Gene Summary

Gene:PRC1; protein regulator of cytokinesis 1
Aliases: ASE1
Summary:This gene encodes a protein that is involved in cytokinesis. The protein is present at high levels during the S and G2/M phases of mitosis but its levels drop dramatically when the cell exits mitosis and enters the G1 phase. It is located in the nucleus during interphase, becomes associated with mitotic spindles in a highly dynamic manner during mitosis, and localizes to the cell mid-body during cytokinesis. This protein has been shown to be a substrate of several cyclin-dependent kinases (CDKs). It is necessary for polarizing parallel microtubules and concentrating the factors responsible for contractile ring assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein regulator of cytokinesis 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Latest Publications: PRC1 (cancer-related)

Zhang Y, Chen H, Zhu H, Sun X
CBX8 promotes tumorigenesis and confers radioresistance in esophageal squamous cell carcinoma cells through targeting APAF1.
Gene. 2019; 711:143949 [PubMed] Related Publications
As a transcriptional repressor, Chromobox 8 (CBX8) overexpression is found to be associated with tumorigenesis in several cancers. However, its role in radiotherapy resistance remains poorly characterized. Our study is the first to explore the correlation between CBX8 and radioresistance. We report here that CBX8 is upregulated in Esophageal Squamous Cell Carcinoma (ESCC) tissues and cells and serves as an indicator of poor prognosis for ESCC patients. CBX8 knockdown inhibits cell proliferation, colony formation capability, DNA repair and promotes cell apoptosis. Moreover, the transcriptome sequencing analysis demonstrates that CBX8 downregulates the expression of Apoptotic protease activating factor 1 (APAF1), which is the core protein that mediates mitochondrial apoptotic pathways. APAF1 depletion could abrogate apoptosis induced by CBX8 knockdown in irradiated ESCC cells. Our results provide novel insight into CBX8 as a therapeutic target to improve the radiosensitivity of ESCC.

Gusev A, Lawrenson K, Lin X, et al.
A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.
Nat Genet. 2019; 51(5):815-823 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10

He M, Chaurushiya MS, Webster JD, et al.
Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.
Science. 2019; 364(6437):283-285 [PubMed] Related Publications
Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example,

Zhu X, Qin M, Li C, et al.
Downregulated Expression of Chromobox Homolog 7 in Hepatocellular Carcinoma.
Genet Test Mol Biomarkers. 2019; 23(5):348-352 [PubMed] Related Publications

Wu L, Zhang D, Zhou L, et al.
FUN14 domain-containing 1 promotes breast cancer proliferation and migration by activating calcium-NFATC1-BMI1 axis.
EBioMedicine. 2019; 41:384-394 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: FUN14 domain-containing 1 (FUNDC1), as a novel member of mitochondria-associated endoplasmic reticulum (ER) membranes associates with mitochondrial division and mitophagy. However, the expression profile and functional roles of FUNDC1 remain largely unclear in human cancer biology, including breast cancer (BC).
METHODS: Immunohistochemistry and western blot analysis were used to determine the expression of FUNDC1 and BMI1 polycomb ring finger oncogene (BMI1). CCK8, cell counting and transwell assays were used to analyze cell proliferation, migration and invasion, respectively. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to detect the transcriptional regulation of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). The prognostic merit of NFATC1 expression was assessed by Kaplan-Meier assay.
FINDINGS: Immunohistochemistry revealed strong immunostaining for FUNDC1 in cytoplasmic and nuclear membrane distribution in BC tissues as compared with normal breast epithelium. Kaplan-Meier survival analysis showed worse outcome for BC patients with high FUNDC1 expression. In vitro assay of gain- and loss-of-function of FUNDC1 suggested that FUNDC1 could stimulate BC cell proliferation, migration and invasion. Furthermore, elevated FUNDC1 level promoted Ca
INTERPRETATION: FUNDC1 might promote BC progression by activating the Ca

Wang Y, Liang Z, Li H, et al.
NSPc1 polycomb protein complex binds and cross‑talks to lncRNAs in glioma H4 cells.
Oncol Rep. 2019; 41(4):2575-2584 [PubMed] Related Publications
Recently, emerging evidence shows that a number of long non‑coding RNAs (lncRNAs) recruit polycomb group (PcG) proteins to specific chromatin loci to silence relevant gene expression. In the present study, we provided evidence that lncRNA candidates, selected by bioinformatic analysis and nervous system polycomb 1 (NSPc1), a key polycomb repressive complex 1 (PRC1) member, were highly expressed in glioma H4 cells in contrast to that noted in non‑cancerous cells. RNA binding protein immunoprecipitation (RIP) assays demonstrated that metastasis associated lung adenocarcinoma transcript 1 (MALAT1), SOX2 overlapping transcript (SOX2OT) and maternally expressed 3 (MEG3) among the 8 candidates bound to the NSPc1 protein complex in glioma H4 cells. Furthermore, overexpression of NSPc1 caused a decrease in the expression of MALAT1 and MEG3 and increased expression of SOX2OT, while NSPc1 downregulation caused the levels of all three genes to increase. Meanwhile, suppression of the expression of MALAT1 increased the expression levels of mRNA and protein of NSPc1, whereas downregulation of the expression of SOX2OT decreased NSPc1 expression. Moreover, a significant decrease in cell growth and increased cell apoptosis were observed in the transfected H4 cells by MTT assay and flow cytometric analysis. The results showed that the reduced co‑expression between NSPc1 and MALAT1/SOX2OT decreased the proliferation and promoted the death of H4 cells more obviously than the respectively decrease in expression of NSPc1, MALAT1 and SOX2OT. Remarkably, the influence of a simultaneously decreased expression of NSPc1 and SOX2OT on promoting cell apoptosis was more obvious than the total effect of the separate downregulation of NSPc1 and SOX2OT on accelerating cell death. However, that impact was partially counteracted in the silencing of the co‑expression of MALAT1 and NSPc1. Furthermore, they cooperated to affect transcription of p21 and OCT4.Briefly, these data suggest NSPc1 polycomb protein complex binding and cross‑talk to lncRNAs in glioma H4 cells, offering new insight into the important function of polycomb protein complex and lncRNA interactions in glioma cells and provide a novel view of potential biomarkers and targets for the diagnosis and therapy of glioma.

