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Targeting MDK Abrogates IFN-γ-Elicited Metastasis inCancers of Various Origins
Luyu Zheng1, Qun Liu2, Ruijun Li1
1Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Abstract:
IFN-γ is a pleiotropic cytokine with immunomodulatory and tumoricidal functions. It has been used as an anti-tumor agent in adjuvant therapies for various cancers. Paradoxically, recent advances have also demonstrated pro-tumorigenic effects of IFN-γ, especially in promoting cancer metastasis, with the mechanism remains unclear. This will undoubtedly hinder the application of IFN-γ in cancer treatment. Here, we verified that IFN-γ treatment led to activation of the epithelial-to-mesenchymal transition (EMT) programme and metastasis in cell lines of various cancers, including the kidney cancer cell line Caki-1, the lung cancer cell line A549, the cervical carcinoma cell line CaSki, the breast cancer cell line BT549 and the colon cancer cell line HCT116. We further disclosed that midkine (MDK), an emerging oncoprotein and EMT inducer, is a common responsive target of IFN-γ in these cell lines. Mechanistically, IFN-γ upregulated MDK via STAT1, a principle downstream effector in the IFN-γ signalling. MDK is elevated in the majority of cancer types in the TCGA database, and its overexpression drove EMT activation and cancer metastasis in all examined cell lines. Targeting MDK using a specific MDK inhibitor (iMDK) broadly reversed IFN-γ-activated EMT, and subsequently abrogated IFN-γ-triggered metastasis. Collectively, our data uncover a MDK-dependent EMT inducing mechanism underlying IFN-γ-driven metastasis across cancers which could be attenuated by pharmacological inhibition of MDK. Based on these findings, we propose that MDK may be used as a potential therapeutic target to eliminate IFN-γ-elicited pro-metastatic adverse effect, and that combined MDK utilization may expand the application of IFN-γ in cancer and improve the clinical benefits from IFN-γ-based therapies.
Insights
Interferon-gamma (IFN-γ) can paradoxically promote cancer metastasis by upregulating midkine (MDK) via STAT1. Inhibiting MDK reverses this effect, suggesting MDK as a therapeutic target to improve IFN-γ cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Interferon-gamma (IFN-γ) is a cytokine with known anti-tumor functions, but recent studies reveal paradoxical pro-tumorigenic roles, particularly in promoting cancer metastasis.
- The precise mechanisms underlying IFN-γ's pro-metastatic effects remain largely unclear, hindering its clinical application in cancer treatment.
Purpose of the Study:
- To investigate the role of IFN-γ in activating epithelial-to-mesenchymal transition (EMT) and metastasis across various cancer cell lines.
- To identify the molecular mechanisms by which IFN-γ promotes metastasis and to evaluate potential therapeutic strategies targeting this pathway.
Main Methods:
- IFN-γ treatment was applied to multiple cancer cell lines (kidney, lung, cervical, breast, colon) to assess EMT and metastatic potential.
- Midkine (MDK) expression and its role in IFN-γ-induced EMT and metastasis were investigated.
- STAT1 signaling pathway involvement in IFN-γ-mediated MDK upregulation was analyzed.
- The efficacy of a specific MDK inhibitor (iMDK) in reversing IFN-γ-induced effects was evaluated.
Main Results:
- IFN-γ treatment consistently activated EMT and promoted metastasis in all tested cancer cell lines.
- Midkine (MDK) was identified as a common downstream target of IFN-γ, upregulated via the STAT1 signaling pathway.
- MDK overexpression was found to drive EMT and metastasis across various cancer types, as evidenced by TCGA database analysis.
- Pharmacological inhibition of MDK using iMDK effectively reversed IFN-γ-induced EMT and abrogated metastasis.
Conclusions:
- IFN-γ promotes cancer metastasis through a MDK-dependent mechanism involving STAT1 activation and subsequent EMT induction.
- Targeting MDK presents a promising therapeutic strategy to counteract the pro-metastatic adverse effects of IFN-γ.
- Inhibition of MDK could potentially expand the clinical utility of IFN-γ in cancer treatment and enhance patient outcomes.
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