COIL

Gene Summary

Gene:COIL; coilin
Aliases: CLN80, p80-coilin
Location:17q22
Summary:The protein encoded by this gene is an integral component of Cajal bodies (also called coiled bodies). Cajal bodies are nuclear suborganelles of varying number and composition that are involved in the post-transcriptional modification of small nuclear and small nucleolar RNAs. The N-terminus of the coilin protein directs its self-oligomerization while the C-terminus influences the number of nuclear bodies assembled per cell. Differential methylation and phosphorylation of coilin likely influences its localization among nuclear bodies and the composition and assembly of Cajal bodies. This gene has pseudogenes on chromosome 4 and chromosome 14. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:coilin
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Amino Acid Sequence
  • Proto-Oncogene Proteins
  • Cell Proliferation
  • Oncogene Fusion Proteins
  • HeLa Cells
  • Apoptosis
  • Protein Structure, Tertiary
  • Nuclear Proteins
  • Base Sequence
  • Cell Line
  • DNA-Binding Proteins
  • Carrier Proteins
  • Zinc Fingers
  • Molecular Sequence Data
  • Sequence Alignment
  • RTPCR
  • Biomarkers, Tumor
  • Lung Cancer
  • Gene Expression
  • Cancer Gene Expression Regulation
  • Microtubule-Associated Proteins
  • Breast Cancer
  • Protein-Tyrosine Kinases
  • Neoplasm Invasiveness
  • Restriction Mapping
  • Neoplasm Proteins
  • Proteins
  • Chromosome Mapping
  • Membrane Proteins
  • HEK293 Cells
  • Cell Movement
  • Chromosome 17
  • Cloning, Molecular
  • Mutation
  • Toll-Like Receptor 9
  • Receptor Protein-Tyrosine Kinases
  • Protein Binding
  • Messenger RNA
  • Uterine Cancer
  • Neoplastic Cell Transformation
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: COIL (cancer-related)

Iriyama N, Takahashi H, Naruse H, et al.
A novel fusion gene involving PDGFRB and GCC2 in a chronic eosinophilic leukemia patient harboring t(2;5)(q37;q31).
Mol Genet Genomic Med. 2019; 7(4):e00591 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Platelet-derived growth factor receptor beta (PDGFRB) rearrangement has been reported in a number of patients with chronic eosinophilic leukemia (CEL), B-acute lymphoblastic leukemia, myeloproliferative neoplasms, and juvenile myelomonocytic leukemia. Here, we report a case of CEL carrying a novel fusion gene involving PDGFRB and GRIP and coiled-coil domain containing 2 (GCC2).
PATIENT AND METHODS: A 54-year-old man presenting with a cough and dyspnea was diagnosed with acute eosinophilic pneumonia. Cytogenetic analysis of the bone marrow revealed the presence of t(2;5)(q37;q31). Fluorescence in situ hybridization analysis in the peripheral blood leukocytes revealed the presence of a split signal at PDGFRB gene. Imatinib treatment was effective, and disappearance of t(2;5)(q37;q31) in the bone marrow was confirmed after three months of imatinib therapy. Whole-genome sequencing was performed in peripheral blood leukocytes collected before imatinib therapy.
RESULTS: A novel fusion gene between exon 22 of GCC2 and exon 12 of PDGFRB was detected and the presence of GCC2-PDGFRB was confirmed by PCR.
CONCLUSION: This is the first case report demonstrating the GCC2 gene as a partner of PDGFRB in the pathogenesis of CEL.

Yang C, Wang Y
Identification of differentiated functional modules in papillary thyroid carcinoma by analyzing differential networks.
J Cancer Res Ther. 2018; 14(Supplement):S969-S974 [PubMed] Related Publications
Purpose: The incidence of papillary thyroid carcinoma (PTC) has dramatically increased over the past two decades. This study aimed to investigate the disparity of gene expression between PTC and normal tissues.
Materials and Methods: Gene chip data of E-GEOD-33630 and E-GEOD-60542 were acquired and downloaded from European Bioinformatics Institute Part of the European Molecular Biology Laboratory website. E-GEOD-33630 data contained 94 test samples (49 PTC and 45 normal tissues), and E-GEOD-60542 data contained 63 test samples (33 PTC and thirty normal tissues). The two sets of data were analyzed by screening differential co-expression network (DCN) and identifying M-differential module.
Results: Three differential modules were gained after statistical comparison between the PTC and normal tissues (P < 0.05). Short coiled-coil protein (SCOC) gene was as the seed gene of module 1, which contained 7 nodes and 9 edges. Moreover, SYPL1 was the seed gene of module 2 with 10 nodes and 16 edges. THAP1 was the seed gene of module 3 that contained 9 nodes and 12 edges.
Conclusion: Analysis and statistical comparison of the gene chip can effectively screen out differential expression genes between the PTC and normal tissues. Based on a large number of samples and gene chip detection, three seed genes of SCOC, SYPL1, and THAP1 are determined. These data provide novel insights into the pathogenesis of PTC. Significant changes in the expression levels between PTC and normal tissues suggest that SCOC, SYPL1, or THAP1 may play a vital role in the incidence and development of PTC, which serve as potential biomarkers for the diagnosis of PTC.

