Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China.
Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
Exp Cell Res. 2022 Sep 1;418(1):113271. doi: 10.1016/j.yexcr.2022.113271. Epub 2022 Jun 25.
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.
癌症干细胞（CSCs）是一种致瘤细胞亚群，导致治疗抵抗、肿瘤复发和转移。本研究旨在探讨高迁移率族 AT 盒 2（HMGA2）在头颈部鳞状细胞癌（HNSCC）进展和 CSCs 调控中的作用及其潜在的分子靶点。通过 qRT-PCR、Western blot 和免疫组织化学检测 HNSCC 标本和细胞中 HMGA2 mRNA 和蛋白的表达水平。通过体外和体内的功能丧失和过表达实验验证 HMGA2 的作用，并通过肿瘤球形成实验评估 CSCs 特性。染色质免疫沉淀（ChIP）和荧光素酶报告基因检测进一步深入了解 HMGA2 调节干细胞特性的分子机制。HMGA2 在 HNSCC 中异常过表达，并促进 CSCs 标志物包括 SOX2、CD133、CD44、ALDH1A1 和 Bmi1 的表达。HMGA2 与 HNSCC 的干性、恶性进展和生存降低相关。荧光素酶报告基因检测表明 Snai2 是 HMGA2 的直接下游靶基因。机制上，ChIP-qPCR 检测表明 HMGA2 被招募到 Snai2 启动子的三个结合位点上，直接促进 HNSCC 中 Snai2 的转录。Snai2 过表达逆转了 HMGA2 干扰对 HNSCC 体外和体内增殖、侵袭和转移以及 CSC 标志物表达的抑制作用。HMGA2 通过直接调节 Snai2 促进 HNSCC 的恶性进展和获得 CSCs 特性，提示靶向 HMGA2-Snai2 轴可能是治疗 HNSCC 的一种有前途的策略。
