Prognostic implications of cell division cycle protein 45 expression in hepatocellular carcinoma

Background The overall prognosis of hepatocellular carcinoma (HCC) is poor and novel prognostic biomarkers might better monitor the progression of HCC. Cell division cycle protein 45 (CDC45) plays a key role in DNA replication and considered to be involved in tumorigenesis. This study investigated CDC45 expression in tumour tissues and defined its prognostic value in HCC patients. Methods We used immunohistochemistry (IHC) staining to examine the expression of CDC45 in tumour tissue specimens and compare them with adjacent normal tissue specimens using a constructed tissue microarray (TMA) and analyzed how clinical features are related to HCC prognosis. Functional enrichment analyses were used to describe significantly involved hallmark pathways of differentially expressed genes (DEGs, which were screened out according to the high or low expression of CDC45 in tumour tissues). Results Our findings showed that the proteome expression of CDC45 was evidently downregulated in HCC tissues compared with matched normal tissues (P < 0.0001). Although we did not find any differences in terms of vascular invasion, metastasis, lymphatic infiltration, or Edmondson grade between patients with high and low CDC45 expression, low CDC45 expression was significantly correlated with microvascular invasion (P = 0.046). Multivariate analysis indicated that CDC45 expression (P = 0.035) was an independent prognostic factor for the overall survival (OS) rate of HCC patients. Patients with CDC45 expression was positively correlated with OS rates among HCC patients (P < 0.05). Functional annotations indicated that CDC45 is involved in the most significant pathways, including the cell cycle, DNA replication, chemical carcinogenesis and drug metabolism–cytochrome P450 pathways. Discussion Our findings showed that low proteomic level of CDC45 was associated with a poor prognosis in HCC patients, indicating that CDC45 might be a novel prognostic marker.

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Prognostic implications of CDC45 expression in hepatocellular carcinoma

10.21203/rs.3.rs-31516/v1 ◽

2020 ◽

Author(s):

Chen Yang ◽

Shufang Xie ◽

Yi Wu ◽

Guoqing Ru ◽

Xianglei He ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cytochrome P450 ◽

Dna Replication ◽

Prognostic Marker ◽

Expression Profiles ◽

Chemical Carcinogenesis ◽

Functional Enrichment ◽

Expression Levels ◽

Transcriptome Expression ◽

Tissue Specimens

Abstract Background The outcomes of hepatocellular carcinoma (HCC) remain poor despite dramatic improvements in treatment, and novel prognostic biomarkers are urgently needed to ameliorate the situation. Cell division cycle protein 45 (CDC45) plays a key role in DNA replication, which is considered to be involved in tumorigenesis and has become a new prognostic marker. This study investigated CDC45 expression in tumour tissues and defined its prognostic value in HCC patients. Methods Differential transcriptional and proteomic expression profiles were obtained and validated using multiple datasets. We then used immunohistochemistry (IHC) staining to examine the expression of CDC45 in tumour tissue specimens and compare them with adjacent normal tissue specimens using a constructed tissue microarray (TMA) and analysed the relationship of clinical features and prognosis in HCC patients. Functional enrichment analyses were used to describe significantly involved hallmark pathways of differentially expressed genes (DEGs). Results Contrary to the transcriptome expression level in the database, our results showed that the proteome expression of CDC45 in was evidently downregulated in HCC compared with normal adjacent tissues (P < 0.0001). Although we did not find any differences in terms of vascular invasion, Edmondson grade, lymphatic infiltration, or metastasis between patients with high and low CDC45 expression in our limited number of HCC samples, low expression of CDC45 was significantly correlated with aggressive characteristics, including microvascular invasion (P = 0.046). In addition, a multivariate analysis indicated that CDC45 expression (P = 0.035) was an independent prognostic factor for the overall survival (OS) rate of patients with HCC. Furthermore, patients with low CDC45 expression levels were significantly correlated with inferior OS rates than patients with high CDC45 expression levels (P < 0.05). Functional annotations indicated that CDC45 is involved in the most significant pathways, including the cell cycle, DNA replication, drug metabolism − cytochrome P450, metabolism of xenobiotics by cytochrome P450, and chemical carcinogenesis pathways. Conclusions Our findings showed that a low protein level of CDC45 was associated with a poor prognosis in HCC patients, indicating that CDC45 might be a novel prognostic marker and help identify new therapeutic targets for HCC.

