Wu Xiang, Li Jin, Yan Tingyuan, Ke Xueping, Li Xin, Zhu Yumin, Yang Jianrong, Li Zhongwu
Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
Cancer Cell Int. 2021 Jul 24;21(1):393. doi: 10.1186/s12935-021-02093-6.
The homeobox gene Homeobox B7 (HOXB7) is overexpressed across a range of cancers and promotes tumorigenesis through varying effects on proliferation, survival, migration and invasion. However, its expression pattern and oncogenic role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we aimed to explore the expression pattern of HOXB7, its clinical significance as well as functional roles in HNSCC.
HOXB7 mRNA expression in HNSCC was determined by data mining and analyses from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The protein abundance of HOXB7 was measured by immunohistochemistry in 119 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The pro-tumorigenic roles of HOXB7 in HNSCC were further delineated in vitro by loss-of-function assay. And a xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for HOXB7.
Bioinformatics analyses showed that HOXB7 mRNA was significantly overexpressed in 8 independent HNSCC datasets from TCGA and GEO databases. HOXB7 protein was markedly upregulated in HNSCC samples as compared to normal counterparts and its overexpression significantly associated with high pathological grade, advanced clinical stage, cervical node metastasis (P = 0.0195, 0.0152, 0.0300) and reduced overall and disease-free survival (P = 0.0014, 0.0007). Univariate and multivariate Cox regression analyses further revealed HOXB7 as an independent prognostic factor for patients' overall survival. Moreover, HOXB7 knockdown significantly inhibited cell proliferation, migration and invasion and induced cell apoptosis in HNSCC cells, and resulted in compromised tumour growth in vivo. Furthermore, CMap (Connectivity map) analysis has identified three potential bioactive small molecule inhibitors (NU-1025, thiamine, vinburnine) for HOXB7 targeted therapy in HNSCC.
Our findings revealed that overexpression of HOXB7 was associates with tumour aggressiveness and unfavourable prognosis by serving a novel prognostic biomarker in HNSCC. Moreover, HOXB7 might be involved in the development and progression of HNSCC as an oncogene, and thereby might be a potential therapeutic target for HNSCC.
同源盒基因同源盒B7（HOXB7）在多种癌症中均有过表达，并通过对增殖、存活、迁移和侵袭的不同影响促进肿瘤发生。然而，HOXB7在头颈部鳞状细胞癌（HNSCC）中的表达模式及其致癌作用仍有待深入研究。在此，我们旨在探究HOXB7在HNSCC中的表达模式、临床意义及其功能作用。
通过对来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的数据挖掘和分析，确定HOXB7 mRNA在HNSCC中的表达情况。采用免疫组织化学方法检测119例原发性HNSCC样本中HOXB7的蛋白丰度，并评估其表达与临床病理参数及患者生存率之间的关联。通过功能缺失实验在体外进一步阐明HOXB7在HNSCC中的促肿瘤作用。并在裸鼠中建立异种移植肿瘤模型，以评估HOXB7在肿瘤生长中的作用。进行连通图（CMap）分析，以鉴定可能是HOXB7潜在抑制剂的生物活性小分子。
生物信息学分析显示，HOXB7 mRNA在来自TCGA和GEO数据库的8个独立HNSCC数据集中显著过表达。与正常对照相比，HOXB7蛋白在HNSCC样本中明显上调，其过表达与高病理分级、晚期临床分期、颈部淋巴结转移显著相关（P = 0.0195、0.0152、0.0300），并导致总生存期和无病生存期缩短（P = 0.0014、0.0007）。单因素和多因素Cox回归分析进一步显示HOXB7是患者总生存期的独立预后因素。此外，HOXB7基因敲低显著抑制HNSCC细胞的增殖、迁移和侵袭，并诱导细胞凋亡，且导致体内肿瘤生长受限。此外，CMap分析已鉴定出三种潜在的生物活性小分子抑制剂（NU-1025、硫胺素、长春花碱）用于HNSCC的HOXB7靶向治疗。
我们的研究结果表明，HOXB7的过表达与肿瘤侵袭性及不良预后相关，可作为HNSCC一种新的预后生物标志物。此外，HOXB7作为一种癌基因可能参与HNSCC的发生发展，因此可能是HNSCC的一个潜在治疗靶点。
