scholarly journals UBE2S interacting with TRIM28 in the nucleus accelerates cell cycle by ubiquitination of p27 to promote hepatocellular carcinoma development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ren-Yu Zhang ◽  
Ze-Kun Liu ◽  
Ding Wei ◽  
Yu-Le Yong ◽  
Peng Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Driver Gene ◽  
Sequencing Analysis ◽  
Whole Exome ◽  
Molecular Therapeutic ◽  
Molecular Therapeutic Targets

AbstractGenomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine. However, identifying a key driver gene or mutation that can be used for hepatocellular carcinoma (HCC) treatment remains difficult. Here, we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S (p. Gly57Ala and p. Lys63Asn). Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious. Further, we observed that wild-type UBE2S, especially in the nucleus, was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC. Functional assays revealed that overexpression of UBE2S promoted the proliferation, invasion, metastasis, and G1/S phase transition of HCC cells in vitro, and promoted the tumor growth significantly in vivo. Mechanistically, UBE2S interacted with TRIM28 in the nucleus, both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression. Most importantly, the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen (HTS) to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo, which may represent a promising strategy for HCC therapy.

scholarly journals KIF15 Promotes Proliferation and Growth of Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yue-Feng Sun ◽  
Hong-Li Wu ◽  
Rui-Fang Shi ◽  
Lin Chen ◽  
Chao Meng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Critical Role ◽  
Great Promise ◽  
Cell Processes ◽  
Multiple Cell ◽  
Molecular Therapeutic ◽  
Molecular Therapeutic Targets

Liver cancer is thought as the most common human malignancy worldwide, and hepatocellular carcinoma (HCC) accounts for nearly 90% liver cancer. Due to its poor early diagnosis and limited treatment, HCC has therefore become the most lethal malignant cancers in the world. Recently, molecular targeted therapies showed great promise in the treatment of HCC, and novel molecular therapeutic targets is urgently needed. KIF15 is a microtubule-dependent motor protein involved in multiple cell processes, such as cell division. Additionally, KIF15 has been reported to participate in the growth of various types of tumors; however, the relation between KIF15 and HCC is unclear. Herein, our study investigated the possible role of KIF15 on the progression of HCC and found that KIF15 has high expression in tumor samples from HCC patients. KIF15 could play a critical role in the regulation of cell proliferation of HCC, which was proved by in vitro and in vivo assays. In conclusion, this study confirmed that KIF15 could be a novel therapeutic target for the treatment of HCC.

scholarly journals Circular RNA hsa_circ_0061395 accelerates hepatocellular carcinoma progression via regulation of the miR-877-5p/PIK3R3 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yanhui Yu ◽  
Lijuan Bian ◽  
Renfei Liu ◽  
Yitong Wang ◽  
Xia Xiao
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Circular Rna ◽  
Cell Counting ◽  
Regulatory Subunit ◽  
Luciferase Reporter ◽  
Hcc Cells

Abstract Background Circular RNA hsa_circ_0061395 (circ_0061395) has been reported to accelerate the advancement of hepatocellular carcinoma (HCC). However, the regulatory mechanism by which circ_0061395 modulates the progression of HCC is unclear. Methods The morphology and size of exosomes were analyzed by transmission electron microscope (TEM) and nanoparticle-tracking analysis (NTA). Protein levels were detected by western blotting. Expression levels of circ_0061395, microRNA (miR)-877-5p, and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) mRNA were assessed by quantitative real time polymerase chain reaction (qRT-PCR). The proliferation, invasion, migration, cell cycle progression, and apoptosis were analyzed by cell counting kit-8 (CCK-8), plate clone, transwell, or flow cytometry assays. The targeting relationship between circ_0061395 or PIK3R3 and miR-877-5p was verified using the dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. Xenograft assay was performed to confirm the biological function of circ_0061395 in HCC. Results Circ_0061395 was upregulated in HCC tissues, serum, cells, and serum-derived exosomes. Circ_0061395 silencing decreased tumor growth in vivo, and induced cell cycle arrest, apoptosis, repressed proliferation, invasion, and migration of HCC cells in vitro. MiR-877-5p was downregulated while PIK3R3 was upregulated in HCC. Circ_0061395 regulated PIK3R3 expression via competitively binding to miR-877-5p. MiR-877-5p inhibitor overturned circ_0061395 knockdown-mediated influence on malignant behaviors of HCC cells. PIK3R3 overexpression reversed the suppressive influence of miR-877-5p mimic on malignant behaviors of HCC cells. Conclusion Circ_0061395 facilitated HCC progression via regulating the miR-877-5p/PIK3R3 axis, providing a new perspective on the advancement of HCC.

