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Microtubule associated protein 9 inhibits liver tumorigenesis by suppressing ERCC3
Jing Zhang1, Jun-Zhe Huang2, Yan-Quan Zhang2
1Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Background:
Chromosomal instability plays an important part in cancer, but its genetic basis in liver tumorigenesis remains largely unclear. We aimed to characterize the mechanistic significance and clinical implication of mitotic regulator microtubule-associated protein 9 (MAP9) in hepatocellular carcinoma (HCC).
Methods:
The biological functions of MAP9 were determined by in vitro tumorigenicity assays. Systematic MAP9 knockout mouse (MAP9∆/∆) and hepatocyte-specific MAP9 knockout mouse (MAP9∆/∆hep) were generated to confirm the role of MAP9 in HCC. The clinical impact of MAP9 was assessed in primary HCC tissue samples.
Findings:
We found that MAP9 was frequently silenced in HCC tissue samples. The transcriptional silence of MAP9 in liver cancer cell lines and tissue samples was mediated by its promoter hypermethylation. MAP9 promoter hypermethylation or downregulation was associated with poor survival and recurrence in patients with HCC. Mechanistically, ectopic expression of MAP9 in LO2 and HepG2 cell lines impaired cell proliferation, colony formation, migration and invasion, and induced cell apoptosis and cycle arrest, whereas knockdown of MAP9 in Miha cell line showed the opposite effects. We found that MAP9∆/∆ mice spontaneously developed a liver hyperplastic nodule and MAP9∆/∆hep accelerated diethylnitrosamine-induced HCC formation. The tumour suppressive effect of MAP9 in HCC was mediated by downregulating excision repair cross-complementation group 3 (ERCC3), a nucleotide excision repair gene. Restoration of ERCC3 expression possessed an oncogenic potency and abrogated the tumour suppressive effects of MAP9.
Interpretation:
MAP9 is a novel tumour suppressor in HCC by inhibiting ERCC3 expression, and serves as a prognostic factor in HCC patients.
Insights
Microtubule-associated protein 9 (MAP9) acts as a tumor suppressor in liver cancer by inhibiting ERCC3. Silenced MAP9 expression predicts poor prognosis for hepatocellular carcinoma (HCC) patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chromosomal instability is crucial in cancer, but its role in liver tumorigenesis is unclear.
- Microtubule-associated protein 9 (MAP9), a mitotic regulator, is investigated for its role in hepatocellular carcinoma (HCC).
Purpose of the Study:
- To characterize the mechanistic significance of MAP9 in liver cancer.
- To determine the clinical implications of MAP9 in hepatocellular carcinoma (HCC).
Main Methods:
- In vitro tumorigenicity assays and MAP9 knockout mouse models (systematic and hepatocyte-specific) were used.
- Biological functions and tumor suppressive effects of MAP9 were assessed.
- Clinical impact was evaluated in primary HCC tissue samples.
Main Results:
- MAP9 was frequently silenced in HCC via promoter hypermethylation, correlating with poor patient survival and recurrence.
- MAP9 suppressed cell proliferation, migration, and invasion, while inducing apoptosis and cell cycle arrest.
- MAP9 knockout mice developed liver tumors, and MAP9 inhibited HCC progression by downregulating ERCC3.
Conclusions:
- MAP9 functions as a novel tumor suppressor in HCC by inhibiting ERCC3 expression.
- MAP9 serves as a valuable prognostic factor for HCC patients.
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