新癌基因CHD1L通过METAP2促进上皮性卵巢癌盆腹腔转移的分子作用与机制的研究

The abdominopelvic cavity metastasis of epithelial ovarian Carcinoma (EOC) is one of leading cause of EOC-related death. Epithelial- mesenchymal transition (EMT) has been suggested to be essential for the maliganent process during cancer cells detachment and anoikis resistance, which will finally lead to EOC abdominopelvic cavity metastasis. We previously reported that CHD1L was frequently overexpressed in EOC tissues and predicted a poor survival of the patients. Importantly, the expression levels of CHD1L in abdominopaelvic metastasis tissues were largely higher than that in their paired primary tumor tissues of EOC patients. Recently, we found that CHD1L could promote EOC cells invasive capacities in vivo and substantially up-regulated the levels of METAP2, suggesting that CHD1L may support EOC’s malignant process through the increasing the expression of METAP2. To further investigate and discover the functions and/or mechanisms of CHD1L in promoting EOC cells metastasis, in the present project, we further designed a series of in vivo to in vitro experiments. The purpose of our project is 1) to verify the functions of CHD1L in promoting abdominopaelvic metastasis by inhibiting the anoikis of EOC cells, 2) to explore the underling mechanisms of CHD1L in supporting EOC cells EMT, as well as the inhibition their anoikis though up-regulation of METAP2, 3) further to discover the precise molecular mechanisms by which CHD1L regulates the expression of the important downstream target, METAP2, as well as its following effects and/or key reasons in promoting EOC cells EMT, anoikis and final abdominopaelvic metastasis. We trust that the data from our present project will provide more experiment evidences for uncovering the precise mechanisms of EOC abdominopaelvic metastasis, so as to find novel therapeutic targets and develop new modalities of treatment.

上皮性卵巢癌（EOC）盆腹腔播散是患者死亡主要原因之一。研究表明：癌细胞上皮-间质转化（EMT）是EOC细胞从原发灶脱落、抵抗失巢凋亡、导致盆腹腔播散和转移的重要条件。我们前期发现CHD1L在 EOC中高表达且与病人不良预后正相关；重要的是CHD1L在盆腹腔转移灶中表达明显高于原发灶；最近我们在预实验中证实CHD1L可促进EOC细胞体外侵袭并上调METAP2表达，提示CHD1L可上调METAP2促进EOC进展。本项目承前启后，拟通过一系列体内和体外实验，明确CHD1L在EOC中通过抑制癌细胞失巢凋亡促进其盆腹腔播散转移功能；确证EOC中CHD1L通过METAP2促进肿瘤细胞发生EMT、抑制失巢凋亡的作用；阐明CHD1L通过调控关键下游分子METAP2的内在分子机制及其对EOC细胞EMT、抗失巢凋亡和盆腹腔播散转移的分子功能与机理；为揭示EOC盆腹腔播散机制和抗癌治疗新靶点提供实验研究基础。

上皮性卵巢癌（EOC）盆腹腔播散是患者死亡的主要原因之一。癌细胞上皮-间质转化（EMT）是EOC细胞从原发灶脱落、抵抗失巢凋亡、导致盆腹腔播散和转移的重要条件。本课题拟分析新癌基因CHD1L在卵巢癌中的表达和临床病理参数的相关性；从动物及细胞水平，探讨CHD1L通过METAP2促进上皮性卵巢癌盆腹腔转移的分子作用与机制。同时探讨通路中新的靶基因，揭示相关机制与参与通路，建立可预测卵巢良恶性肿瘤的相关模型，为卵巢癌的临床诊疗提供新的干预靶点与思路。我们用详实的实验数据证明了CHD1L在 EOC中高表达，且CHD1L在盆腹腔转移灶中表达明显高于原发灶，并与卵巢癌患者不良预后呈正相关；体内外实验均证实CHD1L可促进EOC细胞体外侵袭并上调METAP2表达，促进肿瘤细胞发生EMT，抑制失巢凋亡，从而促进上皮性卵巢癌盆腹腔转移，为揭示EOC盆腹腔播散机制和抗癌治疗新靶点提供实验研究基础。在研究癌细胞抵抗失巢凋亡过程中，我们发现其他新癌基因如SRT2183、SLC12A5、AGBL2等，可能是卵巢癌患者总体生存率的重要独立预后因素。其中重点研究SRT2183，发现其抗癌活性可能是通过诱导卵巢癌细胞自噬，揭示相关机制和参与通路，可能成为卵巢癌细胞抵抗失巢凋亡的另一新靶点。此外，我们建立了一个新的预测卵巢良恶性肿瘤的列线图模型。该模型在早期卵巢癌的诊断中表现出良好的准确性，在预测恶性卵巢肿瘤方面比现有的模型具有更高的效能。