scholarly journals LINC00978 promotes hepatocellular carcinoma carcinogenesis partly via activating the MAPK/ERK pathway

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Quan Zhang ◽  
Shujie Cheng ◽  
Liye Cao ◽  
Jihong Yang ◽  
Yu Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Western Blots ◽  
Cycle Progression

Abstract Objective: To study the role of long non-coding RNA (lncRNA) LINC00978 in hepatocellular carcinoma (HCC) carcinogenesis. Materials and methods: LINC00978 expression level was measured by reverse transcription quantitative real-time PCR (RT-qPCR) in HCC tissues and adjacent healthy liver tissues from 49 HCC patients. MTT assay, colony forming assay, and flow cytometry were performed to evaluate the effects of shRNA-mediated LINC00978 knockdown on HCC cell proliferation, cell cycle progression, and apoptosis in vitro. Xenograft tumor model was performed to determine the effects of LINC00978 knockdown on HCC tumor growth in vivo. Western blot was used to assess the activation of signaling molecules in the apoptosis and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Results: LINC00978 expression was significantly up-regulated in human HCC tissue relative to adjacent normal tissue, and LINC00978 high expression was correlated with poor HCC overall survival. LINC00978 was up-regulated in HCC cell lines. ShRNA-mediated LINC00978 knockdown significantly decreased HCC cell proliferation, and induced HCC cell cycle arrest and apoptosis in vitro. LINC00978 knockdown led to significant decrease in tumor xenograft size in vivo. Western blots revealed LINC00978 inhibition decreased ERK, p38, and c-Jun N-terminal kinase (JNK) phosphorylation in HCC cells. Conclusions: LINC00978 is highly expressed in human HCC tissue and correlates with poor HCC prognosis. LINC00978 promotes HCC cell proliferation, cell cycle progression, and survival, partially by activating the MAPK/ERK pathway. Our findings partially elucidated the roles of LINC00978 in HCC carcinogenesis, and identified a therapeutic target for HCC.

scholarly journals Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
JiangSheng Zhao ◽  
GuoFeng Chen ◽  
Jingqi Li ◽  
Shiqi Liu ◽  
Quan Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
Lung Metastases ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
And Migration ◽  
Healthy Liver

Abstract Background PR55α plays important roles in oncogenesis and progression of numerous malignancies. However, its role in hepatocellular carcinoma (HCC) is unclear. This study aims to characterize the functions of PR55α in HCC. Methods PR55α expressions in HCC tissues and paired healthy liver samples were evaluated using Western blot and tissue microarray immunohistochemistry. We knocked down the expression of PR55α in SMMC-7721 and LM3 cell lines via small interfering and lentivirus. In vitro cell counting, colony formation, migration and invasion assays were performed along with in vivo xenograft implantation and lung metastases experiments. The potential mechanisms involving target signal pathways were investigated by RNA-sequencing. Results PR55α expression level was suppressed in HCC tissues in comparison to healthy liver samples. Decreased PR55α levels were correlated with poorer prognosis (P = 0.0059). Knockdown of PR55α significantly promoted cell proliferation and migration, induced repression of the cell cycle progression and apoptosis in vitro while accelerating in vivo HCC growth and metastasis. Mechanistic analysis indicated that PR55α silencing was involved with MAPK/AKT signal pathway activation and resulted in increased phosphorylation of both AKT and ERK1/2. Conclusions This study identifies PR55α to be a candidate novel therapeutic target in the treatment of HCC.

scholarly journals Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Ying Zhu ◽  
Kun-Bin Ke ◽  
Zhong-Kun Xia ◽  
Hong-Jian Li ◽  
Rong Su ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
G1 Arrest ◽  
Huh7 Cells ◽  
Synergistic Cytotoxicity ◽  
Combination Study ◽  
Experimental Approaches ◽  
Induced Apoptosis

Abstract Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. Results We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. Conclusions The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

scholarly journals ID: 1023 All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth

2017 ◽  
Vol 4 (S) ◽  
pp. 98
Author(s):  
P H Nguyen ◽  
J Giraud ◽  
C Staedel ◽  
L Chambonnier ◽  
P Dubus ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Gastric Carcinoma ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
3D Culture ◽  
All Trans Retinoic Acid

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-transretinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.