Staubitz JI, Schad A, Springer E, et al.
Novel rearrangements involving the RET gene in papillary thyroid carcinoma.
Cancer Genet. 2019; 230:13-20 [PubMed] Related Publications
BACKGROUND: In the field of gene fusions driving tumorigenesis in papillary thyroid carcinoma (PTC), rearrangement of the proto-oncogene RET is the most frequent alteration. Apart from the most common rearrangement of RET to CCDC6, more than 15 partner genes are yet reported. The landscape of RET rearrangements in PTC ("RET-PTC") can notably be enlarged by modern targeted next-generation sequencing, indicating similarities between oncogenic pathways in other cancer types with identical genetic alterations.
METHODS: Targeted next-generation sequencing was performed for two cases of BRAF-wild type PTC with confirmation of the results by Sanger sequencing. A "UniProt" database research was performed to assess protein alterations resulting from RET rearrangements.
RESULTS: RUFY2-RET and KIAA1468-RET were detected. The fusion genes were not present in normal tissue of the index patients. The rearrangement RUFY2-RET lead to a fusion of the RET tyrosine kinase domain to a RUN domain and a coiled-coil domain. For KIAA1468-RET, a fusion to a LisH domain and two coiled-coil domains resulted.
CONCLUSIONS: RUFY2-RET and KIAA1468-RET are novel RET/PTC rearrangements. The fusions were previously described in non-small cell lung cancer. The rearrangement results in a fusion of the RET tyrosine kinase to regulatory domains of RUFY2 and KIAA1468.

Faundes V, Malone G, Newman WG, Banka S
A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population.
J Hum Genet. 2019; 64(2):161-170 [PubMed] Related Publications
Determining the clinical significance of germline and somatic KMT2D missense variants (MVs) in Kabuki syndrome (KS) and cancers can be challenging. We analysed 1920 distinct KMT2D MVs that included 1535 germline MVs in controls (Control-MVs), 584 somatic MVs in cancers (Cancer-MVs) and 201 MV in individuals with KS (KS-MVs). The proportion of MVs likely to affect splicing was significantly higher for Cancer-MVs and KS-MVs than in Control-MVs (p = 0.000018). Our analysis identified significant clustering of Cancer-MVs and KS-MVs in the PHD#3 and #4, RING#4 and SET domains. Areas of enrichment restricted to just Cancer-MVs (FYR-C and between amino acids 3043-3248) or KS-MVs (coiled-coil#5, FYR-N and between amino acids 4995-5090) were also found. Cancer-MVs and KS-MVs tended to affect more conserved residues (lower BLOSUM scores, p < 0.001 and p = 0.007). KS-MVs are more likely to increase the energy for protein folding (higher ELASPIC ∆∆G scores, p = 0.03). Cancer-MVs are more likely to disrupt protein interactions (higher StructMAn scores, p = 0.019). We reclassify several presumed pathogenic MVs as benign or as variants of uncertain significance. We raise the possibility of as yet unrecognised 'non-KS' phenotype(s) associated with some germline pathogenic KMT2D MVs. Overall, this work provides insights into the disease mechanism of KMT2D variants and can be extended to other genes, mutations in which also cause developmental syndromes and cancer.

Tan P, Ye Y, He L, et al.
TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.
PLoS Biol. 2018; 16(11):e3000051 [PubMed] Free Access to Full Article Related Publications
Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10-mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled-coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer.

Lin W, Yip YL, Jia L, et al.
Establishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma.
Nat Commun. 2018; 9(1):4663 [PubMed] Free Access to Full Article Related Publications
The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole-exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC.

Xu K, Tian H, Zhao S, et al.
Long Noncoding RNA LOC441178 Reduces the Invasion and Migration of Squamous Carcinoma Cells by Targeting ROCK1.
Biomed Res Int. 2018; 2018:4357647 [PubMed] Free Access to Full Article Related Publications
In recent years, long noncoding RNAs (lncRNAs) have been reported to have significant regulating effect in human cancer development. Previous studies suggested that dysregulation of lncRNA 441178 (LOC441178) is possibly associated with oral squamous cell carcinoma (OSCC). The postoperative survival time was significantly prolonged in the high-grade OSCC patients with high LOC441178 expression compared with those with low LOC441178 expression, which indicated that LOC441178 may act as a prognostic marker and as a potential tumor suppressor for OSCC. However, the biological molecular mechanisms behind these phenomena remain almost unknown. Here, our studies revealed that LOC441178 suppressed the invasion and migration of squamous carcinoma cells (SCCs). Furthermore, we found that rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) is one of the functionally relevant targets of LOC441178 in squamous cells, which is negatively correlated with LOC441178 in tumor tissues from OSCC patients. In conclusion, our findings demonstrated the inhibition effect of LOC441178 on tumor in OSCC and might have potential implications for OSCC gene therapy. In conclusion, these results suggest that LOC441178 could represent a prognostic indicator for OSCC and be a new target for the diagnosis and treatment of OSCC.

