Supplementary Figure 4 - PDF file 253K, beta-catenin was relocalized to the nucleus at the invasive front of Wnt1-mediated tumor on Hmga2+/+ genotypic backgrounds, but not on the Hmga2-/- genetic background. beta-catenin was detected in the nucleus of the cells at the invasive front consistent with the HMGA2 expressed cells in the Wnt1-mediated tumor on the Hmga2+/+ genetic background (arrows). On the other hand, no beta-catenin relocalization was detected in tumor on the Hmga2-/- genotypic backgrounds. Scale bars represent 100microm
ARTICLE ABSTRACT
The non-histone chromatin-binding protein HMGA2 is expressed predominantly in the mesenchyme before its differentiation, but it is also expressed in tumors of epithelial origin. Ectopic expression of HMGA2 in epithelial cells induces epithelial–mesenchymal transition (EMT), which has been implicated in the acquisition of metastatic characters in tumor cells. However, little is known about in vivo modulation of HMGA2 and its effector functions in tumor metastasis. Here, we report that HMGA2 loss of function in a mouse model of cancer reduces tumor multiplicity. HMGA2-positive cells were identified at the invasive front of human and mouse tumors. In addition, in a mouse allograft model, HMGA2 overexpression converted nonmetastatic 4TO7 breast cancer cells to metastatic cells that homed specifically to liver. Interestingly, expression of HMGA2 enhanced TGFβ signaling by activating expression of the TGFβ type II receptor, which also localized to the invasive front of tumors. Together our results argued that HMGA2 plays a critical role in EMT by activating the TGFβ signaling pathway, thereby inducing invasion and metastasis of human epithelial cancers. Cancer Res; 73(14); 4289–99. ©2013 AACR.
