Qing Li1, Jiannan Qiu2, Hui Yang3, Guangli Sun4, Yuanchang Hu2, Deming Zhu2, Zhengming Deng2, Xuehao Wang5, Jinhai Tang6, Runqiu Jiang7. 1. School of Medicine, Southeast University, No.87, Dingjia Bridge, Nanjing, Jiangsu province, China; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. 2. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. 3. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. 4. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. 5. School of Medicine, Southeast University, No.87, Dingjia Bridge, Nanjing, Jiangsu province, China; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. Electronic address: wangxh@njmu.edu.cn. 6. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China. Electronic address: jhtang@njmu.edu.cn. 7. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No.321, Zhongshan Road, Nanjing, Jiangsu Province, China; Medical School of Nanjing University, No.22, Hankou Road, Nanjing, Jiangsu, China. Electronic address: jiangrq@njmu.edu.cn.
Abstract
The development and progression of hepatocellular carcinoma (HCC) is associated with the presence of cancer stem cells (CSCs). In the present study, kinesin family member 15 (KIF15) expression was shown to be overexpressed in HCC tissues, cell lines, and CSCs. Patients with HCC with high KIF15 expression had shortened overall survival (OS) and high recurrence probability. Downregulation of KIF15 in vitro as well as in HCC organoids resulted in a significant reduction in sphere formation and expression of stemness-related genes. KIF15 downregulation in human HCC xenograft models delayed tumor initiation, growth, and metastasis. KIF15 was also demonstrated to interact with phosphoglycerate dehydrogenase (PHGDH) and inhibit proteasomal degradation of PHGDH, thus promoting CSC phenotype and malignancy via PHGDH-mediated intracellular reactive oxygen species (ROS) imbalance in HCC. Moreover, AAA nuclear coregulator cancer-associated protein (ANCCA) upregulation acts as a key mediator in KIF15 expression upregulation in HCC. Conclusion: In this study, we found that KIF15 promotes the CSC phenotype and malignancy via PHGDH-mediated ROS imbalance in HCC. These findings highlight potential therapeutic targets for HCC.
The development and progression of hepatocellular carcinoma (HCC) is associated with the presence of cancer stem cells (CSCs). In the present study, kinesin family member 15 (KIF15) expression was shown to be overexpressed in HCC tissues, cell lines, and CSCs. Patients with HCC with high KIF15 expression had shortened overall survival (OS) and high recurrence probability. Downregulation of KIF15 in vitro as well as in HCC organoids resulted in a significant reduction in sphere formation and expression of stemness-related genes. KIF15 downregulation in humanHCC xenograft models delayed tumor initiation, growth, and metastasis. KIF15 was also demonstrated to interact with phosphoglycerate dehydrogenase (PHGDH) and inhibit proteasomal degradation of PHGDH, thus promoting CSC phenotype and malignancy via PHGDH-mediated intracellular reactive oxygen species (ROS) imbalance in HCC. Moreover, AAA nuclear coregulator cancer-associated protein (ANCCA) upregulation acts as a key mediator in KIF15 expression upregulation in HCC. Conclusion: In this study, we found that KIF15 promotes the CSC phenotype and malignancy via PHGDH-mediated ROS imbalance in HCC. These findings highlight potential therapeutic targets for HCC.
Authors: Shu Liu; Yewei Zhang; Shien Cui; Dajiang Song; Bo Li; Qian Chen; Guangyu Yao; Bin Gong Journal: Cancer Cell Int Date: 2021-11-13 Impact factor: 5.722