Institute of Cancer Stem Cells, Dalian Medical University, Dalian, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Biochim Biophys Acta Mol Cell Res. 2019 Oct;1866(10):1533-1543. doi: 10.1016/j.bbamcr.2019.07.001. Epub 2019 Jul 10.
CPSF4 was identified as a crucial tumorigenic factor in lung cancer development. However, its precise function and the underlying molecular mechanisms in colon cancer progression remain completely unknown. Here, we demonstrate CPSF4 was highly expressed in human colon cancer cells and tissues. Its knockdown inhibited colorectal cancer progression in vitro, including cell proliferation, migration, invasion and stemness maintenance. In contrast, the ectopic overexpression of CPSF4 had the opposite effects in vitro and in vivo. Further mechanistic studies demonstrated that CPSF4 facilitated colorectal tumorigenesis and development partially through transcriptionally regulating hTERT expression by cooperating with NF-kB1 and co-anchoring at hTERT promoter -321 to -234 fragment. In addition, clinical samples analysis indicated that CPSF4 expression was positively correlated with hTERT, and the simultaneously high expression of CPSF4 and hTERT predicted poor patient outcome. Overall, our findings established CPSF4 as a pro-tumorigenic factor in colorectal cancer progression, and suggested that targeting CPSF4-hTERT axis may represent a promising therapeutic strategy in colon cancer treatment.
CPSF4 被鉴定为肺癌发展中的关键致癌因子。然而，其在结肠癌进展中的确切功能和潜在分子机制仍完全未知。在这里，我们证明 CPSF4 在人结肠癌细胞和组织中高度表达。其敲低抑制结直肠癌细胞的体外进展，包括细胞增殖、迁移、侵袭和干性维持。相比之下，CPSF4 的异位过表达在体外和体内具有相反的效果。进一步的机制研究表明，CPSF4 通过与 NF-kB1 合作并在 hTERT 启动子 -321 到 -234 片段上共同锚定，转录调控 hTERT 的表达，从而促进结直肠肿瘤的发生和发展。此外，临床样本分析表明 CPSF4 的表达与 hTERT 呈正相关，同时 CPSF4 和 hTERT 的高表达预示着患者预后不良。总的来说，我们的研究结果确立了 CPSF4 作为结直肠癌细胞进展中的促癌因子，并表明靶向 CPSF4-hTERT 轴可能代表结肠癌治疗的一种有前途的治疗策略。
