Hoxa13 overexpression drives chromosomal instability and liver tumorigenesis in mice

ABSTRACT: Background and aims: Class I Homeobox (HOX) genes are fundamental components of embryonic patterning and morphogenesis, also implicated in neoplastic transformations. Among them HOXA13, in particular, has been found to be the most overexpressed in HCC and to be associated with worse prognosis. However, no previous work has shown so far a direct causal effect between HOXA13 overexpression and liver tumorigenesis. In this study we aimed to prove the direct oncogenicity of HOXA13 in the liver and to unravel the molecular mechanisms of Hoxa13-induced liver tumorigenesis. Approach and Results:  To unravel the oncogenic mechanism of HOXA13 in vivo, a transgenic mouse model of HOXA13 overexpression in the liver was generated using hydrodynamic tail vein injection coupled with a transposase system. The mice phenotype was followed over time, from 2 weeks up to 1-year post injection. RNA-sequencing was performed to monitor the transcriptomic changes over time. HOXA13-overexpression in the liver led to highly proliferative hepatocytes and correlated with the DNA damage marker yH2AX. 1-year post-injection 50% of the injected mice developed liver tumors of various histological grades and types. RNA-sequencing analysis performed on whole liver extracts of 2 weeks-old mice and tumors showed that the main pathway deregulated by HOXA13 overexpression was cell cycle, in particular G2/M transition and mitotic spindle assembly checkpoint. Additionally, HOXA13-overexpressing livers showed a transcriptomic signature of chromosomal Instability, suggesting a possible mechanism of tumorigenesis driven by genome instability. Conclusions: Our study highlights the role of HOXA13 as a novel oncogenic driver in hepatocarcinogenesis and strongly suggests that its oncogenic properties are least partially mediated by induction of chromosomal instability.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166341 | GEO | 2021/02/09

REPOSITORIES: GEO