title: Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target.
abstract: Therapeutic intervention in neddylation pathway is an emerging area for cancer treatment. Herein, we evaluated the clinical relevance and therapeutic potential of targeting this pathway in intrahepatic cholangiocarcinoma (ICC). Immunohistochemistry of neddylation pathway components in a cohort of 322 cases showed that E1 (NAE1 and UBA3) and E2 (UBC12) enzymes, as well as global NEDD8 conjugation, were upregulated in over 2/3 of human ICC. Notably, NAE1 was identified as an independent prognosticator for postoperative recurrence (P=0.009) and a combination of NEDD8 and NAE1 provided a better power for predicting patient clinical outcomes. In vitro treatment with MLN4924, a small-molecule NEDD8-activating enzyme inhibitor, led to a dose-dependent decrease of viability in both established and primary cholangiocarcinoma cell lines. Additionally, MLN4924 exhibited at least additive effect when combined with cisplatin. By blocking cullins neddylation, MLN4924 inactivated Cullin-Ring ligase (CRL) and caused the accumulation of CRL substrates that triggered cell cycle arrest, senescence or apoptosis. Meanwhile, MLN4924 was well-tolerated and significantly inhibited tumor growth in xenograft model of cholangiocarcinoma. Taken together, our findings indicated that upregulated neddylation pathway was involved in ICC progression and interference in this pathway could be a promising target for ICC therapy.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China. Contributed equally to this work.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China. Contributed equally to this work.
authors.forename: Guang-Yang
authors.initials: GY
authors.lastname: Yu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China. Contributed equally to this work.
authors.forename: Jie-Yi
authors.initials: JY
authors.lastname: Shi
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China. Contributed equally to this work.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Li
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Liu-Xiao
authors.initials: LX
authors.lastname: Yang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Duan
authors.affiliation: Department of Laboratory Medicine, Laboratory of Molecular Biology of Huadong Hospital, Fudan University, Shanghai, P. R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China. Institute of Biomedical Sciences, Fudan University, Shanghai, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Shuang-Jian
authors.initials: SJ
authors.lastname: Qiu
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Jia
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China. Institute of Biomedical Sciences, Fudan University, Shanghai, P. R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002469:Cell Separation; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D003517:Cyclopentanes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000075687:NEDD8 Protein; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D046888:Tissue Array Analysis; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat