Department of Gastroenterology and Hepatology, Bishan Hospital of Chongqing, Bishan Hospital of Chongqing Medical University, Chongqing, China.
Department of Gastroenterology and Hepatology, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University School of Medicine, Chongqing, China.
Gut Liver. 2024 May 15;18(3):476-488. doi: 10.5009/gnl220531. Epub 2023 Jul 17.
BACKGROUND/AIMS: Cancer stem cells (CSCs) are believed to drive tumor development and metastasis. Activin and hepatocyte growth factor (HGF) are important cytokines with the ability to induce cancer stemness. However, the effect of activin and HGF combination treatment on CSCs is still unclear.
In this study, we sequentially treated colorectal cancer cells with activin and HGF and examined CSC marker expression, self-renewal, tumorigenesis, and metastasis. The roles of forkhead box M1 (FOXM1) and sex-determining region Y-box 2 (SOX2), two stemness-related transcription factors, in activin/HGF-induced aggressive phenotype were explored.
Activin and HGF treatment increased the expression of CSC markers and enhanced sphere formation in colorectal cancer cells. The tumorigenic and metastatic capacities of colorectal cancer cells were enhanced upon activin and HGF treatment. Activin and HGF treatment preferentially promoted stemness and metastasis of CD133+ subpopulations sorted from colorectal cancer cells. FOXM1 was upregulated by activin and HGF treatment, and the knockdown of FOXM1 blocked activin/HGF-induced stemness, tumorigenesis, and metastasis of colorectal cancer cells. Similarly, SOX2 was silencing impaired sphere formation of activin/HGF-treated colorectal cancers. Overexpression of SOX2 rescued the stem cell-like phenotype in FOXM1-depleted colorectal cancer cells with activin and HGF treatment. Additionally, the inhibition of FOXM1 via thiostrepton suppressed activin/HGF-induced stemness, tumorigenesis and metastasis.
Sequential treatment with activin and HGF promotes colorectal cancer stemness and metastasis through activation of the FOXM1/SOX2 signaling. FOXM1 could be a potential target for the treatment of colorectal cancer metastasis.
背景/目的：癌症干细胞（CSCs）被认为是肿瘤发生和转移的驱动力。激活素和肝细胞生长因子（HGF）是具有诱导癌症干性能力的重要细胞因子。然而，激活素和 HGF 联合治疗对 CSCs 的影响尚不清楚。
在本研究中，我们依次用激活素和 HGF 处理结直肠癌细胞，检测 CSC 标志物表达、自我更新、肿瘤发生和转移。探讨了叉头框 M1（FOXM1）和性别决定区 Y 框 2（SOX2）这两个与干性相关的转录因子在激活素/HGF 诱导的侵袭表型中的作用。
激活素和 HGF 处理增加了结直肠癌细胞中 CSC 标志物的表达，并增强了球体形成。激活素和 HGF 处理增强了结直肠癌细胞的致瘤和转移能力。激活素和 HGF 处理优先促进了从结直肠癌细胞中分选的 CD133+亚群的干性和转移。FOXM1 被激活素和 HGF 处理上调，FOXM1 的敲低阻断了激活素/HGF 诱导的结直肠癌细胞的干性、肿瘤发生和转移。同样，SOX2 的沉默削弱了激活素/HGF 处理的结直肠癌细胞的球体形成。过表达 SOX2 挽救了激活素和 HGF 处理的 FOXM1 耗尽的结直肠癌细胞的干细胞样表型。此外，通过硫链丝菌素抑制 FOXM1 抑制了激活素/HGF 诱导的干性、肿瘤发生和转移。
激活素和 HGF 的序贯治疗通过激活 FOXM1/SOX2 信号促进结直肠癌细胞的干性和转移。FOXM1 可能是治疗结直肠癌转移的潜在靶点。
