Cell division cycle 34 is highly expressed in hepatitis C virus-positive hepatocellular carcinoma with favorable phenotypes.

Published on Jul 1, 2017in Biomedical Reports
· DOI :10.3892/BR.2017.912
Keiko Takagi4
Estimated H-index: 4
(Nihon University),
Tadatoshi Takayama90
Estimated H-index: 90
(Nihon University)
+ 7 AuthorsKyoko Fujiwara16
Estimated H-index: 16
(Nihon University)
Sources
Abstract
: Despite tremendous efforts to develop curative agents, there are few effective drugs for the treatment of hepatocellular carcinoma (HCC). This is predominantly due to the variations in individual HCC cases. As numerous HCC cases have no mutations in known tumor-associated genes, identification of novel genes involved in the development and progression of human cancers is considered to be an urgent issue. In the present study, surgical specimens of HCC were analyzed for the expression patterns of ubiquitin-conjugating enzyme, cell division cycle 34 (CDC34), which is hypomethylated in its promoter region and exhibits elevated expression levels in mouse skin tumors. The results of the current study clearly indicated that the elevated CDC34 expression level in cancerous regions was significantly associated with favorable clinicopathological features, such as reduced alanine aminotransferase (ALT) levels and histological grades. Similarly, a higher T/N ratio, which is the ratio of CDC34 expression in HCCs to that in non-tumorous tissues, was significantly associated with favorable features, such as a lower indocyanin green retention rate after 15 min (ICG15R), reduced α-fetoprotein and smaller tumor size. These results indicate that the CDC34 expression level in HCC is a marker for predicting the HCC prognosis and that CDC34 acts as a tumor suppressor.
📖 Papers frequently viewed together
10 Authors (Chao-Wei Lee, ..., Ming-Chin Yu)
11 Citations
6 Authors (Wentao Bo, ..., Aixiang Liu)
6 Citations
References25
Newest
#1Cheng-Wei Li (NTHU: National Tsing Hua University)H-Index: 10
#2Ping-Yao Chang (NTHU: National Tsing Hua University)H-Index: 1
Last. Bor-Sen Chen (NTHU: National Tsing Hua University)H-Index: 61
view all 3 authors...
// Cheng-Wei Li 1 , Ping-Yao Chang 1 , Bor-Sen Chen 1 1 Laboratory of Control and Systems Biology, National Tsing Hua University, Hsinchu, Taiwan Correspondence to: Bor-Sen Chen, email: bschen@ee.nthu.edu.tw Keywords: DNA methylation, multiple potential drugs, hepatocarcinogenesis, miRNAs, principal network projection Received: February 19, 2016 Accepted: October 26, 2016 Published: November 04, 2016 ABSTRACT The mechanisms leading to the development and progression of hepatocellular carcinoma (...
11 CitationsSource
#1John Morrow (University of Texas MD Anderson Cancer Center)H-Index: 12
#2Hui Kuan Lin (University of Texas MD Anderson Cancer Center)H-Index: 58
Last. Shuxing ZhangH-Index: 35
view all 4 authors...
Ubiquitination, the structured degradation and turnover of cellular proteins, is regulated by the ubiquitin–proteasome system (UPS). Most proteins that are critical for cellular regulations and functions are targets of the process. Ubiquitination is comprised of a sequence of three enzymatic steps, and aberrations in the pathway can lead to tumor development and progression as observed in many cancer types. Recent evidence indicates that targeting the UPS is effective for certain cancer treatmen...
42 CitationsSource
#1Kyoko Fujiwara (Nihon University)H-Index: 16
#2Srimoyee Ghosh (NEHU: North Eastern Hill University)H-Index: 14
Last. Hiroki Nagase (Nihon University)H-Index: 26
view all 6 authors...
Epigenetic alteration of genomic DNA is a common and key process in carcinogenesis. There is considerable evidence indicating that some of the somatic alterations occurring during carcinogenesis in humans also involve the same processes as those observed in mice. Therefore, we analyzed mouse skin cancer tissues induced by the 2-stage carcinogenesis model to identify skin tumor-specific differentially methylated regions (ST-DMRs) during the multistep carcinogenesis process. We have previously ide...
9 CitationsSource
#1Martin R. Higgs (University of Birmingham)H-Index: 14
#2Hervé Lerat (French Institute of Health and Medical Research)H-Index: 14
Last. Jean-Michel Pawlotsky (French Institute of Health and Medical Research)H-Index: 109
view all 3 authors...
Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events
62 CitationsSource
#1Keiko Takagi (Nihon University)H-Index: 4
#2Kyoko Fujiwara (Nihon University)H-Index: 16
Last. Hiroki Nagase (Nihon University)H-Index: 26
view all 6 authors...