Upregulation of SGOL2 Predicts Poor Prognosis and Facilitates Hepatocellular Carcinoma Progression via Dysregulating the Cell Cycle by Directly Activating MAD2

2021 ◽  
Author(s):  
Qingqing Hu ◽  
Xiaochu Hu ◽  
Yalei Zhao ◽  
Lingjian Zhang ◽  
Ya Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
The Cancer Genome Atlas ◽  
Loss Of Function ◽  
Protein Levels ◽  
Cancer Genome Atlas ◽  
Centromeric Protein ◽  
Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Shugoshin-like protein 2 (SGOL2) is a centromeric protein that ensures the correct and orderly process of mitosis by protecting and maintaining centripetal adhesions during meiosis and mitosis. However, the role of SGOL2 in cancer is not well understood. Methods: The mRNA and protein levels of SGOL2 and survival analysis were conducted in The Cancer Genome Atlas (TCGA) and further validated in 2 independent cohorts. Differential genes correlated with SGOL2 and mitotic arrest deficient 2 like 1 (MAD2) were obtained using LinkedOmics. Subsequently, loss-of-function and rescue assays were carried out in vitro and in vivo to assess the functions of SGOL2 in hepatic tumorigenisis. Findings: We found that SGOL2 was significantly overexpressed in HCC and predicted unfavorable overall survival in HCC patients. Next, we identified 47 differentially expressed genes positively correlated with both SGOL2 and MAD2 to be mainly involved in the cell cycle. In addition, SGOL2 downregulation suppressed the migration, invasion, proliferation, stemness and EMT of HCC cells and inhibited tumorigenesis in vivo. Furthermore, SGOL2 promoted tumor proliferation by activating MAD2-induced cell cycle dysregulation, which could be reversed by the MAD2 inhibitor M2I-1. We also proved that SGOL2 activated MAD2 by directly binding with MAD2. Conclusions: The results of this study showed that SGOL2 acts as an oncogene in HCC cells by directly activating MAD2 and then dysregulating the cell cycle, thereby providing a potential target for HCC patients in the future.

scholarly journals Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Bei Li ◽  
Ang Li ◽  
Zhen You ◽  
Jingchang Xu ◽  
Sha Zhu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Luciferase Assay ◽  
Bioinformatics Analyses ◽  
Mesenchymal Transition ◽  
Rna Immunoprecipitation

Abstract Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated with dysregulated expression of SNHG1 and activation of the cell cycle pathway. SNHG1 was upregulated in HCC tissues and cells, and its knockdown significantly inhibited HCC cell cycle, growth, metastasis, and epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Chromatin immunoprecipitation and RNA immunoprecipitation assays demonstrate that SNHG1 inhibit the transcription of CDKN1A and CDKN2B through enhancing EZH2 mediated-H3K27me3 in the promoter of CDKN1A and CDKN2B, thus resulting in the de-repression of the cell cycle. Dual-luciferase assay and RNA pulldown revealed that SNHG1 promotes the expression of CDK4 by competitively binding to miR-140-5p. In conclusion, we propose that SNHG1 formed a regulatory network to confer an oncogenic function in HCC and SNHG1 may serve as a potential target for HCC diagnosis and treatment.

scholarly journals CDK4/6 inhibitors: a novel strategy for tumor radiosensitization

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Yilan Yang ◽  
Jurui Luo ◽  
Xingxing Chen ◽  
Zhaozhi Yang ◽  
Xin Mei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Studies ◽  
Cell Cycle Progression ◽  
Combined Therapy ◽  
Small Sample ◽  
Combination Strategies ◽  
Novel Strategy ◽  
Underlying Mechanisms

Abstract Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin D-CDK4/6 complex and induce G1 phase arrest. These agents have demonstrated favorable effects when used as monotherapy or combined with endocrine therapy and targeted inhibitors, stimulating further explorations of other combination strategies. Multiple preclinical studies have indicated that CDK4/6 inhibitors exhibit a synergistic effect with radiotherapy both in vitro and in vivo. The principal mechanisms of radiosensitization effects include inhibition of DNA damage repair, enhancement of apoptosis, and blockade of cell cycle progression, which provide the rationale for clinical use. CDK4/6 inhibitors also induce cellular senescence and promote anti-tumor immunity, which might represent potential mechanisms for radiosensitization. Several small sample clinical studies have preliminarily indicated that the combination of CDK4/6 inhibitors and radiotherapy exhibited well-tolerated toxicity and promising efficacy. However, most clinical trials in combined therapy remain in the recruitment stage. Further work is required to seek optimal radiotherapy-drug combinations. In this review, we describe the effects and underlying mechanisms of CDK4/6 inhibitors as a radiosensitizer and discuss previous clinical studies to evaluate the prospects and challenges of this combination.

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