title: HMGA2 is a driver of tumor metastasis.
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.
authors.affiliation: Departments of Medicine and Pathology, Columbia University College of Physicians & Surgeons, New York, USA.
authors.forename: Asahiro
authors.initials: A
authors.lastname: Morishita
authors.forename: M Raza
authors.initials: MR
authors.lastname: Zaidi
authors.forename: Akira
authors.initials: A
authors.lastname: Mitoro
authors.forename: Devipriya
authors.initials: D
authors.lastname: Sankarasharma
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.forename: Kiran
authors.initials: K
authors.lastname: Chada
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D045325:HCT116 Cells; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D025743:HMGA2 Protein; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II