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Cell Division Cycle Associated Genes as Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.657161 ◽

2021 ◽

Vol 8 ◽

Author(s):

Shan-Shan Jiang ◽

Sheng-Jie Ke ◽

Zun-Li Ke ◽

Juan Li ◽

Xiang Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Division ◽

Poor Prognosis ◽

Immune Cell ◽

Expression Profiles ◽

Drinking Behavior ◽

Cell Division Cycle ◽

Prognostic Biomarkers ◽

Normal Tissues ◽

Online Databases

With high mortality and poor prognosis, hepatocellular carcinoma (LIHC) has become the fourth leading cause of cancer-related deaths worldwide. Most of the LIHC patients missed the best treatment period because of the untimely diagnosis. For others, even if they are temporarily cured, they have to face a very low prognostic survival rate and a very high risk of recurrence. Based on the characteristics of abnormal proliferation and uncontrolled growth of tumor cells. Cell Division Cycle Associated (CDCA) family genes, which are responsible for regulating the cell cycle and proliferation, were selected as our research object to explore the mechanism of hepatocarcinogenesis. To this end, we investigated the expression profiles of CDCA family genes in LIHC and corresponding normal tissues, and the effect of CDCAs expression on the survival of prognosis and immune cell infiltration through bioinformatics analysis methods and the publicly accessible online databases. In addition, we also analyzed the expression correlation of CDCAs and screened the neighboring genes related to functional CDCAs. The results revealed that the expression levels of CDCA1/3/5/8 were significantly increased in LIHC, regardless of stage, sex, race, drinking behavior, and other clinical factors. CDCAs expression was significantly correlated with poor prognosis and was positively correlated with the infiltration of dendritic cells, B cells, and macrophages. We also found that the most relevant neighboring genes to CDCAs in LIHC were SGO2, NDC80, BIRC5, INCENP, and PLOD1. In general, our work suggests that CDCA1/3/5/8 has the potential to be a diagnostic gene in hepatocarcinogenesis and prognostic biomarkers for LIHC patients.

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Cell division cycle associated 8: A novel diagnostic and prognostic biomarker for hepatocellular carcinoma

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.17032 ◽

2021 ◽

Author(s):

Xiao‐Han Cui ◽

Qiu‐Ju Peng ◽

Ren‐Zhi Li ◽

Xia‐Jie Lyu ◽

Chun‐Fu Zhu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Division ◽

Prognostic Biomarker ◽

Cell Division Cycle

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Cell division cycle proteinising prognostic biomarker of breast cancer

Bioscience Reports ◽

10.1042/bsr20191227 ◽

2020 ◽

Vol 40 (5) ◽

Author(s):

Lin Cheng ◽

Yu-Zhou Huang ◽

Wei-Xian Chen ◽

Liang Shi ◽

Zhi Li ◽

...

Keyword(s):

