Overexpression of PSF1 is correlated with poor prognosis in hepatocellular carcinoma patients

Background PSF1 is a subunit of the GINS complex which is essential for establishment of DNA replication forks, and the progression of the replisome. Previous studies have shown a close relationship between PSF1 and cell cycle in the proliferation of immature cells as well as tumors. The purpose of this study was to measure PSF1 expression in hepatocellular carcinoma (HCC) tissues, and determine the effects of down-regulation of PSF1 expression on growth of cancer cells, the cell cycle, apoptosis and cell invasiveness. Methods Samples from 137 HCC tissues, 67 from adjacent nontumor tissue and 15 from normal liver were studied using immunochemistry. The HepG2 cell line was used for knockdown experiments studied by RT-PCR, real-time PCR, apoptosis and invasiveness assays. Results PSF1 was overexpressed in HCC tissues compared with normal liver tissues. High PSF1 expression correlated with a more aggressive phenotype as well as worse prognosis in HCC patients. Knockdown of PSF1 expression using small interfering RNA (siRNA) slowed the growth of cancer cell by suppressing the cell cycle progression as well as increasing apoptosis, especially early apoptosis. In addition, the invasiveness of HepG2 cells was also reduced by down-regulation of PSF1. Conclusions These results suggest that the inhibition of PSF1 might provide new therapeutic approaches for HCC.

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Transcriptional down-regulation of metabolic genes by Gdown1 ablation induces quiescent cell re-entry into the cell cycle

10.1101/2020.03.01.971945 ◽

2020 ◽

Author(s):

Miki Jishage ◽

Keiichi Ito ◽

Chi-Shuen Chu ◽

Xiaoling Wang ◽

Masashi Yamaji ◽

...

Keyword(s):

Cell Cycle ◽

Rna Polymerase Ii ◽

Cell Cycle Progression ◽

Normal Liver ◽

Down Regulation ◽

Normal Liver Cell ◽

Pol Ii ◽

P53 Signaling ◽

Metabolic Genes ◽

Highly Expressed Genes

AbstractLiver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1). and up-regulation of p21 through activation of p53 signaling. In the absence of p53, Gdown1-deficient hepatocytes show a severe dysregulation of cell cycle progression, with incomplete mitoses, and a pre-malignant-like transformation. Mechanistically, Gdown1 is associated with elongating Pol II on the highly expressed genes and its ablation leads to reduced Pol II recruitment to these genes, suggesting that Pol II redistribution may facilitate hepatocyte re-entry into the cell cycle. These results establish an important physiological function for a Pol II regulatory factor (Gdown1) in the maintenance of normal liver cell transcription through constraints on cell cycle re-entry of quiescent hepatocytes.

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Caveolin-1 Knockdown Decreases SMMC7721 Human Hepatocellular Carcinoma Cell Invasiveness by Inhibiting Vascular Endothelial Growth Factor-Induced Angiogenesis

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2020/8880888 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Zhi-Bo Zhang ◽

Zheng Shi ◽

Lan-Fang Yang ◽

Hong-Bin Gao

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Proliferation ◽

Structure Formation ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Caveolin 1 ◽

Smmc7721 Cell ◽

Cell Invasiveness

Background. Recently, several studies have demonstrated that caveolin-1 overexpression is involved in apoptosis resistance, angiogenesis, and invasiveness in hepatocellular carcinoma (HCC). However, the mechanisms underlying caveolin-1-mediated tumor progression remain unclear. Methodogy. Lentiviral vectors were used to construct caveolin-1 small interfering RNA- (siRNA-) expressing cells. Secreted VEGF levels in SMMC7721 cells were evaluated by enzyme-linked immunosorbent assay (ELISA). SMMC7721 cell proliferation, cycle, apoptosis, and invasiveness were detected by MTT, flow cytometry, Annexin V-FITC/PI, and invasion assay, respectively. Phospho-eNOS levels in human umbilical vein endothelial cells (HUVECs) cocultured with SMMC7721 cell supernatants were analyzed by Western blot. Capillary-like tubule formation assay was performed to analyze endothelial tubular structure formation in HUVECs treated with supernatants from caveolin-1 siRNA-expressing SMMC7721 cells. SMMC7721 implantation and growth in nude mice were observed. Angiogenesis in vivo was analyzed by immunohistochemical angiogenesis assay. Results. Caveolin-1 siRNA-expressing SMMC7721 cells secreted reduced levels of VEGF. Caveolin-1 RNAi also caused an inhibition of SMMC7721 cell proliferation and cell cycle progression that was accompanied by increased apoptosis. Supernatants from caveolin-1 siRNA-expressing SMMC7721 cells inhibited cell cycle progression and decreased phospho-eNOS levels in HUVECs. Endothelial tubular structure formation in HUVECs treated with supernatants from caveolin-1 siRNA-expressing SMMC7721 cells was considerably reduced. Caveolin-1 siRNA-expressing SMMC7721 cells also showed reduced tumorigenicity and angiogenesis induction in vivo. Conclusion. Our results reveal a novel mechanism, whereby caveolin-1 positively regulates human HCC cell invasiveness by coordinating VEGF-induced angiogenesis.

