The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect
The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect
复制标题
FOXC1/FBP1信号轴通过增强Warburg效应促进结直肠癌增殖
DOI：
10.1038/s41388-018-0469-8
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发表时间：
2019-01-24
期刊：
影响因子：
8
通讯作者：
Li, Dawei
中科院分区：
文献类型：
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作者：
Li, Qingguo;Wei, Ping;Li, Dawei
叉头盒（FOX）转录因子的异常表达在肿瘤发生中起重要作用。然而，FOX家族成员FOXC 1在维持结直肠癌（CRC）恶性肿瘤中的功能尚不清楚。在此，使用组织微阵列的免疫组织化学分析和验证癌症基因组图谱（TCGA）队列中CRC标本中的FOXC 1表达。通过改变FOXC 1在体外和体内的表达来评估FOXC 1表达对CRC细胞增殖和糖酵解的影响。采用细胞和分子生物学方法进行了机制研究。我们的研究结果表明，FOXC 1的表达在大肠癌标本比在相邻的良性组织标本。对获得研究样本的患者进行单变量生存分析，并验证队列表明异位FOXC 1表达与生存期缩短显著相关。在CRC细胞中沉默FOXC 1表达可抑制其增殖和集落形成，并降低其葡萄糖消耗和乳酸产生。相反，FOXC 1过表达具有相反的效果。此外，FOXC 1表达的增加下调了关键糖酵解酶果糖-1，6-二磷酸酶1（FBP 1）的表达。从机制上讲，FOXC 1直接与FBP 1基因的启动子区域结合，并负调控其转录活性。总的来说，异常FBP 1表达有助于CRC的致瘤性，并且FBP 1表达降低与FOXC 1表达增加相结合提供了比FOXC 1单独表达更好的预后信息。因此，FOXC 1/FBP 1轴诱导CRC细胞增殖，重新编程CRC中的代谢，并构成CRC的潜在预后预测因子和治疗靶点。
Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC.