scholarly journals STEAP3 promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR to enhance RAC1-ERK-STAT3 signaling in hepatocellular carcinoma

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Li-Li Wang ◽  
Jie Luo ◽  
Zhang-Hai He ◽  
Ye-Qing Liu ◽  
Hai-Gang Li ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Nuclear Trafficking ◽  
Nuclear Expression ◽  
Stat3 Signaling ◽  
Hcc Cells ◽  
High Expression Level

AbstractSTEAP3 (Six-transmembrane epithelial antigen of the prostate 3, TSAP6, dudulin-2) has been reported to be involved in tumor progression in human malignancies. Nevertheless, how it participates in the progression of human cancers, especially HCC, is still unknown. In the present study, we found that STEAP3 was aberrantly overexpressed in the nuclei of HCC cells. In a large cohort of clinical HCC tissues, high expression level of nuclear STEAP3 was positively associated with tumor differentiation and poor prognosis (p < 0.001), and it was an independent prognostic factor for HCC patients. In HCC cell lines, nuclear expression of STEAP3 significantly promoted HCC cells proliferation by promoting stemness phenotype and cell cycle progression via RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling axes. Through upregulating the expression and nuclear trafficking of EGFR, STEAP3 participated in regulating EGFR-mediated STAT3 transactivity in a manner of positive feedback. In summary, our findings support that nuclear expression of STEAP3 plays a critical oncogenic role in the progression of HCC via modulation on EGFR and intracellular signaling, and it could be a candidate for prognostic marker and therapeutic target in HCC.

scholarly journals Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interacting with EZH2

2020 ◽  
Author(s):  
Dong-Yan Zhang ◽  
Qing-Can Sun ◽  
Xue-Jing Zou ◽  
Yang Song ◽  
Wen-Wen Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Western Blot ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Gene Set Enrichment Analysis ◽  
Luciferase Reporter ◽  
Cycle Progression ◽  
Qrt Pcr ◽  
Hcc Cells

Abstract Background: Dysregulations of lncRNA are responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. Growing number of lncRNAs have been reported in HCC but their functional and mechanistic roles remain unclear. Methods: Gene Set Enrichment Analysis was used to investigate the molecular mechanism of lncRNA UPK1A antisense RNA 1 (UPK1A-AS1). CCK-8 assay, EdU assay, flow cytometry, western blot, and xenograft assay were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells both in vitro and in vivo. Bioinformatics analysis and qRT-PCR were performed to explore the interplay between UPK1A-AS1 and Enhancer of Zeste Homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA-pull down assay, western blot, qRT-PCR, and were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA-seq data from TCGA datasets.Results: We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle related genes including CCND1, CDK2, CDK4, CCNB1 and CCNB2 were significantly upregulated in HCC cells with UPK1A-AS1 overexpression. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to the increasing trimethylation of H27K3. Targeting EZH2 with specific siRNA impaired UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions: Our study reveals that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression via interacting with EZH2 and sponging miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

scholarly journals Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Dong-Yan Zhang ◽  
Qing-Can Sun ◽  
Xue-Jing Zou ◽  
Yang Song ◽  
Wen-Wen Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Western Blotting ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Gene Set Enrichment Analysis ◽  
Luciferase Reporter ◽  
Cycle Progression ◽  
Qrt Pcr ◽  
Hcc Cells

Abstract Background Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. Methods Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. Results We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

scholarly journals Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2

2020 ◽  
Author(s):  
Dong-Yan Zhang ◽  
Qing-Can Sun ◽  
Xue-Jing Zou ◽  
Yang Song ◽  
Wen-Wen Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Western Blotting ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Gene Set Enrichment Analysis ◽  
Luciferase Reporter ◽  
Cycle Progression ◽  
Qrt Pcr ◽  
Hcc Cells

Abstract Background: Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. Methods: Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo . Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. Results: We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions: Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

scholarly journals Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interacting with EZH2

2020 ◽  
Author(s):  
Dong-Yan Zhang ◽  
Qing-Can Sun ◽  
Xue-Jing Zou ◽  
Yang Song ◽  
Wen-Wen Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Western Blot ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Gene Set Enrichment Analysis ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Qrt Pcr ◽  
Hcc Cells

Abstract Background Dysregulations of lncRNA are responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. Growing number of lncRNAs have been reported in HCC but their functional and mechanistic roles remain unclear. Methods Gene Set Enrichment Analysis was used to investigate the molecular mechanism of lncRNA UPK1A antisense RNA 1 (UPK1A-AS1). CCK-8 assay, EdU assay, flow cytometry, western blot, and xenograft assay were used to confirm the role of UPK1A-AS1 in proliferation of HCC cells both in vitro and in vivo. Bioinformatics analysis and qRT-PCR were performed to explore the interplay between UPK1A-AS1 and Enhancer of Zeste Homologue 2 (EZH2). RNA immunoprecipitation, RNA-pull down assay, western blot, qRT-PCR, and were conducted to confirm the interaction between UPK1A-AS1 and EZH2. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA-seq data from TCGA datasets. Results We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle related genes including CyclinD1, CDK2, CDK4, CCNB1 and CCNB2 were significantly upregulated in HCC cells with UPK1A-AS1 overexpression. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to the increasing trimethylation of H27K3. Targeting EZH2 with specific siRNA impaired UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression related genes. Moreover, UPK1A-AS1 was significantly upregulated in HCC, and upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions Our study reveals that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression in an EZH2-dependent manner, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

scholarly journals Keratin 17 Suppresses Cell Proliferation and Epithelial-Mesenchymal Transition in Pancreatic Cancer

