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Targeting MTPN sensitizes pancreatic cancer of wild-type BRCA1/2 to Cisplatin-based chemotherapy

Cancer Gene Therapy volume 32, pages 1245–1258 (2025)Cite this article

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Abstract

The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.

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Fig. 1: Bioinformatics analysis of PC and cisplatin.
Fig. 2: Expression analyses and clinical prognostic significance of MTPN in PC.
Fig. 3: MTPN expression affects the biological behaviors of BRCA1/2 wild-type PC cells.
Fig. 4: MTPN increased PC cells with wild-type BRCA1/2 resistance to cisplatin.
Fig. 5: Regulation of BRCA1/2 by MTPN in PC cells in response to cisplatin.
Fig. 6: Cisplatin resistance is linked to the MTPN-dependent induction of phosphorylated IκBα.
Fig. 7: MTPN-induced cisplatin resistance by activating NF-κB and regulate BRCA1/2.
Fig. 8

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Data availability

Correspondence and requests for materials should be addressed to LF-W (lifuwang@sjtu.edu.cn).

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Acknowledgements

Thanks TCGA for sufficient RNA-sequencing data and clinical information.

Funding

This research was supported by grants from The National Natural Science Foundation of China (81870385, 81672719, 81702740).

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  1. These authors contributed equally: Zhuoxin Wang, Xinyang Huang.

Authors and Affiliations

  1. Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Zhuoxin Wang, Xinyang Huang, Yixun Jin, Tingting Gong, Wei Wu, Berik Kouken, Qi Wang & Lifu Wang

  2. Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Tingting Bai

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Contributions

ZxW, XyH contributed to experiments performance, statistical analysis, results integration, and data collection. ZxW, TtB wrote and revised the manuscript and R scripts. YxJ, TtG and WW executed data acquisition and statistical analysis. LfW, BK and QW designed and supervised the study, interpreted the data, and revised the manuscript.

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Correspondence to Berik Kouken, Qi Wang or Lifu Wang.

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Data from the TCGA and GTEx databases were used in our study. Our research involves human tissues derived from tumor and adjacent normal tissues of PC patients. All patients signed an informed consent form. Ethical approval for this study was obtained from the Ethical Committee of Medical Research. There are no clinical trials or animal experiments in our research. All methods were performed in accordance with the relevant guidelines and regulations.

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Wang, Z., Huang, X., Bai, T. et al. Targeting MTPN sensitizes pancreatic cancer of wild-type BRCA1/2 to Cisplatin-based chemotherapy. Cancer Gene Ther 32, 1245–1258 (2025). https://doi.org/10.1038/s41417-025-00925-5

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