Targeting HCC Therapy: On or Off ToPiX?

Primary liver cancer, the fifth most frequently diagnosed cancer worldwide, is the second most common cause of cancer mortality [1]. Among primary liver cancers, hepatocellular carcinoma (HCC) accounts for 70–85 % of the total liver cancer burden worldwide [2]. Epidemiological evidence suggests that several environmental factors are involved in the development of HCC, including infection with hepatitis B (HBV) and C (HCV) viruses. Globally, HBV is the most frequent underlying cause of HCC, with an estimated 300 million persons with chronic infection worldwide. Chronic HCV infection is also a major risk factor for the development of HCC. There is preliminary evidence indicating that host genetic factors may contribute to progression of HCV [3]. Assessment of host genetic aberrations revealed mutations of the well-known tumor suppressor gene p53 and amplification of the human chromosome 20q region in up to 30 % of HCC cases [4]. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein encoded by a gene located on human chromosome 20q11. Several studies report that multiple tumor types overexpress TPX2; TPX2 expression in HCC tissues correlates with the tumor– node–metastasis stage (TNM), tumor number, and tumor differentiation. Liu et al. [5] described TPX2 as a novel prognostic marker for predicting overall 5-year and disease-free survival of HCC patients. In vitro, TPX2 knockdown significantly inhibited cell proliferation and viability in Hep3B and HepG2 cells. Moreover, TPX2 knockdown noticeably slowed down tumor growth in a nude mouse xenograft model and prominently suppressed HCC cell invasion and migration [6]. TPX2 localizes to the nucleus during S-phase and G2 and at the mitotic spindle poles during mitosis [7] emphasizing its likely involvement in cell division. Yet, the full connection of TPX2 to HCC remains largely undetermined, as only few studies have investigated this protein. In this issue of Digestive Diseases and Sciences, Lian et al. [8] investigated the effects of TPX2 on the cell cycle, on apoptosis, and on the epithelial-to-mesenchymal transition (EMT) fundamental to tumorigenesis. They reported that TPX2 mRNA expression levels were elevated in HCC tumors in 70 paired tumor versus adjacent non-tumor liver tissues, with expression of TPX2 localized to the nuclei. Using siRNA-mediated knockdown loss of TPX2, the authors reported G2/M cell cycle arrest, reduced cell proliferation, and the induction of apoptosis in three cell lines, with alteration of the key cell cycle regulators cyclin A1, B1, D1, and E1, and p21, a regulator of cyclin D1. Genomic lesions in a cell are usually repaired before the onset of DNA replication and cell division. If the damage is not repairable, programed cell death termed apoptosis occurs to limit proliferation of cells with defective DNA. The tumor suppressor protein p53 induces cell cycle arrest or apoptosis, partly through Bax, a transcriptional target of p53. Bax expression was increased in the TPX2-siRNA knockdown HCC-derived cell lines, indicating that TPX2 drives damaged cells through the cell cycle, promoting tumorigenesis. The apoptosis-related enzymes cleaved caspase-3 and caspase-8 were upregulated following TPX2 loss, further supporting the anti-apoptosis function of TPX2 (Fig. 1). & Claudia D. Andl claudia.andl@vanderbilt.edu