Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway
Bin Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorChao Deng
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorLei Wang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorFan Zhou
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorShu Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorWei Kang
Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorPing Zhan
Department of Respiratory Medicine, Jinling Hospital, Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorJuan Chen
The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
Search for more papers by this authorShanshan Shen
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorHuimin Guo
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorMing Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorYi Wang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorFeng Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorWei Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorJiangqiang Xiao
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorBo Kong
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Department of Surgery, Technical University of Munich, Munich, Germany
Search for more papers by this authorHelmut Friess
Department of Surgery, Technical University of Munich, Munich, Germany
Search for more papers by this authorCorresponding Author
Yuzheng Zhuge
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Correspondence
Prof. Yuzheng Zhuge, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Prof. Hongli Yan, Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
Email address: [email protected]
Prof. Xiaoping Zou, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Search for more papers by this authorCorresponding Author
Hongli Yan
Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China
Correspondence
Prof. Yuzheng Zhuge, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Prof. Hongli Yan, Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
Email address: [email protected]
Prof. Xiaoping Zou, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Search for more papers by this authorCorresponding Author
Xiaoping Zou
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Correspondence
Prof. Yuzheng Zhuge, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Prof. Hongli Yan, Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
Email address: [email protected]
Prof. Xiaoping Zou, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Search for more papers by this authorBin Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorChao Deng
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorLei Wang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorFan Zhou
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorShu Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorWei Kang
Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorPing Zhan
Department of Respiratory Medicine, Jinling Hospital, Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorJuan Chen
The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
Search for more papers by this authorShanshan Shen
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorHuimin Guo
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorMing Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorYi Wang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorFeng Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorWei Zhang
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorJiangqiang Xiao
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Search for more papers by this authorBo Kong
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Department of Surgery, Technical University of Munich, Munich, Germany
Search for more papers by this authorHelmut Friess
Department of Surgery, Technical University of Munich, Munich, Germany
Search for more papers by this authorCorresponding Author
Yuzheng Zhuge
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Correspondence
Prof. Yuzheng Zhuge, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Prof. Hongli Yan, Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
Email address: [email protected]
Prof. Xiaoping Zou, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Search for more papers by this authorCorresponding Author
Hongli Yan
Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China
Correspondence
Prof. Yuzheng Zhuge, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Prof. Hongli Yan, Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
Email address: [email protected]
Prof. Xiaoping Zou, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Search for more papers by this authorCorresponding Author
Xiaoping Zou
Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China
Correspondence
Prof. Yuzheng Zhuge, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Prof. Hongli Yan, Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
Email address: [email protected]
Prof. Xiaoping Zou, Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu, China.
Email address: [email protected]
Search for more papers by this authorAbstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and represents a highly malignant tumor with a poor prognosis. Therapeutic modalities for HCC are limited and generally ineffective. UBE2Q1 is a putative E2 ubiquitin conjugating enzyme, and has been shown to be overexpressed in various types of cancers including HCC. How UBE2Q1 contributes to hepatocarcinogenesis remains unknown. Here, we show that UBE2Q1 is up-regulated in HCC cell lines and in a subset of human HCC tissues. Up-regulation of UBE2Q1 in primary HCC tumors was significantly correlated with shorter overall survival and disease-free survival. Mechanistically, we showed that the frequent up-regulation of UBE2Q1 in HCCs was attributed to the recurrent UBE2Q1 gene copy gain at chromosome 1q21. Functionally, we showed that knockdown of UBE2Q1 reduced HCC cell proliferation, promoted apoptosis via induction of GADD45α, and suppressed orthotopic tumorigenicity both in vitro and in vivo. Inactivation of UBE2Q1 also impeded HCC cell migration and invasion in vitro through regulating EMT process, and suppressed HCC metastasis in vivo. Interestingly, our data revealed a role of UBE2Q1 in the regulation of β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway. Our findings indicate that UBE2Q1 is a candidate oncogene involved in HCC development and progression and therefore a potential therapeutic target in applicable HCC patients.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
Supporting Information
Additional Supporting Information may be found online in the supporting information tab for this article.
| Filename | Description |
|---|---|
| mc22747-sup-0001-SupFig-S1.tif261.9 KB |
Figure S1. (A) Gene expression levels of human UBE2Q1 mRNA in normal quiescent (n = 10), cirrhotic (n = 13), dysplasia (n = 17), and HCC (n = 35) livers (clinical data set GSE6764). |
| mc22747-sup-0002-SupFig-S2.tif197.5 KB |
Figure S2. (A-D) Correlation analysis between the UBE2Q1 gene copy number and HCC patients’ gender, history of cirrhosis, tumor grade, or Barcelona-Clinic Liver Cancer (BCLC) staging classification. |
| mc22747-sup-0003-SupFig-S3.tif290 KB |
Figure S3. (A) Measurement of UBE2Q1 protein level in a panel of liver cell lines by Western blotting. |
| mc22747-sup-0004-SupFig-S4.tif202.8 KB |
Figure S4. (A) Real-time RT-PCR analysis of expression of GADD45α in 97H and SK-HEP-1 cells. |
| mc22747-sup-0005-SupFig-S5.tif157.1 KB |
Figure S5. Enumeration of UBE2Q1-, Ki67-, and TUNEL-positive cells in cancer tissues of mice. |
| mc22747-sup-0006-SupFig-S6.tif154.4 KB |
Figure S6. Significant reduction in cell migration and invasion was found in cells transfected with UBE2Q1 siRNA, compared with cells transfected with control siRNA. |
| mc22747-sup-0007-SupLegends-S1.docx28.6 KB | Supporting Legends.S1 |
| mc22747-sup-0008-SupTab-S1.doc30.5 KB |
Table S1. The sequences of UBE2Q1 and GADD45α siRNA. |
| mc22747-sup-0010-SupTab-S2.docx22.9 KB |
Table S2. The primers used in qPCR analysis. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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