Wu M, Liu Z, Zhang A, Li N
Identification of key genes and pathways in hepatocellular carcinoma: A preliminary bioinformatics analysis.
Medicine (Baltimore). 2019; 98(5):e14287 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. However, the precise mechanisms of the development and progression of HCC remain unclear. The present study attempted to identify and functionally analyze the differentially expressed genes between HCC and cirrhotic tissues by using comprehensive bioinformatics analyses.
METHODS: The GSE63898 gene expression profile was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs were performed in DAVID. The STRING database was used to evaluate the interactions of DEGs and to construct a protein-protein interaction (PPI) network using Cytoscape software. Hub genes were selected using the cytoHubba plugin and were validated with the cBioPortal database.
RESULTS: A total of 301 DEGs were identified between HCC and cirrhotic tissues. The GO analysis results showed that these DEGs were significantly enriched in certain biological processes including negative regulation of growth and cell chemotaxis. Several significant pathways, including the p53 signaling pathway, were identified as being closely associated with these DEGs. The top 12 hub genes were screened and included TTK, NCAPG, TOP2A, CCNB1, CDK1, PRC1, RRM2, UBE2C, ZWINT, CDKN3, AURKA, and RACGAP1. The cBioPortal analysis found that alterations in hub genes could result in significantly reduced disease-free survival in HCC.
CONCLUSION: The present study identified a series of key genes and pathways that may be involved in the tumorigenicity and progression of HCC, providing a new understanding of the underlying molecular mechanisms of carcinogenesis in HCC.

Bhaskaran V, Nowicki MO, Idriss M, et al.
The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma.
Nat Commun. 2019; 10(1):442 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
MicroRNA deregulation is a consistent feature of glioblastoma, yet the biological effect of each single gene is generally modest, and therapeutically negligible. Here we describe a module of microRNAs, constituted by miR-124, miR-128 and miR-137, which are co-expressed during neuronal differentiation and simultaneously lost in gliomagenesis. Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation. Synchronizing the expression of these three microRNAs in a gene therapy approach displays significant anticancer synergism, abrogates this epigenetic-mediated, multi-protein tumor survival mechanism and results in a 5-fold increase in survival when combined with chemotherapy in murine glioblastoma models. These transgenic microRNA clusters display intercellular propagation in vivo, via extracellular vesicles, extending their biological effect throughout the whole tumor. Our results support the rationale and feasibility of combinatorial microRNA strategies for anticancer therapies.

Chen X, Hu L, Yang H, et al.
DHHC protein family targets different subsets of glioma stem cells in specific niches.
J Exp Clin Cancer Res. 2019; 38(1):25 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Glioblastomas (GBM) comprise different subsets that exhibit marked heterogeneity and plasticity, leading to a lack of success of genomic profiling in guiding the development of precision medicine approaches against these tumors. Accordingly, there is an urgent need to investigate the regulatory mechanisms for different GBM subsets and identify novel biomarkers and therapeutic targets relevant in the context of GBM-specific niches. The DHHC family of proteins is associated tightly with the malignant development and progression of gliomas. However, the role of these proteins in the plasticity of GBM subsets remains unclear.
METHODS: This study utilized human glioma proneural or mesenchymal stem cells as indicated. The effects of DHHC proteins on different GBM subsets were investigated through in vitro and in vivo assays (i.e., colony formation assay, flow cytometry assay, double immunofluorescence, western blot, and xenograft model). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to detect the protein complexes of ZDHHC18 and ZDHHC23 in various GBM subtypes, and explore the mechanism of DHHC proteins in targeting different subsets of GSCs in specific niches.
RESULTS: ZDHHC18 and ZDHHC23 could target the glioma stem cells of different GBM subsets in the context of their specific niches and regulate the cellular plasticity of these subtypes. Moreover, mechanistic investigations revealed that ZDHHC18 and ZDHHC23 competitively interact with a BMI1 E3 ligase, RNF144A, to regulate the polyubiquitination and accumulation of BMI1. These events contributed to the transition of glioma stem cells in GBM and cell survival under the stressful tumor microenvironment.
CONCLUSIONS: Our work highlights the role of DHHC proteins in the plasticity of GBM subsets and reveals that BMI1 represents a potential therapeutic target for human gliomas.

