MKRN2通过PKM2调控卵巢癌发生发展和化疗耐药的作用及机制研究

The role of Makorin-2 (MKRN2) in ovarian cancer is unknown. Our preliminary results suggest that expression levels of MKRN2 in ovarian cancer cells and tissues were significantly decreased, and overexpression of MKRN2 inhibited the proliferation and invasion of ovarian cancer cells. In our MKRN2 knockout mice, expression levels of PKM2 were significantly increased, and MKRN2 may interact with PKM2. MKRN2 downregulation made ovarian cancer cells resistant to cisplatin treatment. This study is designed to determine expression levels of MKRN2 in ovarian cancer cells and tissues, and determine whether MKRN2 regulates expression of PMK2 by directly interacting with PKM2 and inducing its ubiquitin and proteasome degradation of PMK2, and by regulating the Warburg effect to mediate the development of ovarian cancer and chemotherapy resistance. We will further analyze levels of MKRN2 and PKM2, and test the correlation of their expression levels with ovarian cancer tissue stages, survival, prognosis, and the chemotherapy effects in the patients. This project will elucidate the role and molecular mechanism(s) of MKRN2 in the cancer development and drug resistance, and identify potential new tas) for the diagnosis and treatment of ovarian cancer in the future.

Makorin-2（MKRN2）在卵巢癌中的作用目前还不清楚。我们的前期研究结果提示MKRN2在卵巢癌组织中的表达水平显著降低，过表达MKRN2抑制了卵巢癌细胞的增殖和侵袭能力。在MKRN2基因敲除小鼠的细胞中PKM2的表达水平显著增高，并且MKRN2与PKM2蛋白直接相互作用。沉默MKRN2能促进卵巢癌细胞产生顺铂耐受。本研究将阐明MKRN2在卵巢癌细胞中低表达的作用和机制，研究其是否通过与PKM2蛋白相互作用促进PMK2泛素化和蛋白酶体降解过程，进而影响Warburg效应，调控卵巢癌的发展和化疗耐药。本研究将分析临床卵巢癌组织样品中MKRN2及其下游靶分子的表达水平与化疗耐药和预后的相关性。阐明MKRN2在卵巢癌发生发展和耐药性中的作用和机制，将揭示卵巢癌新的发病机制，为克服顺铂耐药等提供新的理论依据，有望发现新的卵巢癌诊断和治疗靶点。

Makorin-2（MKRN2）在卵巢癌中的作用尚不清楚。我们的研究结果显示，MKRN2在卵巢癌细胞和组织中的表达水平明显降低，过表达MKRN2能抑制细胞增殖、迁移和侵袭，抑制肿瘤的生长，降低卵巢癌细胞对顺铂治疗耐药性，MKRN2下调能促进卵巢癌细胞对顺铂治疗产生耐药性。为了进一步了解MKRN2在卵巢癌细胞中下调的分子机制，我们发现卵巢癌细胞中MKRN2基因启动子区5个CPG的DNA甲基化水平较高，并且miR-582-5p的表达水平较高，介导了MKRN2在卵巢癌细胞中表达水平的下调。我们还发现MKRN2通过抑制泛素蛋白酶体途径而调控NF-κB/COX2信号通路，MKRN2可直接与NF-κB p65发生相互作用，导致p65亚基的泛素化降解。我们还发现MKRN2的表达水平与卵巢癌分期、生存期、预后以及患者化疗效果之间均有显著的相关性。我们进一步研究发现Mkrn2敲除小鼠负荷肿瘤的生长速度显著高于野生型小鼠。本研究揭示了MKRN2表达水平的下调在卵巢癌发展和耐药中的新作用和分子机制，并为未来卵巢癌的诊断和治疗寻找潜在的新靶点。