmacological Targeting of Midkine (MDK) Reveals Stiffness-Dependent Control of Hepatocellular Carcinoma Invasiveness

by
Christiana Christou
1,2,
Kyriacos Agathangelou
3,
Nikolas Dietis
3,
Andreas Stylianou
4,5 and
Vasiliki Gkretsi
1,2,*
1
Biomedical Sciences Program, Department of Life Sciences, School of Life & Health Sciences, European University Cyprus, Nicosia 1516, Cyprus
2
Cancer Metastasis and Adhesions Group, Basic and Translational Cancer Research Center (BTCRC), Nicosia 1516, Cyprus
3
Medical School, University of Cyprus, Nicosia 1678, Cyprus
4
Department of Health Sciences, School of Life & Health Sciences, European University Cyprus, Nicosia 1516, Cyprus
5
Cancer Mechanobiology and Applied Biophysics Group, Basic and Translational Cancer Research Center (BTCRC), Nicosia 1516, Cyprus
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(4), 1766; https://doi.org/10.3390/ijms27041766
Submission received: 10 January 2026 / Revised: 6 February 2026 / Accepted: 10 February 2026 / Published: 12 February 2026
(This article belongs to the Special Issue Adhesion, Invasion, and Metastasis in Cancer Progression)
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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.
Keywords: lamellipodia; liver cancer; cell adhesion; tumor spheroids; zebrafish xenograft; matrix stiffness lamellipodia; liver cancer; cell adhesion; tumor spheroids; zebrafish xenograft; matrix stiffness

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MDPI and ACS Style

Christou, C.; Agathangelou, K.; Dietis, N.; Stylianou, A.; Gkretsi, V. Pharmacological Targeting of Midkine (MDK) Reveals Stiffness-Dependent Control of Hepatocellular Carcinoma Invasiveness. Int. J. Mol. Sci. 2026, 27, 1766. https://doi.org/10.3390/ijms27041766

AMA Style

Christou C, Agathangelou K, Dietis N, Stylianou A, Gkretsi V. Pharmacological Targeting of Midkine (MDK) Reveals Stiffness-Dependent Control of Hepatocellular Carcinoma Invasiveness. International Journal of Molecular Sciences. 2026; 27(4):1766. https://doi.org/10.3390/ijms27041766

Chicago/Turabian Style

Christou, Christiana, Kyriacos Agathangelou, Nikolas Dietis, Andreas Stylianou, and Vasiliki Gkretsi. 2026. "Pharmacological Targeting of Midkine (MDK) Reveals Stiffness-Dependent Control of Hepatocellular Carcinoma Invasiveness" International Journal of Molecular Sciences 27, no. 4: 1766. https://doi.org/10.3390/ijms27041766

APA Style

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(4), 1766. https://doi.org/10.3390/ijms27041766

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