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

Wangjie Jiang1,2, Xiao Yang1, Kuangheng Shi1

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

Oncogene
|September 26, 2023
PubMed

Insights

Mitotic arrest deficient 2 (MAD2) promotes cholangiocarcinoma (CCA) progression and metastasis by disrupting the USP44/LIMA1 complex. High MAD2 levels correlate with poor survival and gemcitabine resistance in CCA patients.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Division

Background:

  • The spindle assembly checkpoint (SAC) is crucial for normal cell division.
  • The role of MAD2 (mitotic arrest deficient 2), a key SAC component, in cholangiocarcinoma (CCA) remains largely unknown.
  • Understanding MAD2's function is vital for developing targeted therapies for CCA.

Purpose of the Study:

  • To investigate the role and underlying mechanism of MAD2 in cholangiocarcinoma (CCA) progression.
  • To explore the potential of MAD2 as a prognostic marker and therapeutic target in CCA.

Main Methods:

  • Utilized patient-derived tumor xenograft (PDTX) models of CCA.
  • Performed immunohistochemistry (IHC) analysis on tissue microarrays (TMA) from CCA patients.
  • Investigated molecular pathways including USP44/LIMA1 complex formation, ubiquitination, and PI3K/AKT signaling.

Main Results:

  • Up-regulated MAD2 was found to enhance CCA progression and lymphatic metastasis.
  • MAD2 disrupts the USP44/LIMA1 complex formation, leading to increased LIMA1 ubiquitination and PI3K/AKT pathway activation.
  • High MAD2 levels correlated with reduced tumor necrosis, diminished gemcitabine efficacy, and poorer patient survival, while low USP44 or LIMA1 also indicated worse outcomes.

Conclusions:

  • MAD2 promotes cholangiocarcinoma progression and metastasis by activating the PI3K/AKT pathway.
  • MAD2 contributes to gemcitabine chemo-resistance in CCA.
  • MAD2 serves as a potential prognostic indicator and a guide for chemotherapy in CCA patients.

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