State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China.
Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China.
Theranostics. 2020 Apr 6;10(12):5209-5224. doi: 10.7150/thno.43640. eCollection 2020.
Angiogenesis, one of the hallmarks of cancer, is essential for both tumor growth and metastasis. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are largely unknown. Here, we report the role of HOXA5 in tumor angiogenesis of HCC. : The expression of miR-130b-3p and HOXA5 was determined by qRT-PCR and immunohistochemistry, respectively. Capillary tube formation assay, chicken chorioallantoic membrane assay, and subcutaneous xenograft experiments were performed to investigate the role of miR-130-3p and HOXA5. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to evaluate the interaction between Sp1, miR-130b-3p and HOXA5. : miR-130b-3p was found up-regulated in HCC and correlated with a poor prognosis. miR-130b-3p promoted HCC angiogenesis both and . Mechanistically, HOXA5 was validated as a direct target of miR-130b-3p. Furthermore, we demonstrated that HOXA5 was down-regulated in HCC and its down-regulation was associated with larger tumor size, shorter overall survival, and higher recurrence probability. Moreover, HOXA5 was significantly associated with angiogenesis biomarkers such as CD31 and CD34. Functional studies revealed that the knockdown of HOXA5 also significantly promoted HCC angiogenesis both and . Knocking-down HOXA5 significantly provoked HCC cells to induce the capillary tube formation, migration and proliferation of endothelial cells. In xenograft animal models, we found that a decrease of HOXA5 effectively enhanced tumor growth and increased microvessel densities. We further demonstrated that miR-130b-3p could be directly transcriptionally regulated by Sp1. : This study showed that a dysregulation in the Sp1/miR-130b-3p/HOXA5 axis contributed to HCC progression and angiogenesis, and that HOXA5 can be considered as a promising therapeutic target for treating HCC.
血管生成是癌症的标志之一，对肿瘤的生长和转移至关重要。然而，其在肝细胞癌（HCC）中的分子机制在很大程度上尚不清楚。在这里，我们报告 HOXA5 在 HCC 肿瘤血管生成中的作用。通过 qRT-PCR 和免疫组织化学分别测定 miR-130b-3p 和 HOXA5 的表达。进行毛细管管形成试验、鸡胚绒毛尿囊膜试验和皮下异种移植实验，以研究 miR-130b-3p 和 HOXA5 的作用。进行荧光素酶报告基因检测和染色质免疫沉淀检测，以评估 Sp1、miR-130b-3p 和 HOXA5 之间的相互作用。结果发现 miR-130b-3p 在 HCC 中上调，并与不良预后相关。miR-130b-3p 促进 HCC 血管生成。机制上，HOXA5 被验证为 miR-130b-3p 的直接靶标。此外，我们证明 HOXA5 在 HCC 中下调，其下调与更大的肿瘤大小、更短的总生存期和更高的复发概率相关。此外，HOXA5 与血管生成生物标志物如 CD31 和 CD34 显著相关。功能研究表明，HOXA5 的敲低也显著促进 HCC 血管生成。HOXA5 的敲低显著促使 HCC 细胞诱导内皮细胞的毛细管形成、迁移和增殖。在异种移植动物模型中，我们发现 HOXA5 的减少有效地增强了肿瘤生长并增加了微血管密度。我们进一步证明 miR-130b-3p 可以被 Sp1 直接转录调控。综上所述，该研究表明 Sp1/miR-130b-3p/HOXA5 轴的失调促进了 HCC 的进展和血管生成，HOXA5 可以被认为是治疗 HCC 的有前途的治疗靶点。
