HMGA2 Contributes to Distant Metastasis and Poor Prognosis by Promoting Angiogenesis in Oral Squamous Cell Carcinoma

Abstract

The highly malignant phenotype of oral squamous cell carcinoma (OSCC), including the presence of nodal and distant metastasis, reduces patient survival. High-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is involved in advanced malignant phenotypes and poor prognosis in several human cancers. However, its biological role in OSCC remains to be elucidated. The purpose of this study was to determine the clinical significance and role of HMGA2 in the malignant potential of OSCC. We first investigated the expression pattern of HMGA2 and its clinical relevance in 110 OSCC specimens using immunohistochemical staining. In addition, we examined the effects HMGA2 on the regulation of vascular endothelial growth factor (VEGF)-A, VEGF-C, and fibroblast growth factor (FGF)-2, which are related to angiogenesis, in vitro. High expression of HMGA2 was significantly correlated with distant metastasis and poor prognosis. Further, HMGA2 depletion in OSCC cells reduced the expression of angiogenesis genes. In OSCC tissues with high HMGA2 expression, angiogenesis genes were increased and a high proportion of blood vessels was observed. These findings suggest that HMGA2 plays a significant role in the regulation of angiogenesis and might be a potential biomarker to predict distant metastasis and prognosis in OSCC.

HMGA Genes and Proteins in Development and Evolution

“…More recently, HMGA1 was shown to interact with the FOXM1 transcription factor for VEGFA promoter binding, inducing tumor angiogenesis in HUVEC cells and in zebrafish xenografts [261]. Similarly, there are also evidences of HMGA2 being involved in the regulation of pro-angiogenic genes like VEGFA, VEGFC, and FGF-2 [262] and in the angiogenesis occurring in diabetic retinopathy [263] ( Figure 3F).…”

HMGA2 as a Critical Regulator in Cancer Development

“…It was shown that metformin decreases angiogenesis and tumor growth by reducing HMGA2 levels in cervical cancer cells through regulation of miR-142-3p . Metformin was suggested to prevent miR-142 sponging to allow targeting of HMGA2 [ 145 ]. It was further reported that miR-1249 suppresses colorectal cancer (CRC) angiogenesis by targeting both VEGFA and HMGA2 through the AKT/mTOR signaling pathway [ 146 ].…”

Potential Utility of Cell Free High Mobility Group AT-hook 2 (HMGA2) as a Prognostic Biomarker in Liquid Biopsies of Oral Squamous Cell Carcinoma

“…Similar findings to our study were reported by Sakata et al who observed a strong correlation of HMGA2 expression with distant metastasis and poor prognosis. However, they explored HMGA2 expression via immunostaining in 110 OSCC patients (Sakata et al, 2019).…”