FOXD3 Regulates CSC Marker, DCLK1-S, and Invasive Potential: Prognostic Implications in Colon Cancer.
FOXD3 Regulates CSC Marker, DCLK1-S, and Invasive Potential: Prognostic Implications in Colon Cancer.
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DOI：
10.1158/1541-7786.mcr-17-0287
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发表时间：
2017-12
期刊：
影响因子：
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通讯作者：
Singh P
中科院分区：
文献类型：
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作者：
Sarkar S;O'Connell MR;Okugawa Y;Lee BS;Toiyama Y;Kusunoki M;Daboval RD;Goel A;Singh P
人类双皮质素样激酶 1 (DCLK1) 基因的 5' (α)-启动子在结肠癌发生过程中发生表观遗传沉默，导致人类结肠腺癌 (hCRC) 中经典长 (L)-亚型 1 (DCLK1-L) 的表达丧失。相反，hCRC 表达来自 DCLK1 替代 (β) 启动子的短 (S)-亚型 2 (DCLK1-S)。目前的研究检查了 (β) 启动子的转录活性在正常细胞与癌细胞中是否受到抑制。基于计算机和分子方法，发现 FOXD3 有效抑制 (β)-启动子的转录活性。 FOXD3 在人结肠癌细胞 (hCCC) 中甲基化，FOXD3 表达丧失，从而允许 DCLK1(S) 变体在 hCCC/hCRC 中表达。在一组 CRC 患者样本 (n = 92) 中测量了 FOXD3/DCLK1(S/L) 的相对水平，并与总生存期 (OS) 相关。与表达低 DCLK1(S) 的患者相比，表达高 DCLK1(S) 的患者，无论是否有低 FOXD3，其 OS 均明显较差。 DCLK1-L 的相对水平与 OS 不相关。在一项试点回顾性研究中，与低风险患者（未患 CRC）的腺瘤相比，高风险患者（在 15 年内出现 CRC）的结肠腺瘤表现出 DCLK1(S) 染色显着较高，FOXD3 染色显着较低。最新结果强烈表明测量腺瘤中的 DCLK1(S)/FOXD3 具有预后价值。 DCLK1(S) 的过度表达而非 DCLK1(L) 导致 hCCC 的侵袭潜力显着增加，这可能解释了 DCLK1-S 高表达肿瘤患者的预后较差。根据这些数据，FOXD3 是正常细胞中 DCLK1-S 表达的有效抑制因子； hCCC/hCRC 中 FOXD3 的缺失使得 DCLK1-S 上调，从而赋予细胞强大的侵袭潜力。
The 5′ (α)-promoter of the human doublecortin-like kinase 1 (DCLK1) gene becomes epigenetically silenced during colon carcinogenesis, resulting in loss of expression of the canonical long(L)-isoform1 (DCLK1-L) in human colon adenocarcinomas (hCRCs). Instead, hCRCs express a short(S)-isoform2 (DCLK1-S) from an alternate (β)-promoter of DCLK1. The current study, examined if the transcriptional activity of the (β)-promoter is suppressed in normal versus cancerous cells. On the basis of in silico and molecular approaches, it was discovered that FOXD3 potently inhibits the transcriptional activity of the (β)-promoter. FOXD3 becomes methylated in human colon cancer cells (hCCC), with loss of FOXD3 expression, allowing expression of the DCLK1(S) variant in hCCCs/hCRCs. Relative levels of FOXD3/DCLK1(S/L) were measured in a cohort of CRC patient specimens (n = 92), in relation to overall survival (OS). Patients expressing high DCLK1(S), with or without low FOXD3, had significantly worse OS compared with patients expressing low DCLK1(S). The relative levels of DCLK1-L did not correlate with OS. In a pilot retrospective study, colon adenomas from high-risk patients (who developed CRCs in <15 years) demonstrated significantly higher staining for DCLK1(S) + significantly lower staining for FOXD3, compared with adenomas from low-risk patients (who remained free of CRCs). Latter results strongly suggest a prognostic value of measuring DCLK1(S)/FOXD3 in adenomas. Overexpression of DCLK1(S), but not DCLK1(L), caused a significant increase in the invasive potential of hCCCs, which may explain worse outcomes for patients with high DCLK1-S–expressing tumors. On the basis of these data, FOXD3 is a potent repressor of DCLK1-S expression in normal cells; loss of FOXD3 in hCCCs/hCRCs allows upregulation of DCLK1-S, imparting a potent invasive potential to the cells.