Li Weizhi, Li Yingchao, Li Peijie, Ma Fuquan, Liu Mengying, Kong Shuzhen, Xue Hui
Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Front Oncol. 2022 Jun 29;12:822760. doi: 10.3389/fonc.2022.822760. eCollection 2022.
Hepatocellular carcinoma (HCC) remains a worldwide burden. However, the mechanisms behind the malignant biological behavior of HCC remain unclear. The homeobox (HOX) family could act as either promoters or suppressors in different kinds of malignancies. Our study discovered the role of HOXB5 in regulating HCC progression.
The HOXB5 expression was assessed by RT-PCR analysis in human HCC samples and cell lines. HOXB5 transcriptional regulation of the EGFR was verified by the luciferase reporter assay and chromatin immunoprecipitation experiment. The oncogenic role of HOXB5 in HCC progression was analyzed by CCK8, colony-forming, and transwell assays.
Upregulation of HOXB5 was found in human HCC, and was strongly correlated with HCC tumor size, tumor-nodule metastasis, TNM stage, and relatively unfavorable OS and DFS. Ectopic expression of HOXB5 promoted the capacity of cell growth and clonogenicity, while the inhibition of HOXB5 decreased the proliferation and clonogenicity potential by CCK8 and colony-forming assays. In addition, HOXB5 also promoted cell migration by transwell experiment. Mechanism studies elucidated that HOXB5 triggers HCC progression direct transcriptional activation of EGFR. The upregulation of HOXB5 is regulated by miR-200a-3p and miR-181-5p. Transfection of miR-200a-3p and miR-181-5p mimics blocked the cell proliferation and migration regulated by HOXB5, while overexpression of the 3'-UTR mutant HOXB5 abolished the suppressive effect of miR-200a-3p and miR-181-5p, but not the wild-type HOXB5.
HOXB5 is a promising prognostic factor in human HCC. Targeting miR-200a-3p and the miR-181-5p/HOXB5/EGFR signaling pathway may provide new options for the treatment strategies of HCC.
肝细胞癌（HCC）仍是一项全球性负担。然而，HCC恶性生物学行为背后的机制仍不清楚。同源盒（HOX）家族在不同类型的恶性肿瘤中既可以作为促进因子，也可以作为抑制因子。我们的研究发现了HOXB5在调节HCC进展中的作用。
通过RT-PCR分析评估人HCC样本和细胞系中HOXB5的表达。通过荧光素酶报告基因检测和染色质免疫沉淀实验验证HOXB5对表皮生长因子受体（EGFR）的转录调控。通过CCK8、集落形成和Transwell实验分析HOXB5在HCC进展中的致癌作用。
在人HCC中发现HOXB5上调，且与HCC肿瘤大小、肿瘤结节转移、TNM分期以及相对较差的总生存期（OS）和无病生存期（DFS）密切相关。HOXB5的异位表达促进了细胞生长和克隆形成能力，而通过CCK8和集落形成实验抑制HOXB5则降低了增殖和克隆形成潜力。此外，通过Transwell实验发现HOXB5还促进了细胞迁移。机制研究表明，HOXB5通过直接转录激活EGFR触发HCC进展。HOXB5的上调受miR-200a-3p和miR-181-5p调控。转染miR-200a-3p和miR-181-5p模拟物可阻断HOXB5调节的细胞增殖和迁移，而过表达3'-UTR突变型HOXB5可消除miR-200a-3p和miR-181-5p的抑制作用，但野生型HOXB5则无此作用。
HOXB5是人类HCC中一个有前景的预后因子。靶向miR-200a-3p和miR-181-5p/HOXB5/EGFR信号通路可能为HCC的治疗策略提供新的选择。
