Wang Dong, Wang Tingting, An Yongbo, Jin Lan, Wang Jin, Wu Guocong, Yao Hongwei, Zhang Zhongtao, Li Jun
Department of General Surgery, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.
Discov Oncol. 2021 Mar 22;12(1):10. doi: 10.1007/s12672-021-00403-y.
Chemoresistance often occurs during 5-fluorouracil (5-Fu) treatment of colorectal cancer (CRC). It is significant to explore the potential strategies to sensitize colorectal cancer cells to 5-Fu treatment. We studied the sensitization of Nephroblastoma overexpressed protein (NOV) on 5-Fu treatment. NOV was overexpressed and knocked down in HT115 and RKO cells respectively. Cell proliferation experiments and related mechanism studies by RT-qPCR and Western blot were performed Subsequently. Nude mouse xenograft model was established to test the inhibitory effect of 5-FU on CRC cells in vivo. In this study, we found that NOV mRNA expression was significantly lower in tumor tissues than that in the normal tissues (P < 0.05). The cell proliferation was reduced in the HT115-NOVexp groups (P < 0.05) and increased in the RKO-NOVkd groups (P < 0.05) than that in the control groups and NC groups. The RT-PCR and Western Blot results showed that NOV inhibited the expression of activator protein (AP)-1 (P < 0.05) and promoted the expression of Caspase-8/3 (P < 0.05) in CRC cells in vitro. NOV also improved the inhibitory effect of 5-Fu on inhibiting colorectal cancer proliferation in a tumor cell xenotransplantation nude mouse model. NOV inhibited the expression of AP-1 and JUK and promoted the expression of Caspase-8/3 in cancer tissues in a tumor cell xenotransplantation nude mouse model. In summary, NOV can sensitize CRC cells towards 5-Fu-mediated inhibitory effect on cell proliferation and its sensitization may be achieved by the JNK/AP-1/Caspase-8/Caspase-3 pathway.
在结直肠癌（CRC）的5-氟尿嘧啶（5-Fu）治疗过程中，化疗耐药经常出现。探索使结直肠癌细胞对5-Fu治疗敏感的潜在策略具有重要意义。我们研究了肾母细胞瘤过表达蛋白（NOV）对5-Fu治疗的增敏作用。分别在HT115和RKO细胞中过表达和敲低NOV。随后进行细胞增殖实验以及通过逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法（Western blot）进行相关机制研究。建立裸鼠异种移植模型以测试5-FU在体内对CRC细胞的抑制作用。在本研究中，我们发现肿瘤组织中NOV mRNA表达明显低于正常组织（P < 0.05）。与对照组和阴性对照（NC）组相比，HT115-NOVexp组细胞增殖减少（P < 0.05），而RKO-NOVkd组细胞增殖增加（P < 0.05）。RT-PCR和Western Blot结果显示，在体外，NOV抑制结直肠癌细胞中激活蛋白（AP）-1的表达（P < 0.05），并促进半胱天冬酶-8/3的表达（P < 0.05）。在肿瘤细胞异种移植裸鼠模型中，NOV还增强了5-Fu对抑制结直肠癌增殖的作用。在肿瘤细胞异种移植裸鼠模型中，NOV抑制癌组织中AP-1和JUK的表达，并促进半胱天冬酶-8/3的表达。总之，NOV可使CRC细胞对5-Fu介导的细胞增殖抑制作用敏感，其增敏作用可能通过JNK/AP-1/半胱天冬酶-8/半胱天冬酶-3途径实现。
