Guo Fengbiao, Li Jinping, Qi Yaozhi, Hou Jianqing, Chen Haibin, Jiang Shi-Wen
1Department of Histology and Embryology, Shantou University Medical College, Shantou, 515041 Guangdong China.
2Center of Reproductive Medicine, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, 214123 Jiangsu China.
Cancer Cell Int. 2020 May 12;20:163. doi: 10.1186/s12935-020-01248-1. eCollection 2020.
Paclitaxel is a first-line chemotherapy drug for pancreatic, ovarian, endometrial cancers and other malignancies. However, its efficacy is often compromised by decreased cell sensitivity or the development of resistance. Human epididymis protein 4 (HE4) is highly expressed in gynecologic and pancreatic cancer tissues, and its serum levels are used for patient triage and assistant diagnosis of gynecologic cancers. Previous studies have shown that HE4 overexpression could promote cancer cell proliferation and the growth of tumor xenografts, which suggests its potential involvement in cancer chemosensitivity.
Two pancreatic cancer cell lines, Capan-1 and Suit-2, were transiently transfected with an HE4 overexpression plasmid, and transfected cells were treated with paclitaxel. S-phase cells were labeled using BrdU, and cell positivity rates were determined by counting BrdU-positive cells. Following HE4 overexpression and/or drug treatment, a western blotting analysis was performed to determine the protein alterations of PCNA and p21, two important cell cycle regulators.
HE4 overexpression not only promoted the proliferation of the Capan-1 pancreatic cells, but also significantly decreased cell sensitivity to paclitaxel. Results from western blotting showed that paclitaxel inhibited cell proliferation by decreasing the expression of PCNA and increasing the expression of p21. Data analysis indicated interactive actions between HE4 function and paclitaxel effects, both converging to cell cycle regulation.
These findings suggest that HE4 could be a potential therapeutic target for the sensitization of pancreatic cancer cells to paclitaxel treatment. HE4 expression levels may be used to predict the sensitivity of pancreatic cancer patients to paclitaxel.
紫杉醇是用于治疗胰腺癌、卵巢癌、子宫内膜癌及其他恶性肿瘤的一线化疗药物。然而，其疗效常因细胞敏感性降低或耐药性的产生而受到影响。人附睾蛋白4（HE4）在妇科和胰腺癌组织中高表达，其血清水平用于妇科癌症患者的分类及辅助诊断。既往研究表明，HE4过表达可促进癌细胞增殖及肿瘤异种移植瘤的生长，提示其可能参与癌症化疗敏感性。
用HE4过表达质粒瞬时转染两种胰腺癌细胞系Capan-1和Suit-2，对转染后的细胞进行紫杉醇处理。用BrdU标记S期细胞，通过计数BrdU阳性细胞确定细胞阳性率。在HE4过表达和/或药物处理后，进行蛋白质印迹分析以确定细胞周期的两个重要调节因子PCNA和p21的蛋白质变化。
HE4过表达不仅促进了Capan-1胰腺癌细胞的增殖，还显著降低了细胞对紫杉醇的敏感性。蛋白质印迹结果显示，紫杉醇通过降低PCNA的表达和增加p21的表达来抑制细胞增殖。数据分析表明，HE4功能与紫杉醇作用之间存在交互作用，二者均作用于细胞周期调控。
这些发现表明，HE4可能是使胰腺癌细胞对紫杉醇治疗敏感的潜在治疗靶点。HE4表达水平可用于预测胰腺癌患者对紫杉醇的敏感性。
