Departments of Medicine and Pathology, Columbia University College of Physicians & Surgeons, New York, USA.
Cancer Res. 2013 Jul 15;73(14):4289-99. doi: 10.1158/0008-5472.CAN-12-3848. Epub 2013 May 30.
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.
非组蛋白染色质结合蛋白 HMGA2 在其分化前主要在间充质中表达，但也在上皮来源的肿瘤中表达。HMGA2 在上皮细胞中的异位表达诱导上皮-间充质转化（EMT），这与肿瘤细胞获得转移特性有关。然而，关于 HMGA2 的体内调节及其在肿瘤转移中的效应功能知之甚少。在这里，我们报告说，在癌症的小鼠模型中 HMGA2 功能丧失会降低肿瘤的多发性。在人和小鼠肿瘤的侵袭前沿鉴定出 HMGA2 阳性细胞。此外，在小鼠同种异体移植模型中，HMGA2 的过表达将非转移性 4TO7 乳腺癌细胞转化为专门归巢到肝脏的转移性细胞。有趣的是，HMGA2 的表达通过激活 TGFβ 型 II 受体的表达增强了 TGFβ 信号，该受体也定位于肿瘤的侵袭前沿。总之，我们的研究结果表明，HMGA2 通过激活 TGFβ 信号通路在 EMT 中发挥关键作用，从而诱导人上皮性癌症的侵袭和转移。
