AI Article Synopsis
- The spindle assembly checkpoint (SAC) is crucial for normal cell division, and this study examines the role of MAD2, a key player in SAC, in cholangiocarcinoma (CCA), focusing on its impact on cancer progression.
- Researchers discovered that elevated levels of MAD2 promote CCA progression and lymphatic spread by disrupting the USP44/LIMA1 complex, which leads to enhanced cancer cell survival and resistance to gemcitabine, a common chemotherapy drug.
- The findings indicate that high MAD2 levels, along with low levels of USP44 or LIMA1, are linked to poorer survival outcomes for CCA patients, suggesting MAD2 could serve as a potential biomarker for prognosis and treatment planning.
Article 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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| http://dx.doi.org/10.1038/s41388-023-02849-6 | DOI Listing |
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