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ITGB1 Drives Hepatocellular Carcinoma Progression by Modulating Cell Cycle Process Through PXN/YWHAZ/AKT Pathways

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.711149 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jinghe Xie ◽

Tingting Guo ◽

Zhiyong Zhong ◽

Ning Wang ◽

Yan Liang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Cycle Progression ◽

Bioinformatics Analysis ◽

Cycle Progression ◽

Migration Assay ◽

Normal Tissues ◽

Polymerase Chain ◽

Interfering Rna ◽

Normal Controls

Integrin β1 (ITGB1), which acts as an extracellular matrix (ECM) receptor, has gained increasing attention as a therapeutic target for the treatment of hepatocellular carcinoma (HCC). However, the underpinning mechanism of how ITGB1 drives HCC progression remains elusive. In this study, we first found that ITGB1 expression was significantly higher in HCC tissues than in normal controls by bioinformatics analysis. Furthermore, bioinformatics analysis revealed that paxillin (PXN) and 14-3-3 protein zeta (YWHAZ) are the molecules participating in ITGB1-regulated HCC tumor cell cycle progression. Indeed, immunohistochemistry (IHC) revealed that ITGB1, paxillin, and YWHAZ were strongly upregulated in paired HCC tissue compared with adjacent normal tissues. Notably, the inhibition of ITGB1 expression by small interfering RNA (siRNA) resulted in the downregulated expression of PXN and YWHAZ in primary HCC cells, as assessed by western blot and immunostaining. In addition, ITGB1 knockdown markedly impaired the aggressive behavior of HCC tumor cells and delayed cell cycle progression as determined by cell migration assay, drug-resistance analysis, colony formation assay, quantitative real-time polymerase chain reaction (qRT-PCR), and cell cycle analysis as well as cell viability measurements. More importantly, we proved that xenograft ITGB1high tumors grew more rapidly than ITGB1low tumors. Altogether, our study showed that the ITGB1/PXN/YWHAZ/protein kinase B (AKT) axis enhances HCC progression by accelerating the cell cycle process, which offers a promising approach to halt HCC tumor growth.

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Tumor suppressive role of mitochondrial sirtuin 4 in induction of G2/M cell cycle arrest and apoptosis in hepatitis B virus-related hepatocellular carcinoma

Cell Death Discovery ◽

10.1038/s41420-021-00470-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Fung-Yu Huang ◽

Danny Ka-Ho Wong ◽

Wai-Kay Seto ◽

Lung-Yi Mak ◽

Tan-To Cheung ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Hepatitis B Virus ◽