Peng F, Li Q, Niu SQ, et al.
ZWINT is the next potential target for lung cancer therapy.
J Cancer Res Clin Oncol. 2019; 145(3):661-673 [PubMed] Related Publications
PURPOSE: We aimed to analyze the expression of ZWINT, NUSAP1, DLGAP5, and PRC1 in tumor tissues and adjacent tissues with public data.
METHODS: The expression patterns of four genes were detected in cancer tissues and adjacent tissues by qRT-PCR. The overall survival analysis was used to explore these genes in lung adenocarcinoma and squamous cell carcinoma patients. Knockdown assays were used to select the most suitable gene among these four genes. Cell function assays with the knockdown gene were conducted in A549 and NCL H226 cells. The role of the knockdown gene in lung cancer was dissected in a mice tumor model. Transcriptome sequencing analyses with the knockdown gene were analyzed.
RESULTS: Overexpression of these genes was significantly detected in cancer tissues (P < 0.01). Overall survival revealed that high expression of these genes is closely related with poor prognosis of lung adenocarcinoma patients (P < 0.05). Knockdown of ZWINT reduced proliferation in NCI H226 and A549 cells (P < 0.05). Knockdown also inhibited cell migration, invasion, apoptosis, and colony formation (P < 0.05). ZWINT knockdown reduced tumor volume (P < 0.05). Transcriptome sequencing of ZWINT knockdown-treated A549 and NCI H226 cells indicated that 100 and 426 differentially expressed genes were obtained, respectively. Gene ontology analysis suggested that binding, biological regulation, and multicellular organismal processes were the most enriched. KEGG analysis revealed that TNF, P53, and PI3K signal networks would be the most potential ZWINT-related pathways and were identified by Western blot analysis.
CONCLUSIONS: ZWINT may be a novel target for lung cancer therapy.

Zhang S, Zhang H, Ghia EM, et al.
Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody.
Proc Natl Acad Sci U S A. 2019; 116(4):1370-1377 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2

Li L, Peng M, Xue W, et al.
Integrated analysis of dysregulated long non-coding RNAs/microRNAs/mRNAs in metastasis of lung adenocarcinoma.
J Transl Med. 2018; 16(1):372 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Lung adenocarcinoma (LUAD), largely remains a primary cause of cancer-related death worldwide. The molecular mechanisms in LUAD metastasis have not been completely uncovered.
METHODS: In this study, we identified differentially expressed genes (DEGs), miRNAs (DEMs) and lncRNAs (DELs) underlying metastasis of LUAD from The Cancer Genome Atlas database. Intersection mRNAs were used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and co-expression network analysis. In addition, survival analyses of intersection mRNAs were conducted. Finally, intersection mRNAs, miRNAs and lncRNAs were subjected to construct miRNA-mRNA-lncRNA network.
RESULTS: A total of 1015 DEGs, 54 DEMs and 22 DELs were identified in LUAD metastasis and non-metastasis samples. GO and KEGG pathway analysis had proven that the functions of intersection mRNAs were closely related with many important processes in cancer pathogenesis. Among the co-expression interactions network, 22 genes in the co-expression network were over the degree 20. These genes imply that they have connections with many other gene nodes. In addition, 14 target genes (ARHGAP11A, ASPM, HELLS, PRC1, TMPO, ARHGAP30, CD52, IL16, IRF8, P2RY13, PRKCB, PTPRC, SASH3 and TRAF3IP3) were found to be associated with survival in patients with LUAD significantly (log-rank P < 0.05). Two lncRNAs (LOC96610 and ADAM6) acting as ceRNAs were identified based on the miRNA-mRNA-lncRNA network.
CONCLUSIONS: Taken together, the results may provide a novel perspective to develop a multiple gene diagnostic tool for LUAD prognosis, which might also provide potential biomarkers or therapeutic targets for LUAD.

Isshiki Y, Iwama A
Emerging role of noncanonical polycomb repressive complexes in normal and malignant hematopoiesis.
Exp Hematol. 2018; 68:10-14 [PubMed] Related Publications
Polycomb group (PcG) proteins are the key epigenetic regulators of normal hematopoiesis and the dysregulation of their functions is closely involved in the pathogenesis of hematological malignancies. These proteins function in the multimeric complexes called polycomb repressive complex (PRC) 1 and 2. In addition to canonical PRC1, four noncanonical PRC1 complexes have been identified. In contrast to canonical PRC1, which is recruited to its target sites in a manner dependent on H3K27me3, noncanonical PRC1 complexes are recruited to their target sites independently of H3K27me3. Among them, PRC1.1, consisting of PCGF1, RING1A/B, KDM2B, and BCL6 corepressor (BCOR) or BCLRL1, regulates diverse biological processes, including pluripotency, reprogramming, and hematopoiesis. PRC1.1 has been implicated in myelopoiesis and lymphopoiesis and is targeted by somatic gene mutations in various hematological malignancies. These findings revealed the more complex regulation of epigenetic cellular memory by PcG proteins than we expected and propose PRC1.1 as a novel therapeutic target in hematological malignancies.

