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Abstract：
Lung squamous cell carcinoma (LSCC) is a deadly cancer in the world. Histone demethylase Jmjd2c is a key epigenetic regulator in various tumors, while the molecular mechanism underlying Jmjd2c regulatory in LSCC is still unclear. We used the aldehyde dehydrogenasebright (ALDHbri+) subtype as a research model for cancer stem cells (CSCs) in LSCC and detected the sphere formation ability and the proportion of ALDHbri+ CSCs with Jmjd2c interference and caffeic acid (CA) treatment. Additionally, we carried out bioinformatic analysis on the expression file of Jmjd2c RNAi mice and performed western blotting, qRT-PCR, Co-IP and GST pull-down assays to confirm the bioinformatic findings. Moreover, we generated Jmjd2c-silenced and Jmjd2c-SOX2-silenced ALDHbri+ tumor-bearing BALB/c nude mice to detect the effects on tumor progression. The results showed that Jmjd2c downregulation inhibited the sphere formation and the proportion of ALDHbri+ CSCs. The SOX2 decreased expression significantly in Jmjd2c RNAi mice, and they were positively co-expressed according to the bioinformatic analysis. In addition, SOX2 expression decreased in Jmjd2c shRNA ALDHbri+ CSCs, Jmjd2c and SOX2 proteins interacted with each other. Furthermore, Jmjd2c interference revealed significant blocking effect, and Jmjd2c-SOX2 interference contributed even stronger inhibition on ALDHbri+ tumor progression. The Jmjd2c and SOX2 levels were closely related to the development and prognosis of LSCC patients. This study indicated that Jmjd2c played key roles on maintaining ALDHbri+ CSC activity in LSCC by interacting with transcription factor SOX2. Jmjd2c might be a novel molecule for therapeutic targets and biomarkers in the diagnosis and clinical treatment of lung cancer.
摘要：
肺鳞状细胞癌（LSCC）是世界上致命的癌症。组蛋白去甲基酶Jmjd2c是各种肿瘤的关键表观遗传调节因子，而Jmjd2c调控LSCC的分子机制尚不清楚。我们使用醛脱氢酶布莱特（ALDHbri）亚型作为LSCC中癌症干细胞（CSCs）的研究模型，并检测了Jmjd2c干扰和咖啡酸（CA）处理的ALDHbriCSs的球体形成能力和比例。此外,我们对Jmjd2cRNAi小鼠的表达文件进行了生物信息学分析，并进行了蛋白质印迹，qRT-PCR,Co-IP和GST下拉测定以确认生物信息学发现。此外，我们产生了Jmjd2c沉默和Jmjd2c-SOX2沉默的ALDHbri+荷瘤BALB/c裸鼠来检测对肿瘤进展的影响。结果表明，Jmjd2c下调抑制了ALDHbri+CSCs的球体形成和比例。SOX2在Jmjd2cRNAi小鼠中的表达明显降低，根据生物信息学分析，它们呈阳性共表达。此外,SOX2在Jmjd2cshRNAALDHbri+CSCs中的表达降低，Jmjd2c和SOX2蛋白相互作用。此外，Jmjd2c干扰显示出显著的阻断效应，和Jmjd2c-SOX2干扰对ALDHbri肿瘤进展的抑制作用更强。Jmjd2c和SOX2水平与LSCC患者的发展及预后密切相关。本研究表明，Jmjd2c通过与转录因子SOX2相互作用，在维持LSCC中ALDHbri+CSC活性中起关键作用。Jmjd2c可能是肺癌诊断和临床治疗中的治疗靶点和生物标志物的新分子。
