Yu Shuqian, Shen Jiayu, Fei Jing, Zhu Xiaoqing, Yin Meichen, Zhou Jianwei
Department of Gynecology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, People's Republic of China.
Department of Gynecology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, People's Republic of China.
Onco Targets Ther. 2020 Jan 23;13:709-718. doi: 10.2147/OTT.S223304. eCollection 2020.
Few screening markers for malignant transformation in borderline ovarian tumors (BOT) have been clearly established. The kinase noncatalytic C-lobe domain containing 1 (KNDC1), a brain-specific Ras guanine nucleotide exchange factor, negatively regulates dendrite growth. However, the biological role and underlying mechanism of KNDC1 in human cancers, including ovarian cancer (OC), remain unknown.
Gene chip screening was used to detect the expression of mRNA in normal ovarian tissues, BOT tissues, and OC tissues. And results were further validated by RT-qPCR, Western blotting and immunohistochemistry. overexpression and knockdown ovarian cancer cells were established to study the possible pathways that KNDC1 was involved. The effects of KNDC1 on the malignant behaviors of ovarian tumors were also investigated both in vitro and in vivo.
We observed that the expression of mRNA and KNDC1 protein in OC was significantly downregulated compared with BOT. Subsequent investigation revealed that knockdown of enhanced the proliferation of ovarian cancer cells in vitro via induction of ERK1/2 phosphorylation, whereas reinforcing the expression of attenuated the ERK1/2 activity. Similarly, knockdown of also promoted cell proliferation in vivo. Survival analysis showed that lower predicted a poor progression-free survival (PFS) for patients.
Collectively, we conclude that KNDC1 might function as a tumor suppressor in ovarian tumors, inhibiting the proliferation of ovarian cells by suppressing ERK1/2 activity and hindering the malignant transformation of BOT.
目前尚未明确建立用于检测卵巢交界性肿瘤（BOT）恶变的筛查标志物。激酶非催化C叶结构域包含蛋白1（KNDC1）是一种脑特异性Ras鸟嘌呤核苷酸交换因子，可负向调节树突生长。然而，KNDC1在包括卵巢癌（OC）在内的人类癌症中的生物学作用及潜在机制仍不清楚。
采用基因芯片筛查检测正常卵巢组织、BOT组织和OC组织中mRNA的表达。并通过RT-qPCR、蛋白质免疫印迹和免疫组织化学进一步验证结果。构建KNDC1过表达和敲低的卵巢癌细胞系，以研究KNDC1可能参与的信号通路。同时在体外和体内研究KNDC1对卵巢肿瘤恶性行为的影响。
我们观察到，与BOT相比，OC中mRNA和KNDC1蛋白的表达显著下调。随后的研究表明，敲低KNDC1可通过诱导ERK1/2磷酸化增强体外卵巢癌细胞的增殖，而增强KNDC1的表达则减弱ERK1/2活性。同样，敲低KNDC1在体内也促进细胞增殖。生存分析表明，KNDC1表达较低预示着患者无进展生存期（PFS）较差。
综上所述，我们得出结论，KNDC1可能在卵巢肿瘤中起抑癌作用，通过抑制ERK1/2活性抑制卵巢细胞增殖，并阻碍BOT的恶变。
