Human HOXA10 Lentivirus (CMV)

Dysregulation of the HOX family of transcription factors is frequently observed in a variety of human cancers. Here, researchers found that the HOX gene family is consistently upregulated in NPC and identified HOXA10 as one of the most upregulated HOX genes. Importantly, HOXA10 overexpression is associated with transcriptional activation of multiple oncogenes essential for NPC carcinogenesis, including S phase kinase-related protein 2 (SKP2), calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), and matrix metalloproteinase 1 (MMP1). Mechanistically, overexpression of SKP2 induces degradation of the cell cycle inhibitor p27, leading to rapid cell cycle progression and cell proliferation. Overexpression of CAMKK2 is associated with enhanced mTOR signaling activity to meet the increased demand for protein synthesis in rapidly growing NPC cells. In addition, overexpression of MMP1 promotes NPC cell migration and invasion and contributes to cancer metastasis and progression. Thus, overexpression of HOXA10 promotes NPC growth and metastasis by transcriptionally activating various oncogenic pathways.

SKP2 is a ubiquitin ligase involved in cell cycle regulation, and its main target is p27, an inhibitor of cell cycle regulation. Here, to overexpress HOXA10, the researchers constructed a lentiviral vector expressing HOXA10 (Lv-HOXA10) and a negative control (Lv-NC). As shown in Figures 1a and b, HOXA10 overexpression induced SKP2 upregulation and SKP2-mediated p27 degradation through a ubiquitin-mediated mechanism, which may eventually lead to cell cycle progression and rapid cell proliferation. Consistent with this, the expression of Ki-67, a cell proliferation marker, was significantly increased in NPC cells overexpressing HOXA10 (Figure 1b). In addition, after HOXA10 overexpression, the cell growth rate was greatly increased and more colonies were formed (Figures 1c to f). In contrast, when SMIP004 was used to inhibit SKP2 in cells overexpressing HOXA10, more p27 accumulated in the cells (Figure 1b), resulting in inhibition of the cell cycle and cell proliferation. This was manifested by decreased Ki-67 expression in SMIP004-treated cells (Figure 1b), as well as decreased cell growth rate and colony-forming ability (Figure 1c to f). These findings suggest that HOXA10 can promote NPC cell proliferation by inducing SKP2 expression (Figure 1a).

Figure 1. HOXA10 promotes cell cycle progression and cell proliferation through up-regulating SKP2. (Gong D, et al., 2021)