2020 ◽  
Vol 7 ◽  
Author(s):  
Yong Zeng ◽  
Min Zou ◽  
Yan Liu ◽  
Keting Que ◽  
Yunbing Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Pancreatic Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Mesenchymal Transition

Keratin 17 (K17), a member of type I acidic epithelial keratin family, has been reported to be upregulated in many malignant tumors and to be involved in promoting the development of tumors. However, the precise role of K17 in progression of pancreatic cancer is still unknown. In this study, we found that K17 expression was highly expressed in pancreatic cancer tissues and cell lines and that upregulated expression was associated with the pathological grade and poor prognosis. K17 expression served as an independent predictor of pancreatic cancer survival. Meanwhile, we showed that knocking down K17 induced pancreatic cancer cell proliferation, colony formation and tumor growth in xenografts in mice. However, K17 upregulation inhibited pancreatic cancer cell proliferation and colony formation. Further mechanistic study revealed that K17 knockdown promoted cell cycle progression by upregulating CyclinD1 expression and repressed cell apoptosis. However, K17 upregulation suppressed cell cycle progression by decreasing CyclinD1 expression, and induced apoptosis by increasing the levels of cleaved Caspase3. In addition, K17 knockdown promoted pancreatic cancer cell migration and invasion, but K17 upregulation suppressed cell migration and invasion. Moreover, knocking down K17 promoted epithelial-mesenchymal transition (EMT) in pancreatic cancer cell by inhibiting E-cadherin expression and inducing Vimentin expression, and the effects of K17 upregulation were opposite to that of K17downregulation. Taken together, our findings suggest that K17 functions as a potential tumor suppressor, even though it is upregulated in pancreatic cancer.

scholarly journals Structural mechanism of Myb–MuvB assembly

2018 ◽  
Vol 115 (40) ◽  
pp. 10016-10021 ◽  
Author(s):  
Keelan Z. Guiley ◽  
Audra N. Iness ◽  
Siddharth Saini ◽  
Sarvind Tripathi ◽  
Joseph S. Lipsick ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Biochemical Analysis ◽  
Adaptor Protein ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Structural Mechanism ◽  
Transcriptional Regulatory ◽  
Regulatory Complex ◽  
Cycle Dependent

The MuvB transcriptional regulatory complex, which controls cell-cycle-dependent gene expression, cooperates with B-Myb to activate genes required for the G2 and M phases of the cell cycle. We have identified the domain in B-Myb that is essential for the assembly of the Myb–MuvB (MMB) complex. We determined a crystal structure that reveals how this B-Myb domain binds MuvB through the adaptor protein LIN52 and the scaffold protein LIN9. The structure and biochemical analysis provide an understanding of how oncogenic B-Myb is recruited to regulate genes required for cell-cycle progression, and the MMB interface presents a potential therapeutic target to inhibit cancer cell proliferation.

scholarly journals LpCat1 Promotes Malignant Transformation of Hepatocellular Carcinoma Cells by Directly Suppressing STAT1

2021 ◽  
Vol 11 ◽  
Author(s):  
Weidan Ji ◽  
Zhangxiao Peng ◽  
Bin Sun ◽  
Lei Chen ◽  
Qin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Clinical Gene Therapy ◽  
First Time ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a malignant cancer with rapid proliferation and high metastasis ability. To explore the crucial genes that maintain the aggressive behaviors of cancer cells is very important for clinical gene therapy of HCC. LpCat1 was reported to be highly expressed and exert pro-tumorigenic effect in a variety of cancers, including HCC. However, its detailed molecular mechanism remained unclear. In this study, we confirmed that LpCat1 was up-regulated in HCC tissues and cancer cell lines. The overexpressed LpCat1 promoted the proliferation, migration and invasion of HCC cells, and accelerated cell cycle progression, while knocking down LpCat1 significantly inhibited cell proliferation, migration and invasion in vitro and in vivo, and arrested HCC cells at G0/G1 phase. Moreover, we proved for the first time that LpCat1 directly interacted with STAT1 which was generally recognized as a tumor suppressor in HCC. High levels of LpCat1 in HCC could inhibit STAT1 expression, up-regulate CyclinD1, CyclinE, CDK4 and MMP-9, and decrease p27kip1 to promote cancer progression. Conversely, down-regulation of LpCat1 would cause the opposite changes to repress the viability and motility of HCC cells. Consequently, we concluded that LpCat1 was a contributor to progression and metastasis of HCC by interacting with STAT1.

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