Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Key Laboratory of Tumour Immunopathology of Ministry of Education of China, Third Military Medical University, Chongqing, People's Republic of China.
J Pathol. 2015 Aug;236(4):467-78. doi: 10.1002/path.4541. Epub 2015 May 22.
Semaphorin-3F (SEMA3F), an axonal repulsant in nerve development, has been shown to inhibit the progression of human colorectal cancer (CRC); however, the underlying mechanism remains elusive. In this study we found a negative correlation between the levels of SEMA3F and CXCR4 in CRC specimens from 85 patients, confirmed by bioinformatics analysis of gene expression in 229 CRC samples from the Cancer Genome Atlas. SEMA3F(high) /CXCR4(low) patients showed the lowest frequency of lymph node and distant metastasis and the longest survival. Mechanistically, SEMA3F inhibited the invasion and metastasis of CRC cells through PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis. Specifically, ASCL2 enhanced the invasion and metastasis of CRC cells in vitro and expression of ASCL2 correlated with distant metastasis, tumour size and poor overall survival in CRC patients. Treatment of CRC cells with the CXCR4 antagonist AMD3100 attenuated SEMA3F knockdown-induced invasion and metastasis of CRC cells in vitro and in vivo. Our study thus demonstrates that SEMA3F functions as a suppressor of CRC metastasis via down-regulating the ASCL2-CXCR4 axis.
信号蛋白 3F（SEMA3F）是神经发育中的一种轴突排斥物，已被证明可抑制人类结直肠癌（CRC）的进展；然而，其潜在机制仍不清楚。在这项研究中，我们在 85 名患者的 CRC 标本中发现了 SEMA3F 水平与 CXCR4 之间的负相关，这一结果通过对癌症基因组图谱中 229 个 CRC 样本的基因表达进行生物信息学分析得到了证实。SEMA3F(高)/CXCR4(低)患者的淋巴结和远处转移频率最低，生存时间最长。在机制上，SEMA3F 通过 PI3K-AKT 依赖性下调 ASCL2-CXCR4 轴抑制 CRC 细胞的侵袭和转移。具体而言，ASCL2 增强了 CRC 细胞在体外的侵袭和转移，ASCL2 的表达与 CRC 患者的远处转移、肿瘤大小和总体生存不良相关。用 CXCR4 拮抗剂 AMD3100 处理 CRC 细胞可减弱 SEMA3F 敲低诱导的 CRC 细胞在体外和体内的侵袭和转移。因此，我们的研究表明，SEMA3F 通过下调 ASCL2-CXCR4 轴发挥 CRC 转移的抑制作用。
