Abstract 453: The role of centrosome amplification in HCC

Abstract

Abstract Centrosome is the major microtubule organizing center (MTOC) in mammalian cells which maintain cell polarity, organization of microtubules and regulate cell cycle progression. In normal cells, centrosome duplication cycle is tightly coupled with cell cycle, DNA synthesis, mitosis as these event were controlled by parallel pathways. Centrosomal defect is reported in numerous type of solid and hematologic malignancy, both structurally (enlarged PCM, string-like etc) and numerically (<2 or >=3). Centrosome amplification (CA, n>=3) is the most commonly reported. CA is casually linked to chromosomal instability (CIN), tumor-initiation, advanced tumor stage and chemo-resistance. CA arises through multiple distinct but non-redundant mechanisms in tumor, for example, aberrant cell cycle, hypoxia, and chemotherapy. Recently studies suggest CA might not be responsible for HCC initiation. Yet, around 90% of HCC cells carry certain degree of CA. It is associated with p53 mutation and tumor-aneuploidy but no other clinicopathological features. The role of CA in HCC progression deserve a more comprehensive study. To investigate the role of CA in HCC, first, we use CA20, an expression signature-score includes centrosomal structural genes and genes results in CA when dyregulated. We use CA20 as surrogate marker to evaluate the clinical outcome of CA in HCC from GEO datasets. CA carrying HCC was found to have poor overall survival and larger tumor size. Next, we developed several inducible PLK4 overexpressing HCC cell line. Preliminary data shown that PLK4 overexpression concomitantly leaded to centrosome over-duplication in HCC cell lines. Functionally, PLK4 overexpression resulted in increased cell migration, but retarded growth rate in p53+/+ HCC cells. Furthermore, we identified another cell cycle-related kinase - Aurora A, as a novel interacting partner of PLK4 suggest that these kinases work together to promote malignant transformation. Citation Format: Sai Fung Yeung, Yick Pang Ching. The role of centrosome amplification in HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 453.