Ets-domain transcription factor Ets21c and nuclear receptor Ftz-F1 are novel effectors of JNK promoting tumor malignancy. Drosophila melanogaster

Cancer represents a complex family of diseases, characterized by the uncontrolled malignant growth of a particular cell type and by metastatic dissemination of these transformed cells to secondary sites. The hallmark tumor features emerge as a result of aberrant cellular signaling and pathological gene expression driven by cooperating genetic lesions. Being the convergence points of signaling pathways, transcription factors play crucial roles in cancer. Here, we define a transcription factor network that triggers an abnormal gene expression program promoting malignancy of clonal tumors, generated in Drosophila imaginal disc epithelium by overexpressing oncogenic Ras (RasV12) in a background lacking the tumor suppressor gene scribble (scrib1). We show that the nuclear receptor Ftz-F1 and the ETS-domain transcription factor Ets21c are upregulated in the rasV12scrib1 tumors in response to activated Jun-N-terminal kinase (JNK) signaling. Depletion of either Ftz-F1 or Ets21c improves viability of Drosophila larvae suffering from tumors, and this effect can be further enhanced by simultaneous removal of the Jun-dimerizing partner Fos. We identified Fos as a key mediator of JNK-induced differentiation defects and further show that Ftz-F1 and Fos are required for tumor invasiveness. However, only Ets21c can efficiently substitute for JNK and cooperate with RasV12 to induce invasive tumors that recapitulate hallmarks of malignant rasV12scrib1 tumors including elevated matrix metalloprotease (MMP1) and insulin-like peptide 8 (Dilp8) expression. In conclusion, our study provides functional evidence for a network of cooperating transcription factor that dictates target gene expression and promotes tumor phenotypes in response to aberrant JNK signaling. Overall design: 20 samples analyzed, 4 control samples

癌症是一类复杂的疾病家族，其特征为特定细胞类型不受控制的恶性增殖，以及这些转化细胞向继发部位的转移性扩散。标志性肿瘤特征源于协同遗传损伤驱动的异常细胞信号转导与病理性基因表达。作为信号通路的交汇点，转录因子（transcription factor）在癌症中发挥关键作用。
本研究构建了一套转录因子网络，该网络可触发异常基因表达程序，促进克隆性肿瘤的恶性表型；该肿瘤由果蝇成虫盘上皮细胞在缺失抑癌基因（tumor suppressor gene）scribble（scrib1）的背景下，过表达致癌性Ras（oncogenic Ras，RasV12）所诱导产生。研究发现，核受体Ftz-F1与ETS结构域转录因子Ets21c在响应激活的Jun-N端激酶（Jun-N-terminal kinase, JNK）信号的rasV12scrib1肿瘤中表达上调。敲低Ftz-F1或Ets21c均可提升携带肿瘤的果蝇幼虫的存活率，且同时敲除Jun二聚化伴侣Fos可进一步增强该效果。
本研究鉴定出Fos是JNK诱导的分化缺陷的关键介质，并进一步证实Ftz-F1与Fos是肿瘤侵袭性所必需的。然而，仅Ets21c可有效替代JNK，并与RasV12协同诱导侵袭性肿瘤，该肿瘤可重现恶性rasV12scrib1肿瘤的标志性特征，包括升高的基质金属蛋白酶（matrix metalloprotease, MMP1）与胰岛素样肽8（insulin-like peptide 8, Dilp8）的表达。
综上，本研究为一套协同转录因子网络提供了功能证据：该网络可调控靶基因表达，并响应异常JNK信号以促进肿瘤表型。
整体实验设计：共分析20份样本，其中包含4份对照样本。