Xu Y, Yao Y, Leng K, et al.
Increased Expression of Circular RNA circ_0005230 Indicates Dismal Prognosis in Breast Cancer and Regulates Cell Proliferation and Invasion via miR-618/ CBX8 Signal Pathway.
Cell Physiol Biochem. 2018; 51(4):1710-1722 [PubMed] Related Publications
BACKGROUND/AIMS: Circular RNAs (circRNAs) are a class of non-coding RNAs. They have been proved to be critically involved in tumorigenesis and progression of malignancies through competing endogenous RNA (ceRNA) mechanism. Nevertheless, the exploration between circRNAs and pathogenesis of breast cancer (BC) is limited. Previously, circ_0005230 was identified upregulated in BC tissues screened by circRNA microarray. In the present study, we aimed to investigate the expression pattern, functional role, and mechanism of circ_0005230 in BC.
METHODS: qRT-PCR was conducted to elucidate the expression levels of circ_0005230 in BC tissues and cells. Additionally, the clinical severity and prognostic value were investigated. CCK-8, colony-forming, flow cytometric assays were performed. Animal study was conducted to validate the in vitro data. What's more, Transwell assays were induced to detect the cell metastatic properties of circ_0005230 exerts in BC cells. Luciferase reporter assay was used to measure the mechanism of circ_0005230.
RESULTS: circ_0005230 was overexpressed in BC tissue specimens and cell lines. The overexpression of circ_0005230 was related to adverse phenotypes in the patients with BC. In addition, circ_0005230 could be regarded as a prognostic predictor in BC patients. In vitro and in vivo data demonstrated the cell growth promoting role of circ_0005230. Moreover, circ_0005230 could also promote cell migratory and invasive capacities. For the mechanism investigation, circ_0005230 was proved to be a sponge of miR-618, and expression of miR-618 could regulate CBX8 expression via targeting the 3'UTR of CBX8. Rescue assays also illustrated an oncogenic function of circ_0005230 in BC via acting as a miR-618 sponge to promote CBX8 expression.
CONCLUSION: circ_0005230/miR-618/CBX8 axis might play a key role in BC tumorigenesis and development.

Li J, Wang Y, Ge J, et al.
Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer.
Cell Physiol Biochem. 2018; 51(1):262-277 [PubMed] Related Publications
BACKGROUND/AIMS: Cancer stem cells (CSCs) are largely responsible for tumor relapse and metastatic behavior. Doublecortin-like kinase 1 (DCLK1) was recently reported to be a biomarker for gastrointestinal CSCs and involved in the epithelial-mesenchymal transition (EMT) and tumor progression. B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) is a crucial regulator of CSC self-renewal, malignant transformation and EMT, and a previous study from our group showed that Bmi-1 is upregulated in pancreatic cancer progression and participates in EMT. However, it remains unclear whether DCLK1 is involved in pancreatic cancer or whether DCLK1 is associated with the altered level of Bmi-1 expression.
METHODS: The correlation of DCLK1 expression and clinical features of pancreatic cancer was analyzed in 210 paraffin-embedded archived pancreatic cancer specimens by immunohistochemical analysis. The biological effects of DCLK1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays, cell migration by wound healing assay and cell invasion by Transwell invasion assay. We further investigated the effect of therapeutic siRNA targeting DCLK1 on pancreatic cancer cell growth in vivo. Moreover, the molecular mechanism by which DCLK1 upregulates Bmi-1 expression was explored using real-time PCR, western blotting and Co-immunoprecipitation assay.
RESULTS: DCLK1 is overexpressed in pancreatic cancer and is related to metastasis and prognosis. Knockdown of DCLK1 markedly suppressed cell growth in vitro and in vivo and also inhibited the migration and invasion of pancreatic cancer cells. Furthermore, we found that DCLK1 silencing could inhibit EMT in cancer cells via downregulation of Bmi-1 and the mesenchymal markers Snail and Vimentin and upregulation of the epithelial marker E-cadherin. Moreover, high DCLK1 expression in human pancreatic cancer samples was associated with a mesenchymal phenotype and increased cell proliferation. Further co-immunoprecipitation indicated that DCLK1 did not interact with Bmi-1 directly.
CONCLUSION: Our data suggest that upregulation of DCLK1 may contribute to pancreatic cancer metastasis and poor prognosis by increasing Bmi-1 expression indirectly. The findings indicate that inhibiting DCLK1 expression might be a novel strategy for pancreatic cancer therapy.

Wu Y, Tian S, Chen Y, et al.
miR-218 inhibits gastric tumorigenesis through regulating Bmi-1/Akt signaling pathway.
Pathol Res Pract. 2019; 215(2):243-250 [PubMed] Related Publications
BACKGROUND: Previous studies indicated that miR-218 was deregulated in gastric cancer patients and correlated with tumor invasion and prognosis. The aim of this study was to clarify the effect of miR-218 on the malignant behavior of gastric cancer and its role in regulating Bmi-1/Akt signaling pathway.
MATERIALS AND METHODS: We used miR-218 mimic to transfect gastric cancer cell lines AGS and SGC-7901, and the overexpression efficiency was validated using qRT-PCR assay. MTT assay and Transwell chamber system were performed to detect the effect of miR-218 on cell proliferation, invasion and migration on gastric cancer. Western blot and qRT-PCR assay was used to test the role of miR-218 in regulating Bmi-1/Akt signaling pathway.
RESULTS: As shown in our research, ectopic expression of miR-218 in gastric cancer cells inhibits the proliferation, invasion and migration of gastric cancer cells. In addition, miR-218 re-expression inhibits the expression of Bmi-1 and its downstream target p-Akt
CONCLUSIONS: miR-218 inhibits the proliferation, invasion and migration of gastric cancer cells through modulating EMT process and the expression of MMPs via Bmi-1/Akt signaling pathway.

