Although previous studies have established a prominent role for HMGA1 (formerly HMG-I/Y) in aggressive human
cancers, the role of HMGA2 (formerly HMGI-C) in malignant transformation has not been clearly defined. The
HMGA gene family includes HMGA1, which encodes the HMGA1a and
HMGA1b protein isoforms, and HMGA2, which encodes HMGA2. These
chromatin-
binding proteins function in transcriptional regulation and recent studies also suggest a role in cellular senescence. HMGA1
proteins also appear to participate in cell cycle regulation and malignant transformation, whereas HMGA2 has been implicated primarily in the pathogenesis of benign, mesenchymal
tumors. Here, we show that overexpression of HMGA2 leads to a transformed phenotype in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA2 expression blocks the transformed phenotype in metastatic human
non-small cell lung cancer cells. Moreover, we show that HMGA2
mRNA and
protein are overexpressed in primary human
lung cancers compared with normal tissue or indolent
tumors. In addition, there is a statistically significant correlation between
HMGA2 protein staining by immunohistochemical analysis and
tumor grade (P < 0.001). Our results indicate that HMGA2 is an oncogene important in the pathogenesis of human
lung cancer. Although additional studies with animal models are needed, these findings suggest that targeting HMGA2 could be therapeutically beneficial in
lung cancer and other
cancers characterized by increased HMGA2 expression.