Abstract 1421: Targeting ASPM suppresses the tumorigenicity of human hepatocellular carcinoma cells via ASPM-TPX2 axis disruption and result in increased chromosome segregation error
Authors: Pan Hung-Wei , Lin Zhong-Zhe , Huang Guan-Jin 
Published: April 2023

Abstract
Aneuploidy and chromosomal instability (CIN) are common abnormalities in human cancer, might arise from a lesion in the chromosome segregation machinery. CIN has a tumour suppressive role because of excessive genomic damage and subsequent apoptosis or other forms of cell death. Therefore, induced massive chromosome instability and led to cellular death in cancer cells can be one of the most successful strategies for cancer therapy. ASPM is a critical regulator of cell-cycle progression, DNA damage and genome stability. In our previous work, we showed that ASPM was often overexpressed in human HCC and associated with tumor malignance progression and poor prognosis. However, the molecular roles of ASPM in the liver cancer cells still unclear. In this study, our results indicated that targeting ASPM caused a rising impaired chromosomal instability resulting in multinuclearity, mitosis progression prolong, increased multicentrosomes, chromosome segregation error and led to chromosome numbers variation in liver cancer cells. Finally, ASPM inhibition led to cell cycle progression arrest and apoptosis in liver cancer cells. Moreover, in vitro tumor spheroid assay and in vivo xenografts mouse model showed a therapeutic opportunity. Our results indicated the effect of ASPM silencing was led to chromosome segregation error in liver cancer cell. In mechanism analysis, the TPX2 was similar binary expression with ASPM in HCC and as downstream target. In our previous work, targeting TPX2 suppresses the tumorigenesis of hepatocellular carcinoma cells resulting in arrested mitotic phase progression and increased genomic instability. However, silenced ASPM or TPX2 both led to deregulated cyclin B2 protein expression. These results indicated ASPM-TPX2-Cyclin B2 axis was co-expression and TPX2-Cyclin B2 should be the potential downstream targets of ASPM. Moreover, in this study, ASPM was interacted with TPX2 and co-localized at mitotic spindle pore. Overexpression of EGFP-TPX2 was semi-restored the cell fitness caused by ASPM inhibition in liver cancer cells. Taken together, our results indicated that ASPM play important roles in cell proliferation, tumorigenesis and cell cycle progression in HCC cells. These results suggested a new insight into the mechanism of ASPM depletion through deregulated TPX2 and result in Cyclin B2 protein downregulation and contributed to cancer cell growth arrest, chromosome instability and cell death in hepatocellular carcinoma.
Citation Format: Hung-Wei Pan, Zhong-Zhe Lin, Guan-Jin Huang. Targeting ASPM suppresses the tumorigenicity of human hepatocellular carcinoma cells via ASPM-TPX2 axis disruption and result in increased chromosome segregation error [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1421.