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) 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 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063135 | PMC |
| http://dx.doi.org/10.1016/j.ebiom.2020.102701 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Frequency of RPGRIP1 and MAP9 genetic modifiers of canine progressive retinal atrophy, in 132 breeds of dog.
Anim Genet
August 2024
Department of Veterinary Medicine, Canine Genetics Centre, University of Cambridge, Cambridge, UK.
Article Synopsis
- * A study genotyped these variants in 132 different dog breeds, finding that they are present in multiple breeds, but the frequency of each variant is usually specific to certain subsets of breeds.
- * The data suggests these variants have ancient origins, and breeders might selectively avoid breeding dogs that are homozygous for both variants due to the more severe health issues they cause.
Sex-specific genetic architecture of blood pressure.
Nat Med
March 2024
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (P ≤ 5 × 10; P > 5 × 10) and 142 were male-specific (P ≤ 5 × 10; P > 5 × 10); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1.
View Article and Find Full Text PDFMAP9/MAPH-9 supports axonemal microtubule doublets and modulates motor movement.
Dev Cell
January 2024
Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address:
Article Synopsis
- Microtubule doublets (MTDs) consist of an incomplete microtubule attached to a complete one and are found in cilia across many species, but how they form and are maintained is not well understood.
- Research identified the protein MAP9 (and its C. elegans homolog MAPH-9) as crucial for MTD assembly, which binds specifically to MTDs, influenced by tubulin modification.
- The absence of MAPH-9 leads to structural defects in MTDs and affects cilia function, indicating that MAP9/MAPH-9 is likely important in maintaining ciliary motor regulation and MTD structure in both worms and mammals.
Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine -associated cone-rod dystrophy.
Front Cell Neurosci
August 2023
Division of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Photoreceptors possess a highly specialized primary cilium containing expanded ciliary membrane discs called the outer segment. The photoreceptor cilium is essential for the maintenance of the outer segment, and pathogenic variants in more than 50 cilia-related genes have been identified as causing non-syndromic inherited retinal diseases in patients. The retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) is a structural protein localized to the photoreceptor cilium and biallelic variants have been associated with non-syndromic human inherited retinal diseases.
View Article and Find Full Text PDFZn2+ decoration of microtubules arrests axonal transport and displaces tau, doublecortin, and MAP2C.
J Cell Biol
August 2023
Department of Biological Sciences, University of Denver, Denver, CO, USA.
Article Synopsis
- Intracellular Zn2+ levels rise due to neuronal depolarization, but its immediate effects on neuron function are not well understood.
- Elevated Zn2+ concentrations decrease the movement of lysosomes and mitochondria in primary rat hippocampal neurons and HeLa cells by inhibiting motor proteins without affecting their binding to microtubules.
- Zn2+ binds directly to microtubules and promotes the detachment of specific proteins (like tau and DCX) from them, indicating that Zn2+ plays a crucial role in regulating axonal transport and related microtubule processes.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!