Department of Obstetrics and Gynaecology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.
Department of Obstetrics and Gynaecology, Xiangyang Central Hospital, Xiangyang, P.R. China.
J Cell Mol Med. 2019 Jun;23(6):4005-4018. doi: 10.1111/jcmm.14286. Epub 2019 Apr 16.
Jagged1, the essential ligand of the Notch signalling pathway, is highly expressed in metastatic prostate cancer, and its high expression in breast cancer is linked to poor survival rates. However, the mechanism of Jagged1's involvement in platinum-resistant ovarian cancer has not been thoroughly elucidated to date. The purpose of the present study was to investigate the roles of Jagged1 in the platinum resistance of ovarian cancer and its possible mechanisms. Compared with a platinum responsive group of ovarian epithelial cell carcinomas, we found the positive staining intensity of Notch1, Notch2, Jagged1, STAT3 and Epithelial-mesenchymal transition (EMT) proteins were lower in a platinum-resistant group. The DDP-resistant ovarian cancer cell line (C13K) had a higher IC50 of DDP than its parental cell line (OV2008) (P < 0.05) and acquired an EMT phenotype and invasive characteristics. Inhibiting or knockdown of Jagged1 expression could not only reduce its capacity of migration and invasion but also reverse EMT and down-regulate the expression of serine 727-phosphorylated STAT3 (pS727) at the protein level but not total STAT3 or tyrosine 705-phosphorylated STAT3 (pY705) in C13K cells. Furthermore, it was found that crosstalk between the Jagged1/Notch and JAK/STAT3 signalling pathways were involved in Jagged1-promoting EMT in C13K cells. Experiments in vivo showed a reduced micrometastatic tumour burden in the lung, liver and spleen of mice implanted with C13K cells with knocked-down Jagged1 compared with mice implanted with control cells. All of these results demonstrate that Jagged1 can crosstalk with the JAK/STAT3 pathway, and they all cooperate to promote the aberrant occurrence of EMT, further reinforcing the abilities of invasion and migration of platinum-resistant ovarian cancer in vivo and in vitro.
锯齿 1 是 Notch 信号通路的必需配体，在转移性前列腺癌中高度表达，其在乳腺癌中的高表达与生存率降低有关。然而，锯齿 1 参与铂耐药卵巢癌的机制尚未得到充分阐明。本研究旨在探讨锯齿 1 在卵巢癌铂耐药中的作用及其可能的机制。与一组铂反应性卵巢上皮细胞癌相比，我们发现铂耐药组 Notch1、Notch2、锯齿 1、STAT3 和上皮间质转化（EMT）蛋白的阳性染色强度较低。DDP 耐药卵巢癌细胞系（C13K）的 DDPIC50 高于其亲本细胞系（OV2008）（P<0.05），并获得 EMT 表型和侵袭特性。抑制或敲低锯齿 1 的表达不仅可以降低其迁移和侵袭能力，而且可以逆转 EMT 并下调 C13K 细胞中丝氨酸 727 磷酸化 STAT3（pS727）的蛋白水平，但不影响总 STAT3 或酪氨酸 705 磷酸化 STAT3（pY705）。此外，还发现 Jagged1/Notch 和 JAK/STAT3 信号通路之间的串扰参与了 Jagged1 促进 C13K 细胞 EMT 的过程。体内实验表明，与对照细胞相比，敲低 Jagged1 的 C13K 细胞植入的小鼠肺、肝和脾中的微转移瘤负担减少。所有这些结果表明，Jagged1 可以与 JAK/STAT3 通路相互作用，它们共同合作促进 EMT 的异常发生，进一步增强了铂耐药卵巢癌细胞在体内和体外的侵袭和迁移能力。