Breast Cancer ◽

Cell Division ◽

Growth Factor Receptor ◽

Prognostic Index ◽

Nottingham Prognostic Index ◽

Cell Division Cycle ◽

Breast Cancer Patients ◽

Prognostic Effect ◽

Normal Tissues ◽

Cancer Tissues

Abstract Cell division cycle protein (CDC20) has been observed to be expressed higher in various kinds of human cancers and was associated with poor prognosis. However, studies on role of CDC20 in breast cancer are seldom reported till now, most of which are not systematic and conclusive. The present study was performed to analyze the expression pattern, potential function, and distinct prognostic effect of CDC20 in breast cancer using several online databases including Oncomine, bc-GenExMiner, PrognoScan, and UCSC Xena. To verify the results from databases, we compared the mRNA CDC20 expression in breast cancer tissues and adjacent normal tissues of patients by real-time PCR. We found that CDC20 was expressed higher in different types of breast cancer, comparing with normal tissues. Moreover, the patients with a more advanced stage of breast cancer tended to express higher level CDC20. CDC20 was expressed higher in breast cancer tissues than normal tissues from patients in our hospital, consistent with the results from databases. Estrogen receptor (ER) and progesterone receptor (PR) status were negatively correlated with CDC20 level. Conversely, Scarff–Bloom–Richardson (SBR) grade, Nottingham prognostic index (NPI), epidermal growth factor receptor-2 (HER-2) status, basal-like status, and triple-negative status were positively related to CDC20 expression in breast cancer patients with respect to normal individuals. Higher CDC20 expression correlated with worse survival. Finally, a positive correlation between CDC20 and Targeting protein for Xenopus kinesin-like protein 2 (TPX2) expression was revealed. CDC20 could be considered as a potential predictive indicator for prognosis of breast cancer with co-expressed TPX2 gene.

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Comprehensive analysis of miRNA sequencing profiles identifies novel deregulated and prognostic biomarkers in hepatocellular carcinoma

10.21203/rs.3.rs-20213/v1 ◽

2020 ◽

Author(s):

Hui Zhang ◽

Senmiao Ni ◽

Changxian Li ◽

Haoming Zhou ◽

Jianling Bai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Negative Binomial ◽

Cox Regression ◽

Risk Groups ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Normal Tissues ◽

Mirna Sequencing ◽

Incident Cases

Abstract Background: Liver cancer is the fourth most common cause of cancer-related death and rank sixth in terms of incident cases. We aim to identify a set of miRNAs and a miRNA-based signature related to tumorigenesis and prognosis in patients with hepatocellular carcinoma (HCC). Methods: We analyzed the miRNA sequencing profiles of 373 HCC patients downloaded from The Cancer Genome Atlas LIHC program. The isoform quantification profiles were transformed into 5p and 3p mature miRNA names. Differentially expressed (DE) miRNAs between tumor and adjacent normal tissues were identified by Wald test based on the negative binomial distribution. Prognostic miRNAs associated with overall survival were confirmed by multivariate Cox proportional hazards models. The miRNA-based signatures were obtained from the linear predictors of cox regression, and the prognostic performance was compared by Harrel’s C-index and revealed by the restricted mean survival (RMS) curve. Results: The selected twelve DE miRNAs showed a good performance to classify tumor tissues from normal tissues. Meanwhile, a miRNA-based prognostic signature of eight mature miRNAs was constructed, which significantly stratified patients into high- vs low-risk groups in terms of overall survival (hazard ratio, 4.11; 95% CI, 2.71-6.24; P<0.001). When integrated with clinical information, the composite miRNA-clinical signature showed improved prognostic accuracy relative to the eight-miRNA signature alone. As we set the follow-up time at 5 years, the estimated RMST difference between low- and high-risk group stratified by miRNA index was 1.39 (95% CI: 0.95-1.83) months, which is lesser than the difference between miRNA-clinical risk groups (1.63, 95%CI: 1.20-2.06). Functional enrichment analysis indicated that the target mRNAs of selected miRNAs were mainly enriched in cancer-related pathways and vital cell biological processes. Conclusions: The proposed DE miRNAs and miRNA-clinical signature are promising biomarkers for discrimination and predicting overall survival respectively in HCC patients. These biomarkers may have significant relevance for development of new drug research and targeting therapies for HCC patients.

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Multiomics profiling of the expression and prognosis of MCMs in endometrial carcinoma

Bioscience Reports ◽

10.1042/bsr20211719 ◽

2021 ◽

Author(s):

Hua Lan ◽

Jing Yuan ◽

Xingyu Chen ◽

Chu Liu ◽

Xiaohui Guo ◽

...

