ZNF587激活STAT3信号通路从而增强结直肠癌干细胞样表型的研究

It has been demonstrated that tumor relapse and metastasis is the main cause of death of colorectal cancer patients. Current knowledge indicates that enhancement of stem cell-like phenotype in cancer cells significantly contributes to relapse and metastasis, however the direct mechanism underlying is still far from clear. The activity of STAT3, an important transcription factor required for stem cell-like phenotype, is tightly controlled by its binding factors. Through analysis of the STAT3 binding factors in colorectal cancer, we found ZNF587 is a novel binding partner of STAT3. Moreover, highly expression of ZNF587 activates STAT3 signaling and induces multiple stem cell-like phenotype in colorectal cancer. Further investigation shows that ZNF587 competes PIAS3 for binding with STAT3, which blocks the specific inhibition of Stat3 mediated by PIAS3,and eventually enhances the transcription activity of STAT3. Moreover,ZNF587 is positively correlated with the STAT3 activation signature and predicts poor prognosis of patient in colorectal cancer specimens. In the current study, we aim to get substantial understanding of the biological functions of ZNF587 and the mechanism underlying ZNF587 mediated STAT3 activation during colorectal tumorigenesis and progression, which is crucial for prevention and therapeutic strategy by targeting ZNF587 in colorectal cancer.

复发与转移是结直肠癌患者死亡的主要原因，肿瘤的复发转移与肿瘤细胞干细胞样表型的增强密切相关，但结直肠癌中肿瘤干细胞样表型增强的分子机制尚未明了。作为激活干细胞样表型的重要转录因子，STAT3活性受其结合因子的调控。通过分析结直肠癌细胞中STAT3的结合因子,我们发现ZNF587是一个全新的STAT3结合分子，高表达ZNF587可激活STAT3信号并诱导结直肠癌细胞的多种干细胞样表型。进一步研究中我们发现ZNF587通过与PIAS3竞争性结合STAT3，抵抗PIAS3对STAT3的特异性抑制作用进而增强STAT3的转录活性。在临床样品中ZNF587与STAT3激活的表达谱模式高度正相关,且ZNF587高表达预示着结直肠癌患者的不良预后。在本研究中我们将进一步对ZNF587在结直肠癌中的生物学功能及其对STAT3信号的调控机制进行深入探讨，为通过干预ZNF587防治结直肠癌提供了理论基础。

结直肠癌是我国发病率最高的恶性肿瘤之一，但结直肠癌复发转移的具体分子机制尚未明了。通过前期分析，我们发现高表达ZNF587可诱导结直肠癌细胞的多种干细胞样表型。在临床样品中ZNF587高表达预示着结直肠癌患者的不良预后。在本研究中我们初步发现ZNF587在实验室结直肠癌细胞系中表达较正常肠道黏膜组织升高；然后选取临床手术标本验证发现，同一结直肠癌患者中，癌组织中ZNF587表达水平明显高于癌旁组织；最后，通过免疫组化分析，提示ZNF587是结直肠癌患者预后不良的独立预测因子。本研究的完成，为临床提供了一个新的预测结直肠癌患者预后的因子，为后续通过干预ZNF587防治结直肠癌提供了理论基础。