Background Hepatocellular carcinoma (HCC) is one of the most common human malignancies in the world, and its prognosis is generally poor. Epigenetic alteration such as DNA methylation has been shown to be important in the development of human cancers including HCC. Here, we analyzed the methylation status of ZAR1, which has been reported to be aberrantly methylated in a few human cancers.
12 CitationsSource
#1Lindsey N. Micel (CU: University of Colorado Boulder)H-Index: 4
#2John J. Tentler (CU: University of Colorado Boulder)H-Index: 28
Last. Gail Eckhardt (Livestrong Foundation)
view all 4 authors...
The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to...
123 CitationsSource
#1Alexander V. Ivanov (EIMB: Engelhardt Institute of Molecular Biology)H-Index: 29
#2Birke BartoschH-Index: 47
Last. Sergey N. KochetkovH-Index: 21
view all 5 authors...
Hepatitis C virus (HCV) is the etiological agent accounting for chronic liver disease in approximately 2–3% of the population worldwide. HCV infection often leads to liver fibrosis and cirrhosis, various metabolic alterations including steatosis, insulin and interferon resistance or iron overload, and development of hepatocellular carcinoma or non-Hodgkin lymphoma. Multiple molecular mechanisms that trigger the emergence and development of each of these pathogenic processes have been identified ...
133 CitationsSource
#1Ann-Lii Cheng (NTU: National Taiwan University)H-Index: 90
#2Zhongzhen Guan (SYSU: Sun Yat-sen University)H-Index: 8
Last. Yoon-Koo Kang (UOU: University of Ulsan)H-Index: 77
view all 16 authors...
Abstract Background The phase III Sorafenib Asia–Pacific (AP) trial—conducted in China, Taiwan and South Korea – confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib. Methods In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 40...
195 CitationsSource
#1Stanley M. Lemon (UNC: University of North Carolina at Chapel Hill)H-Index: 109
#2David R. McGivern (UNC: University of North Carolina at Chapel Hill)H-Index: 24
Although infection with hepatitis C virus (HCV) has become a leading cause of hepatocellular carcinoma, the mechanisms by which it results in carcinogenesis remain a subject of debate. Here, we explore the possibility that HCV replication impairs cellular DNA damage responses, thereby promoting instability of the infected host cell genome, and that HCV exerts a direct cancer-promoting effect in addition to eliciting immune-mediated inflammation and apoptosis of hepatocytes contributing to hepato...
73 CitationsSource
#1H. van Malenstein (Katholieke Universiteit Leuven)H-Index: 2
#2J. van Pelt (Katholieke Universiteit Leuven)H-Index: 15
Last. Chris Verslype (Katholieke Universiteit Leuven)H-Index: 54
view all 3 authors...
Abstract Hepatocellular carcinoma has an increasing incidence and high mortality. Treatment options are limited if the disease is not diagnosed in its early stage. The natural course of the disease is aggressive but not always predictable. Molecular profiling is a promising tool for classification in order to optimize prognosis prediction and treatment for an individual patient. In the last decade a large amount of studies has been conducted to better classify hepatocellular carcinomas. The focu...
63 CitationsSource
Cited By3
Newest
#1Xin-Chun Zhao (CAS: Chinese Academy of Sciences)H-Index: 3
#2Guizhen Wang (CAS: Chinese Academy of Sciences)H-Index: 29
Last. Guang-Biao Zhou (CAS: Chinese Academy of Sciences)H-Index: 34
view all 21 authors...
Abstract Background How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. Methods A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in pati...
5 CitationsSource
#1K.M. Williams (MUSC: Medical University of South Carolina)H-Index: 5
#2Shuo Qie (MUSC: Medical University of South Carolina)H-Index: 9
Last. Shaun K. Olsen (MUSC: Medical University of South Carolina)H-Index: 22
view all 6 authors...
Ubiquitin (Ub) signaling requires the sequential interactions and activities of three enzymes, E1, E2, and E3. Cdc34 is an E2 that plays a key role in regulating cell cycle progression and requires unique structural elements to function. The molecular basis by which Cdc34 engages its E1 and the structural mechanisms by which its unique C-terminal extension functions in Cdc34 activity are unknown. Here, we present crystal structures of Cdc34 alone and in complex with E1, and a Cdc34~Ub thioester ...
18 CitationsSource
To systematically identify ubiquitin pathway genes that are critical to lung carcinogenesis, we used a genome-wide silencing method in this study to knockdown 696 genes in non-small cell lung cancer (NSCLC) cells. We identified 31 candidates that were required for cell proliferation in two NSCLC lines, among which the E2 ubiquitin conjugase CDC34 represented the most significant one. CDC34 was elevated in tumor tissues in 67 of 102 (65.7%) NSCLCs, and smokers had higher CDC34 than nonsmokers. Th...
1 CitationsSource