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MAD2 activates IGF1R/PI3K/AKT pathway and promotes cholangiocarcinoma progression by interfering USP44/LIMA1 complex

Oncogene volume 42, pages 3344–3357 (2023)Cite this article

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Abstract

Spindle assembly checkpoint (SAC) plays an essential part in facilitating normal cell division. However, the clinicopathological and biological significance of mitotic arrest deficient 2 like 1 (MAD2/MAD2L1), a highly conserved member of SAC in cholangiocarcinoma (CCA) remain unclear. We aim to determine the role and mechanism of MAD2 in CCA progression. In the study, we found up-regulated MAD2 facilitated CCA progression and induced lymphatic metastasis dependent on USP44/LIMA1/PI3K/AKT pathway. MAD2 interfered the binding of USP44 to LIMA1 by sequestrating more USP44 in nuclei, causing impaired formation of USP44/LIMA1 complex and enhanced LIMA1 K48 (Lys48)-linked ubiquitination. In therapeutic perspective, the data combined eleven cases of CCA PDTX model showed that high-MAD2 inhibits tumor necrosis and diminishes the inhibition of cell viability after treated with gemcitabine-based regimens. Immunohistochemistry (IHC) analysis of tissue microarray (TMA) for CCA patients revealed that high-MAD2, low-USP44 or low-LIMA1 level are correlated with worse survival for patients. Together, MAD2 activates PI3K/AKT pathway, promotes cancer progression and induces gemcitabine chemo-resistance in CCA. These findings suggest that MAD2 might be an excellent indicator in prognosis analysis and chemotherapy guidance for CCA patients.

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Fig. 1: MAD2 was upregulated in CCA.
Fig. 2: MAD2 enhanced CCA proliferation, metastasis, invasiveness, and lymph-angiogenesis in vitro.
Fig. 3: MAD2 facilitated CCA development in vivo.
Fig. 4: MAD2 promoted CCA progression in PI3K/AKT signaling dependent manner.
Fig. 5: MAD2 interacted with LIMA1 and facilitated its degradation.
Fig. 6: USP44 interacted with and hindered LIMA1 degradation.
Fig. 7: CCA cells with MAD2 suppression are more sensitive to gemcitabine.

Data availability

All data generated or analyzed during this study are included in this published article. Additional data underlying the study are available on request to the corresponding authors.

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Acknowledgements

The authors would like to thank pathologists in the First Affiliated Hospital of Nanjing Medical University for evaluating HE and IHC slides and the professional technicians in Nanjing Personal Oncology Biological Technology Co. Ltd for their guidance.

Funding

This work was supported by Jiangsu Provincial Key Research and Development Program (BE2016789).

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Author notes

  1. These authors contributed equally: Wangjie Jiang, Xiao Yang, Kuangheng Shi.

Authors and Affiliations

  1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Wangjie Jiang, Xiao Yang, Kuangheng Shi, Yaodong Zhang, Xiaoli Shi, Jifei Wang, Yuming Wang, Anlan Chenyan, Jijun Shan, Yirui Wang, Jiang Chang, Ruixiang Chen, Tao Zhou, Yue Yu, Changxian Li & Xiangcheng Li

  2. Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China

    Wangjie Jiang, Yaodong Zhang, Yue Yu, Changxian Li & Xiangcheng Li

  3. Personaloncology Biological Technology Co., Ltd, Nanjing, Jiangsu, China

    Yanping Zhu

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Contributions

Study concept and design: XL, CL; Acquisition of data: XS, JW, YumingW, AC, JS, YiruiW, JC, RC, TZ; Analysis and interpretation of data: WJ, YaodongZ; Drafting of the manuscript: WJ; Critical revision of the manuscript for important intellectual content: XL, YY and CL; Obtained funding: XL, CL; Administrative, technical, or material support: YanpingZ and YY; Study supervision: XL and CL.

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Correspondence to Changxian Li or Xiangcheng Li.

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Jiang, W., Yang, X., Shi, K. et al. MAD2 activates IGF1R/PI3K/AKT pathway and promotes cholangiocarcinoma progression by interfering USP44/LIMA1 complex. Oncogene 42, 3344–3357 (2023). https://doi.org/10.1038/s41388-023-02849-6

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