Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Outpatient, The Affiliated Hospital of Qingdao University, Qingdao, China.
J Cell Biochem. 2018 Mar;119(3):2864-2874. doi: 10.1002/jcb.26461. Epub 2017 Dec 12.
Homeobox A3 (HOXA3), one of HOX transcription factors, regulates gene expression during embryonic development. HOXA3 expression has been reported to be associated with several cancers; however, its role in colon cancer and underlying mechanism are still unclear. The expression of HOXA3 in 232 paired of human colon tumor and adjacent non-tumorous tissues were measured by qPCR. The relationship between HOXA3 expression and clinical outcomes were analyzed by Kaplan-Meier survival curves analysis. Human colon cancer cell lines HT29 and HTC116 were transfected with HOXA3 siRNA, or HOXA3 expressing vector, and then cell proliferation and apoptosis were assessed, respectively. Western blot was performed to detect the activation of EGFR/Ras/Raf/MEK/ERK signaling pathway. Moreover, HOXA3-overexpressing and HOXA3-suppressing HT29 cells were subcutaneous injected into nod mice to confirm the regulation of HOXA3 on EGFR/Ras/Raf/MEK/ERK signaling in regulating tumor growth. HOXA3 was upregulated in colon tumor tissues and cell lines, and upregulated expression of HOXA3 was associated with low survival rate. Knockdown of HOXA3 suppressed cell viability and clone formation, while induced cell apoptosis. HOXA3 knockdown could not induce the increase of cell apoptosis on the condition of EGFR overexpression. In vivo xenograft studies, HOXA3-suppressing cells showed less tumorigenic. Moreover, HOXA3 knockdown suppressed the activation of EGFR/Ras/Raf/MEK/ERK signaling pathway. To conclude, this study indicated that HOXA3 might act as a promoter of human colon cancer formation by regulating EGFR/Ras/Raf/MEK/ERK signaling pathway. HOXA3 might be a potential therapeutic target for the treatment of colon cancer.
Homeobox A3 (HOXA3)，作为同源盒转录因子家族的一员，在胚胎发育过程中调节基因表达。已有报道称 HOXA3 的表达与多种癌症相关，但 HOXA3 在结肠癌中的作用及其潜在机制仍不清楚。本研究采用 qPCR 检测了 232 对人结肠癌组织及其配对的癌旁组织中 HOXA3 的表达。采用 Kaplan-Meier 生存曲线分析 HOXA3 表达与临床结局的关系。用 HOXA3 siRNA 或 HOXA3 表达载体转染人结肠癌 HT29 和 HTC116 细胞系，分别评估细胞增殖和凋亡情况。采用 Western blot 检测 EGFR/Ras/Raf/MEK/ERK 信号通路的激活情况。此外，将过表达和敲低 HOXA3 的 HT29 细胞皮下注射到裸鼠中，以验证 HOXA3 对 EGFR/Ras/Raf/MEK/ERK 信号通路在调控肿瘤生长中的调节作用。HOXA3 在结肠癌组织和细胞系中呈高表达，且高表达与低生存率相关。敲低 HOXA3 抑制细胞活力和克隆形成，同时诱导细胞凋亡。在 EGFR 过表达的情况下，敲低 HOXA3 不能诱导细胞凋亡增加。体内异种移植研究表明，敲低 HOXA3 的细胞成瘤能力降低。此外，敲低 HOXA3 可抑制 EGFR/Ras/Raf/MEK/ERK 信号通路的激活。综上所述，该研究表明 HOXA3 可能通过调节 EGFR/Ras/Raf/MEK/ERK 信号通路而作为人结肠癌形成的促进因子。HOXA3 可能成为结肠癌治疗的潜在靶点。