Song X, Tang T, Li C, et al.
CBX8 and CD96 Are Important Prognostic Biomarkers of Colorectal Cancer.
Med Sci Monit. 2018; 24:7820-7827 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies worldwide, with high morbidity and mortality rates. The purpose of this study was to identify potential biomarkers in the progression of CRC. MATERIAL AND METHODS Gene and isoform expression datasets of CRC was downloaded from The Cancer Genome Atlas (TCGA). EBSeq of R was used for the normalization of gene and isoform expression, as well as the identification of differential expression genes (DEGs) and isoforms (DEIs) of CRC samples compared with normal samples. The enriched functions of DEGs and DEIs were obtained based on the Database for Annotation, Visualization and Integrated Discovery (DAVID). An independent dataset, GSE38832, was downloaded from the Gene Expression Omnibus (GEO) database for survival analysis of genes with sustained decreased/increased expression values at both gene and isoform levels with the development of CRC. RESULTS A total of 2301 genes and 4241 isoforms were found to be significantly differentially expressed in stage I-IV CRC samples. They are closely associated with muscle or cell system activity. Sixteen genes were screened out with sustained decreased/increased expression values at both gene and isoform levels with the development of CRC. Aberrant CBX8 and CD96 expressions were found to be significantly associated with CRC survival. CONCLUSIONS Through combined analysis of gene and isoform expression profiles, we identified several potential biomarkers that may play an important role in the development of CRC and could be helpful in its early diagnosis and treatment.

Juckett LT, Lin DI, Madison R, et al.
A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR.
Oncology. 2019; 96(2):101-109 [PubMed] Related Publications
BACKGROUND: The Polycomb Repressive Complex 1 (PRC1) regulates epigenetic silencing and is manifestly linked to rare cancer types. The X-linked BCOR gene (BCL-6 Corepressor) is a member of the PRC1 complex and potentiates transcriptional repression through BCL6 binding of PRC1. Accumulating evidence suggests that internal tandem duplications (ITD) of BCOR are oncogenic drivers in a subset of pediatric sarcomas and rare adult tumors.
OBJECTIVE: We reviewed the genomic profiles of a large series of advanced cancer patients to determine the frequency and genomic spectrum of ITD of BCOR across cancer.
METHODS: Tissues from 140,411 unique advanced cancers were sequenced by hybrid-capture-NGS-based comprehensive genomic profiling of 186-315 genes plus introns from 14 to 28 genes commonly rearranged in cancer, as well as RNA for 265 genes for a portion of these cases.
RESULTS: BCOR-ITDs were present in 0.024% of all cases (33/140,411). Of this dataset, sarcoma cancer types were most frequent, 63.6% (21/33), either of uterine origin 52.4% (11/21), or pediatric (nonuterine) 42.8% (9/21). The identified BCOR-ITDs occurred most frequently in exon 15, near C-terminus, 69.7% (23/33), with a mean insertion length of 31.7 codons (range 30-38). Of uterine cases, an expert gynecologic pathology central review identified all these cases as having a similar high-grade morphology consistent with endometrial stromal sarcomas (ESS), and 90% of cases having a round cell component. Of the uterine sarcoma cases harboring exon 15 BCOR-ITDs, none simultaneously carried gene fusions typically associated with ESS.
CONCLUSION: BCOR-ITDs define a rare subset of pediatric sarcomas and clinically aggressive endometrial stromal sarcoma cases, as defined by NGS for the first time. Our findings help delineate the pan-cancer landscape of this alteration and suggest the need for focused investigation to delineate the pro-oncogenic function of BCOR, along with any sensitivity to targeted therapies.

Salimi M, Eskandari E
Association of Elevated Peripheral Blood Micronucleus Frequency and Bmi-1 mRNA Expression with Metastasis in Iranian Breast Cancer Patients
Asian Pac J Cancer Prev. 2018; 19(10):2723-2730 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Background: In order to find cytogenetic and molecular metastasis biomarkers detectable in peripheral blood the spontaneous genomic instability expressed as micronuclei and Bmi-1 expression in peripheral blood of breast cancer (BC) patients were studied in different stages of the disease compared with unaffected first-degree relatives (FDRs) and normal control. Methods: The Cytokinesis Block Micronuclei Cytome (CBMN cyt) and nested real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) assays, were respectively used to measure genomic instability and Bmi-1 gene expression in 160 Iranian individuals comprised of BC patients in different stages of the disease, unaffected FDRs and normal control groups. Result: The frequency of micronuclei and Bmi-1 expression were dramatically higher in distant metastasis compared with non-metastatic BC. In spite of micronucleus frequency with no association with lymph node (LN) involvement and hormone receptor status, the Bmi-1 expression level was higher in LN positive and triple negative patients. Conclusion: Our results indicate that increased genomic instability expressed as micronuclei and higher Bmi-1 expression in peripheral blood are associated with metastasis in breast cancer. Therefore implementation of micronucleus assay and Bmi-1 expression analysis in blood as possible cytogenetic and molecular biomarkers in clinical level may potentially enhance the quality of management of patients with breast cancer.

