Changes in mRMA/protein expression and signaling pathways in in vivo passaged mouse ovarian cancer cells

The cure rate for late stage epithelial ovarian cancer (EOC) has not significantly improved over several decades. New and more effective targets and treatment modalities are urgently needed. RNA-seq analyses of a syngeneic EOC cell pair, representing more and less aggressive tumor cells in vivo were conducted. Bioinformatics analyses of the RNA-seq data and biological signaling and function studies have identified new targets, such as ZIP4 in EOC. Many up-regulated tumor promoting signaling pathways have been identified which are mainly grouped into three cellular activities: 1) cell proliferation and apoptosis resistance; 2) cell skeleton and adhesion changes; and 3) carbohydrate metabolic reprogramming. Unexpectedly, lipid metabolism has been the major down-regulated signaling pathway in the more aggressive EOC cells. In addition, we found that hypoxic responsive genes were at the center stage of regulation and detected functional changes were related to cancer stem cell-like activities. Moreover, our genetic, cellular, biochemical, and lipidomic analyses indicated that cells grown in 2D vs. 3D, or attached vs. suspended had dramatic changes. The important clinical implications of peritoneal cavity floating tumor cells are supported by the data proved in this work. Overall, the RNA-seq data provide a landscape of genetic alterations during tumor progression.

数十年来，晚期上皮性卵巢癌（epithelial ovarian cancer, EOC）的治愈率始终未出现显著改善，亟需开发更为高效的新型治疗靶点与治疗手段。本研究针对一对分别对应体内侵袭性强弱不同肿瘤细胞的同基因上皮性卵巢癌细胞系，开展了RNA测序（RNA-seq）分析。通过对测序数据进行生物信息学分析，并结合生物学信号通路与功能实验，本研究鉴定出上皮性卵巢癌的新型靶点，例如ZIP4。研究共鉴定出多条上调的促瘤信号通路，这些通路主要可归为三类细胞活动：1）细胞增殖与抗凋亡；2）细胞骨架与黏附特性改变；3）糖代谢重编程。令人意外的是，在侵袭性更强的上皮性卵巢癌细胞中，脂质代谢竟是主要的下调信号通路。此外，本研究发现缺氧应答基因处于调控网络的核心位置，且检测到的功能变化与类肿瘤干细胞活动密切相关。通过遗传学、细胞学、生物化学以及脂质组学分析，本研究证实：以二维（2D）与三维（3D）培养方式，或贴壁与悬浮状态培养的细胞，其表型存在显著差异。本研究的数据亦证实了腹腔漂浮肿瘤细胞所具备的重要临床价值。总体而言，本研究的RNA-seq数据完整呈现了肿瘤进展过程中的遗传改变全景。