CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis
CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis
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DOI：
10.18632/aging.103648
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发表时间：
2020-08-31
期刊：
影响因子：
5.2
通讯作者：
Liu, Side
中科院分区：
文献类型：
--
作者：
Lai, Qiuhua;Li, Qingyuan;Liu, Side
CTCF 在多种癌症中过度表达，在调节侵袭性方面发挥着至关重要的作用，但人们对 CTCF 是否驱动结直肠癌进展知之甚少。在这里，我们确定了 CTCF 在结直肠癌中的促肿瘤作用。我们的研究表明，与邻近的非癌性结直肠组织相比，结直肠癌标本中 CTCF 表达上调。 CTCF的过度表达促进结直肠癌细胞增殖和肿瘤生长，而在CTCF敲低细胞中观察到相反的作用。使用蛋白质印迹分析在 CTCF 过表达细胞中观察到 GLI1、Shh、PTCH1 和 PTCH2 水平升高。 CCK-8 和细胞凋亡检测显示 5-氟尿嘧啶化疗敏感性与 CTCF 表达呈负相关。此外，我们还发现P53是结直肠癌中CTCF的直接转录靶基因。 Western blot 和核提取物测定表明，抑制 P53 可以抵消 CTCF 敲低引起的 Hedgehog 信号通路抑制。总之，我们发现了 CTCF 调节的关键作用，可能涉及 P53-Hedgehog 轴，并强调了结直肠癌特异性潜在治疗靶点作为疾病进展或临床反应生物标志物的临床效用。
CTCF is overexpressed in several cancers and plays crucial roles in regulating aggressiveness, but little is known about whether CTCF drives colorectal cancer progression. Here, we identified a tumor-promoting role for CTCF in colorectal cancer. Our study demonstrated that CTCF was upregulated in colorectal cancer specimens compared with adjacent noncancerous colorectal tissues. The overexpression of CTCF promoted colorectal cancer cell proliferation and tumor growth, while the opposite effects were observed in CTCF knockdown cells. Increased GLI1, Shh, PTCH1, and PTCH2 levels were observed in CTCF-overexpressing cells using western blot analyses. CCK-8 and apoptosis assays revealed that 5-fluorouracil chemosensitivity was negatively associated with CTCF expression. Furthermore, we identified that P53 is a direct transcriptional target gene of CTCF in colorectal cancer. Western blot and nuclear extract assays showed that inhibition of P53 can counteract Hedgehog signaling pathway repression induced by CTCF knockdown. In conclusion, we uncovered a crucial role for CTCF regulation that possibly involves the P53-Hedgehog axis and highlighted the clinical utility of colorectal cancer-specific potential therapeutic target as disease progression or clinical response biomarkers.yy