Bakhshinyan D, Venugopal C, Adile AA, et al.
BMI1 is a therapeutic target in recurrent medulloblastoma.
Oncogene. 2019; 38(10):1702-1716 [PubMed] Related Publications
Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.

Kahn SA, Wang X, Nitta RT, et al.
Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma.
Nat Commun. 2018; 9(1):4121 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.

Xiong Y, Liu L, Qiu Y, Liu L
MicroRNA-29a Inhibits Growth, Migration and Invasion of Melanoma A375 Cells in Vitro by Directly Targeting BMI1.
Cell Physiol Biochem. 2018; 50(1):385-397 [PubMed] Related Publications
BACKGROUND/AIMS: Melanoma is one of the most aggressive malignant tumors, with increasing incidence, poor prognosis, and lack of any effective targeted therapies. Abnormal expression of miR-29a has been found in several types of cancers, including melanoma. In this study, experiments were performed to investigate the role of miR-29a in melanoma, and the molecular mechanism by which miR-29a represses melanoma.
METHODS: miR-29 and Bmi1 expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability, apoptosis, migration and invasion were respectively determined by Cell Counting Kit-8 assay, Propidium iodide (PI) fluorescein isothiocynate (FITC)-Annexin V staining assay, wound healing assay and transwell assay. Luciferase reporter assay was performed to determine a target gene of miR-29a. Western blot was used to analyze protein expression of apoptosis-related proteins, Bmi1, Wnt/β-catenin and Nuclear factor-κB (NF-κB) pathway target genes.
RESULTS: miR-29a was down-regulated in all tested melanoma cell lines. Up-regulation of miR-29a effectively inhibited cell viability, migration, and invasion, but promoted apoptosis in A375 cells. Bmi1 was a direct target gene of miR-29a. Transfection with miR-29a mimic decreased cell migration and invasion and Bmi1 expression in Malme-3M cells, SK-MEL-2, SK-MEL-5, and M14 cell lines. Moreover, miR-29a might suppress growth, migration and invasion of A375 cells by negatively regulating Bmi1. In addition, our results demonstrated that transfection with miR-29a mimic effectively blocked Wnt/β-catenin and NF-κB pathways via down-regulating Bmi1.
CONCLUSION: miR-29a could be functioned as a potential tumor suppressor through direct regulation of Bmi1 in melanoma cells.

Bilgiç F, Gerçeker E, Boyacıoğlu SÖ, et al.
Potential role of chromatin remodeling factor genes in atrophic gastritis/gastric cancer risk.
Turk J Gastroenterol. 2018; 29(4):427-435 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND/AIMS: Atrophic gastritis (AG), intestinal metaplasia (IM), and Helicobacter pylori (HP) are the risk factors for the development of gastric cancer (GC). Chromatin remodeling is one of the epigenetic mechanisms involved in the carcinogenesis of GC. The purpose of this study was to investigate the expression profiles of defined chromatin remodeling genes in gastric mucosal samples and their values as gastric carcinogenesis biomarkers.
MATERIALS AND METHODS: In total, 95 patients were included in the study. Patients were divided into 3 groups as: GC group (n=34), AG group (n=36), and control group (n=25). AG group was further divided into subgroups based on the presence of HP and IM in gastric mucosa. Chromatin remodeling gene expressions were analyzed using real-time PCR (RT-PCR) array in all groups. Data were evaluated using the RT-qPCR primer assay data analysis software.
RESULTS: EED, CBX3, and MTA1 were more overexpressed, whereas ARID1A, ING5, and CBX7 were more underexpressed in the AG and GC groups compared with the controls. No significant differences were observed between the AG and GC groups concerning the expression of these 6 genes, although the fold change levels of these genes in the GC group were well above than in the AG group. EED, CBX3, and MTA1 were significantly more overexpressed in HP- and IM-positive AG subgroup compared with the HP- or IM-negative AG subgroup.
CONCLUSION: In conclusion, our results provide an evidence of epigenetic alterations in AG. Expressions of EED, CBX3, MTA1, ARID1A, ING5, and CBX7 may be considered as promising markers to be used in GC screening for patients with AG.