Keyword(s):

Cell Division ◽

Dna Replication ◽

Endometrial Carcinoma ◽

Expression Pattern ◽

Drug Sensitivity ◽

Experimental Studies ◽

Functional Enrichment ◽

Dna Hypomethylation ◽

Clinical Value ◽

Tissue Samples

Minichromosome maintenance (MCM) family members are a group of genes involved in regulating DNA replication and cell division and have been identified as oncogenes in various cancer types. Several experimental studies have suggested that MCMs are dysregulated in endometrial carcinoma (EC). However, the expression pattern, clinical value and functions of different MCMs have yet to be analyzed systematically and comprehensively. We analyzed expression, survival rate, DNA alteration, PPT network, GGI network, functional enrichment cancer hallmarks and drug sensitivity of MCMs in patients with EC based on diverse datasets, including Oncomine, GEPIA, Kaplan-Meier Plotter, HPA, Sangerbox and GSCALite databases. The results indicated that most MCM members were increased in EC and showed a prognostic value in survival analysis, which were considerately well in terms of PFS and OS prognostic prediction. Importantly, functional enrichment, PPI network and GGI network suggested that MCMs interact with proteins related to DNA replication and cell division, which may be the mechanism of MCM promote EC progression. Further data mining illustrated that MCMs have broad DNA hypomethylation levels and high levels of copy number aberrations in tumor tissue samples, which may be the mechanism causing the high expression level of MCMs. Moreover, MCM2 can activate or suppress diverse cancer-related pathways and is implicated in EC drug sensitivity. Taking together, our findings illustrate the expression pattern, clinical value and function of MCMs in EC and implies that MCMs are potential targets for precision therapy and new biomarkers for the prognosis of patients with EC.

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Higher expression of cell division cycle-associated protein 5 predicts poorer survival outcomes in hepatocellular carcinoma

Aging ◽

10.18632/aging.103501 ◽

2020 ◽

Vol 12 (14) ◽

pp. 14542-14555

Author(s):

Shengzhong Hou ◽

Xing Chen ◽

Mao Li ◽

Xing Huang ◽

Haotian Liao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Division ◽

Cell Division Cycle ◽

Survival Outcomes

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Genetic control of the cell division cycle in yeast II. Genes controlling DNA replication and its initiation

Journal of Molecular Biology ◽

10.1016/0022-2836(72)90246-x ◽

1972 ◽

Vol 67 (2) ◽

pp. 339 ◽

Cited By ~ 1

Keyword(s):

Cell Division ◽

Dna Replication ◽

Genetic Control ◽

Cell Division Cycle

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Dynamics of pre-replication complex proteins during the cell division cycle

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2003.1360 ◽

2004 ◽

Vol 359 (1441) ◽

pp. 7-16 ◽

Cited By ~ 50

Author(s):

Supriya G. Prasanth ◽

Juan Méndez ◽

Kannanganattu V. Prasanth ◽

Bruce Stillman

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Dna Replication ◽

Origin Recognition Complex ◽

Cell Division Cycle ◽

Vital Functions ◽

A Cell ◽

Bona Fide ◽

Mcm Proteins ◽

Key Participants

Replication of the human genome every time a cell divides is a highly coordinated process that ensures accurate and efficient inheritance of the genetic information. The molecular mechanism that guarantees that many origins of replication fire only once per cell–cycle has been the area of intense research. The origin recognition complex (ORC) marks the position of replication origins in the genome and serves as the landing pad for the assembly of a multiprotein, pre–replicative complex (pre–RC) at the origins, consisting of ORC, cell division cycle 6 (Cdc6), Cdc10–dependent transcript (Cdt1) and mini–chromosome maintenance (MCM) proteins. The MCM proteins serve as key participants in the mechanism that limits eukaryotic DNA replication to once–per–cell–cycle and its binding to the chromatin marks the final step of pre–RC formation, a process referred to as ‘replication licensing’. We present data demonstrating how the MCM proteins associate with the chromatin during the G1 phase, probably defining pre–RCs and then anticipate replication fork movement in a precisely coordinated manner during the S phase of the cell cycle. The process of DNA replication must also be carefully coordinated with other cell–cycle processes including mitosis and cytokinesis. Some of the proteins that control initiation of DNA replication are likely to interact with the pathways that control these important cell–cycle transitions. Herein, we discuss the participation of human ORC proteins in other vital functions, in addition to their bona fide roles in replication.

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