HMGA2-Snai2 axis regulates tumorigenicity and stemness of head and neck squamous cell carcinoma

Cancer stem cells (CSCs) are a tumorigenic cell subpopulation, which contributes to treatment resistance, tumor recurrence, and metastasis. This study aimed to investigate the role and underlying molecular targets of high mobility group AT-hook 2 (HMGA2) in the progression and CSCs regulation of head and neck squamous cell carcinoma (HNSCC). HMGA2 mRNA and protein expression levels were examined in HNSCC specimens and cells by qRT-PCR, Western blot, and immunohistochemistry. The roles of HMGA2 were validated via loss-of-function and exogenous overexpression experiments in vitro and in vivo, and CSCs properties were assessed by tumorsphere formation assay. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays provided further insight into the molecular mechanisms by which HMGA2 regulates stemness. HMGA2 was abnormally overexpressed in HNSCC, and it promoted the expression of the CSCs markers including SOX2, CD133, CD44, ALDH1A1, and Bmi1. HMGA2 was correlated with stemness, malignant progression, and reduced survival in HNSCC. Luciferase reporter assay indicated that Snai2 was a direct downstream target gene of HMGA2. Mechanistically, ChIP-qPCR assay showed that HMGA2 was recruited to three binding sites on the Snai2 promoter, directly facilitating the transcription of Snai2 in HNSCC. Snai2 overexpression reversed the inhibitory effect of HMGA2 interference on the proliferation, invasion, and metastasis of HNSCC and CSC marker expression in vitro and in vivo. HMGA2 promoted the malignant progression of HNSCC and acquired CSCs properties through direct regulation of Snai2, thereby suggesting that targeting the HMGA2-Snai2 axis might be a promising therapeutic strategy for HNSCC.