Yu J, Hu M, Chen W, Wen Z
Expression of B Cell-Specific Moloney Murine Leukemia Virus Integration Site 1 (BMI-1) and WW Domain-Containing Oxidoreductase (WWOX) in Liver Cancer Tissue and Normal Liver Tissue.
Med Sci Monit. 2018; 24:6673-6679 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND The aim of this study was to compare the expression levels of mRNA of the B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) and the WW domain-containing oxidoreductase (WWOX) genes and their protein products in tissues from patients with liver cancer with normal liver tissues from patients without liver cancer. MATERIAL AND METHODS The liver cancer group (N=56) included patients with available tissue samples of histologically confirmed liver cancer. The control group (N=24) included histologically confirmed normal liver tissue samples. Immunofluorescence staining and Western blot were used to detect and compare protein expression of Bmi-1 and WWOX in liver tissues in the liver cancer group and the control group. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect and compare mRNA expression of BMI-1 and WWOX in liver tissues in the liver cancer group and the control group. Expression levels of the protein and mRNA levels and the clinicopathological features including patient prognosis in liver cancer were evaluated statistically using analysis of variance (ANOVA). RESULTS There were significant differences in the expression levels of protein and mRNA of BMI-1 and WWOX between the liver cancer group and the control group. BMI-1 mRNA and protein expression were significantly increased, and WWOX mRNA and protein expression were significantly reduced in liver cancer tissue, compared with normal liver tissue (p<0.05). CONCLUSIONS In liver cancer tissue compared with normal liver, the expression of BMI-1 and WWOX mRNA and their protein products were upregulated and down-regulated, respectively.

Zhu K, Li K, Yuan DW, et al.
Clinicopathological and Prognostic Significance of Expression of B-Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (BMI-1) Gene and Protein in Gastrointestinal Stromal Tumors.
Med Sci Monit. 2018; 24:6414-6421 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND Gastrointestinal stromal tumor (GIST) is an uncommon visceral sarcoma that arises predominantly in the gastrointestinal tract. Since GISTs are encountered infrequently and inflexible to traditional therapy, the aim of the present study was to explore the correlation of B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI-1) mRNA and BMI-1 protein levels with the clinicopathological characteristics and prognosis significance of GISTs. MATERIAL AND METHODS GIST tissues and normal tissues were collected from 156 patients who had undergone surgical treatment. RT-qPCR and immunohistochemistry were used to measure the BMI-1 mRNA and protein levels in GIST tissues and normal tissues. Univariate survival analysis was used for determination of the factors that affect prognosis of GIST patients. Cox proportional hazards model was plotted to determine the independent risk factors for prognosis of GIST patients. RESULTS The BMI-1 mRNA and protein levels in GIST tissues were higher than those in normal tissues. BMI-1 mRNA and positive protein levels were correlated with the National Institutes of Health (NIH) risk grade, tumor diameter and infiltration, and metastasis. There was a short survival period for the patients with a positive protein level and a high mRNA level of BMI-1. The site of primary tumor, tumor diameter, NIH risk grade, infiltration, and metastasis, as well as BMI-1 mRNA and protein levels were independent risk factors for prognosis of GIST patients. CONCLUSIONS Taken together, these findings suggest there might be a relationship between BMI-1 mRNA and protein levels, and clinicopathological characteristics, including NIH risk grade, tumor size as well as infiltration and metastasis, of GIST patients. In addition, BMI-1 mRNA and protein levels were identified as independent risk factors for prognosis of GIST patients.

Chan HL, Beckedorff F, Zhang Y, et al.
Polycomb complexes associate with enhancers and promote oncogenic transcriptional programs in cancer through multiple mechanisms.
Nat Commun. 2018; 9(1):3377 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Polycomb repressive complex 1 (PRC1) plays essential roles in cell fate decisions and development. However, its role in cancer is less well understood. Here, we show that RNF2, encoding RING1B, and canonical PRC1 (cPRC1) genes are overexpressed in breast cancer. We find that cPRC1 complexes functionally associate with ERα and its pioneer factor FOXA1 in ER+ breast cancer cells, and with BRD4 in triple-negative breast cancer cells (TNBC). While cPRC1 still exerts its repressive function, it is also recruited to oncogenic active enhancers. RING1B regulates enhancer activity and gene transcription not only by promoting the expression of oncogenes but also by regulating chromatin accessibility. Functionally, RING1B plays a divergent role in ER+ and TNBC metastasis. Finally, we show that concomitant recruitment of RING1B to active enhancers occurs across multiple cancers, highlighting an under-explored function of cPRC1 in regulating oncogenic transcriptional programs in cancer.

BMI1 and PTEN are key determinants of breast cancer therapy: A plausible therapeutic target in breast cancer.
Gene. 2018; 678:302-311 [PubMed] Related Publications
BMI-1 (B-lymphoma Mo-MLV insertion region 1) is a key protein partner in polycomb repressive complex 1 (PRC1) that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A which affects gene expression pattern involved in various cellular processes such as cell proliferation, growth, DNA repair, apoptosis and senescence. In many cancers, Overexpression of BMI1correlates with advanced stages of disease, aggressive clinicopathological behavior, poor prognosis resistance to radiation and chemotherapy. BMI1 is emerging as a key player in EMT, chemo-resistance and cancer stemness. Overexpression is observed in various cancer types such as breast, primary hepatocellular carcinoma (HCC), gastric, ovarian, head and neck, pancreatic and lung cancer. Studies have shown that experimental reduction of BMI protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increases susceptibility to cytotoxic agents and radiation therapy. Thus, inhibition of BMI1 expression particularly in breast cancer stem cells can be used as a potential strategy for the complete elimination of tumor and to prevent disease relapse. On other hand PTEN is known to be an important tumor suppressor next to p53. In many cancers particularly in breast cancer, p53 and PTEN undergo mutations. Studies have indicated the functional and mechanistic link between the BMI-1oncoprotein and tumor suppressor PTEN in the development and progression of cancer. The current review focuses on recent findings of how oncogenicity and chemo-resistance are caused by BMI1. It also highlights the transcriptional regulation between BMI1 and PTEN that dictates the therapeutic outcome in cancers where the functional p53 is absent. Herein, we have clearly demonstrated the regulation of transcription at genomic loci of BMI1 and PTEN in cancerous tissue or cells and the possible epigenetic regulation by histone deacetylase inhibitors (HDACi) at BMI1 and PTEN loci that may provide some clue for the possible therapy against TNBC in near future.