Cell Lines ◽

Cell Cycle Progression ◽

Normal Liver ◽

Cycle Progression ◽

B Virus ◽

Induce Cell Cycle Progression

AbstractHepatocellular carcinoma (HCC) is developed from uncontrolled cell growth after the malignant transformation of hepatocytes. The hepatitis B virus (HBV) X protein (HBx) has shown to induce cell cycle progression and hepatocarcinogenesis. A sub-fraction of HBx is localized in the mitochondria. Sirtuin 4 (SIRT4), a mitochondrial protein, has been demonstrated to play a tumor-suppressive role in many cancers, including HCC. However, little is known about the association between mitochondrial HBx and SIRT4 during hepatocarcinogenesis. We aimed to investigate the clinical significance and functional role of SIRT4 in HBV-related HCC. SIRT4 expression was significantly lower in the HCC tissues collected from 30 patients with HBV-related HCC than in normal liver tissues from control patients (p < 0.0001). TCGA data analysis indicated that SIRT4 expression was also lower in patients with HBV infection than in those without, and SIRT4 levels were positively associated with better patient survival. Similarly, HCC cell lines had lower SIRT4 expression than normal liver cell lines (all p < 0.01). Among the HCC cell lines, those harbored HBV had a lower SIRT4 expression than those without HBV (p < 0.0001). In vitro experiments revealed that stable HBx transfection suppressed SIRT4 expression in both HepG2 and Huh7 cells (both p < 0.001). Ectopic SIRT4 overexpression alone could induce cellular senescence through arresting cell-cycle progression at G2/M, and inducing cell apoptosis in HCC cells. Mechanistically, SIRT4 upregulated cell-cycle governing genes p16 and p21 protein expression, suppressed CyclinB1/Cdc2 and Cdc25c which normally induce cell-cycle progression, and suppressed survivin to induce apoptosis. Our findings demonstrate the interaction between HBV and SIRT4 in the context of HCC. SIRT4 involves in G2/M DNA damage checkpoint control and genomic stability in hepatocarcinogenesis, which could be targeted for future anticancer strategies.

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Calreticulin down-regulation inhibits the cell growth, invasion and cell cycle progression of human hepatocellular carcinoma cells

Diagnostic Pathology ◽

10.1186/s13000-015-0382-1 ◽

2015 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Ruo Feng ◽

Jianwen Ye ◽

Chuang Zhou ◽

Lei Qi ◽

Zhe Fu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Growth ◽

Cell Cycle Progression ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Down Regulation ◽

Cycle Progression ◽

Hepatocellular Carcinoma Cells ◽

Human Hepatocellular Carcinoma Cells

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Enhanced cell cycle progression and down regulation of p21Cip1/Waf1 by PRL tyrosine phosphatases

Cancer Letters ◽

10.1016/s0304-3835(03)00517-2 ◽

2003 ◽

Vol 202 (2) ◽

pp. 201-211 ◽

Cited By ~ 59

Author(s):

Sean R. Werner ◽

Paul A. Lee ◽

Matthew W. DeCamp ◽

Dring N. Crowell ◽

Stephen K. Randall ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Tyrosine Phosphatases ◽

Down Regulation ◽

Cycle Progression

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Cubic Membranes Formation in Synchronized Human Hepatocellular Carcinoma Cells Reveals a Possible Role as a Structural Antioxidant Defense System in Cell Cycle Progression

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.617406 ◽

2020 ◽

Vol 8 ◽

Author(s):

Deqin Kong ◽

Rui Liu ◽

Jiangzheng Liu ◽

Qingbiao Zhou ◽

Jiaxin Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Cycle Progression ◽

S Phase ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Cycle Progression ◽

Hepatocellular Carcinoma Cells ◽

G2 Phase ◽

Human Hepatocellular Carcinoma Cells

Cubic membranes (CMs) represent unique biological membrane structures with highly curved three-dimensional periodic minimal surfaces, which have been observed in a wide range of cell types and organelles under various stress conditions (e. g., starvation, virus-infection, and oxidation). However, there are few reports on the biological roles of CMs, especially their roles in cell cycle. Hence, we established a stable cell population of human hepatocellular carcinoma cells (HepG2) of 100% S phase by thymidine treatment, and determined certain parameters in G2 phase released from S phase. Then we found a close relationship between CMs formation and cell cycle, and an increase in reactive oxygen species (ROS) and mitochondrial function. After the synchronization of HepG2 cells were induced, CMs were observed through transmission electron microscope in G2 phase but not in G1, S and M phase. Moreover, the increased ATP production, mitochondrial and intracellular ROS levels were also present in G2 phase, which demonstrated a positive correlation with CMs formation by Pearson correlation analysis. This study suggests that CMs may act as an antioxidant structure in response to mitochondria-derived ROS during G2 phase and thus participate in cell cycle progression.

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