Milosevic M, Lazarevic M, Toljic B, et al.
Characterization of stem-like cancer cells in basal cell carcinoma and its surgical margins.
Exp Dermatol. 2018; 27(10):1160-1165 [PubMed] Related Publications
BACKGROUND: Understanding the pathogenesis of basal cell carcinoma (BCC) and identifying the cells responsible for propagation and recurrence are crucial for the development of new treatment strategies. The aim of this study was to characterize the cells isolated from BCC and its margin.
METHODS: Primary cultures were established from 10 BCCs, their respective close resection margins (3 mm) and 10 control tissues. Stem cell markers analysis was carried out by real-time PCR and/or flow cytometry. Spheroid formation and MTT assays were also performed.
RESULTS: Real-time PCR showed a higher expression of embryonic (Oct4, Sox2 and Nanog) and mesenchymal (CD44 and CD73) stem cell markers in tumors compared to margins and controls (P < 0.05). Bmi-1 and GPR49 were also upregulated in tumors in comparison with margins. Both tumor and margin cells, but not normal, had the capacity to form spheroids. During passages, the number of spheres increased, while the diameter decreased. Tumor cells showed higher chemo-resistance compared to margin and control cells.
CONCLUSIONS: Basal cell carcinomas expressed stem cell markers, pointing to the existence of a cancer cell side population with stemness characteristics. Margin also appeared to harbour a small number of cancer-initiating cells.

Liu J, Wang D, Long Z, et al.
CircRNA8924 Promotes Cervical Cancer Cell Proliferation, Migration and Invasion by Competitively Binding to MiR-518d-5p /519-5p Family and Modulating the Expression of CBX8.
Cell Physiol Biochem. 2018; 48(1):173-184 [PubMed] Related Publications
BACKGROUND/AIMS: Circular RNAs (circRNAs) play a significant role in the development and progression of various human cancers. However, the expression and function of circRNAs in cervical cancer (CC) have rarely been explored. The aim of this study was to investigate the biological function of circRNA8924 in CC and elucidate the possible molecular mechanism involved.
METHODS: Quantitative polymerase chain reaction was used to determine mRNA expression of circRNA8924, miR-518d-5p/519-5p and CBX8 in CC tissues and cells. CBX8 protein expression was measured by Western blotting. The CCK-8 assay was used to evaluate cell proliferation, and the transwell assay to determine cell migration and invasion. The luciferase reporter assay was used to determine the direct regulation of miR-518d-5p/519-5p and circRNA8924 or CBX8 Results: The study demonstrated that the expression level of circRNA8924 in CC was significantly higher than that in the adjacent normal tissues (P < 0.001), and that it was also associated with tumor size, FIGO staging and myometrial invasion. The knockdown of circRNA8924 significantly inhibited the proliferation, migration and invasion of CC cells SiHa and HeLa. The expression level of miR-518d-5p/519-5p was negatively correlated with circRNA8924, and circRNA8924 regulated CBX8 by competitively binding to miR-518d-5p/519-5p.
CONCLUSIONS: CircRNA8924 is highly expressed in CC tissue and can be considered a competitive endogenous RNA of the miR-518d-5p/519-5p family to promote the malignant biological behavior of CC cells. It is suggested that it may serve as a new biomarker for CC diagnosis and disease progression and provide potential targets for targeted therapy.

Pulikkan JA, Hegde M, Ahmad HM, et al.
CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia.
Cell. 2018; 174(1):172-186.e21 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The fusion oncoprotein CBFβ-SMMHC, expressed in leukemia cases with chromosome 16 inversion, drives leukemia development and maintenance by altering the activity of the transcription factor RUNX1. Here, we demonstrate that CBFβ-SMMHC maintains cell viability by neutralizing RUNX1-mediated repression of MYC expression. Upon pharmacologic inhibition of the CBFβ-SMMHC/RUNX1 interaction, RUNX1 shows increased binding at three MYC distal enhancers, where it represses MYC expression by mediating the replacement of the SWI/SNF complex component BRG1 with the polycomb-repressive complex component RING1B, leading to apoptosis. Combining the CBFβ-SMMHC inhibitor with the BET inhibitor JQ1 eliminates inv(16) leukemia in human cells and a mouse model. Enhancer-interaction analysis indicated that the three enhancers are physically connected with the MYC promoter, and genome-editing analysis demonstrated that they are functionally implicated in deregulation of MYC expression. This study reveals a mechanism whereby CBFβ-SMMHC drives leukemia maintenance and suggests that inhibitors targeting chromatin activity may prove effective in inv(16) leukemia therapy.

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