Zhang W, Liu K, Pei Y, et al.
Mst1 regulates non-small cell lung cancer A549 cell apoptosis by inducing mitochondrial damage via ROCK1/F‑actin pathways.
Int J Oncol. 2018; 53(6):2409-2422 [PubMed] Free Access to Full Article Related Publications
Mammalian STE20-like kinase 1 (Mst1) is well recognized as a major tumor suppressor in cancer development, growth, metabolic reprogramming, metastasis, cell death and recurrence. However, the roles of Mst1 in non-small cell lung cancer (NSCLC) A549 cell phenotypic alterations remain to be elucidated. The present study aimed to explore the functional role and underlying mechanisms of Mst1 with regards to A549 cell proliferation, migration and apoptosis; this study focused on mitochondrial homeostasis and Rho-associated coiled-coil containing protein kinase 1 (ROCK1)/F‑actin pathways. The results demonstrated that Mst1 was downregulated in A549 cells compared with in a normal pulmonary epithelial cell line. Subsequently, overexpression of Mst1 in A549 cells reduced cell viability and promoted cell apoptosis. Furthermore, overexpression of Mst1 suppressed A549 cell proliferation and migration. At the molecular level, the reintroduction of Mst1 in A549 cells led to activation of mitochondrial apoptosis, as evidenced by a reduction in mitochondrial potential, overproduction of ROS, cytochrome c release from the mitochondria into the nucleus, and upregulation of pro-apoptotic protein expression. In addition, Mst1 overexpression was closely associated with impaired mitochondrial respiratory function and suppressed cellular energy metabolism. Functional studies illustrated that Mst1 overexpression activated ROCK1/F-actin pathways, which highly regulate mitochondrial function. Inhibition of ROCK1/F-actin pathways in A549 cells sustained mitochondrial homeostasis, alleviated caspase-9-dependent mitochondrial apoptosis, enhanced cancer cell migration and increased cell proliferation. In conclusion, these data firmly established the regulatory role of Mst1 in NSCLC A549 cell survival via the modulation of ROCK1/F-actin pathways, which may provide opportunities for novel treatment modalities in clinical practice.

Huang L, Li X, Gao W
Long non-coding RNA linc-ITGB1 promotes cell proliferation, migration, and invasion in human hepatoma carcinoma by up-regulating ROCK1.
Biosci Rep. 2018; 38(5) [PubMed] Free Access to Full Article Related Publications

Zhong Y, Yang S, Wang W, et al.
The interaction of Lin28A/Rho associated coiled-coil containing protein kinase2 accelerates the malignancy of ovarian cancer.
Oncogene. 2019; 38(9):1381-1397 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignant diseases, however, the molecular mechanism of ovarian cancer is not well defined. Previous studies have found that RNA binding protein Lin28A is a key factor of maintain the pluripotency of stem cells, and it is positively correlated with the degree of several cancers (breast, prostate, liver cancer, etc). Our previous study shows that Lin28A is highly expressed in OC tissues and is involved in the regulation of OC cell biological behavior. In this study, we confirmed that high expression of Lin28A promoted the survival, invasion, metastasis, and inhibited the apoptosis of OC cells. Lin28A interacts with Rho associated coiled-coil containing protein kinase2 (ROCK2) but not ROCK1 and upregulates the expression of ROCK2 in OC cells. The binding sites of each other were identified by truncated mutations and Immuno-precipitaion (IP) assay. After knock down of ROCK2 in cells with high expression of Lin28A, the survival, invasion, metastasis was significantly inhibited and early apoptosis was increased in OC cells and OC xenograft in nude mice. Our experimental data also showed that knock down of ROCK2 but not ROCK1 inhibited the invasion by decreasing the expression of N-cadherin, Slug, β-catenin and increasing ZO-1 expression. Simultaneously, knock down of ROCK2 induced cell apoptosis by increasing cleaved Caspase-9,cleaved Caspase-7, and cleaved Caspase-3. Taken together, Lin28A regulated the biological behaviors in OC cells through ROCK2 and the interaction of Lin28A/ROCK2 may be a new target for diagnosis and gene therapy of OC.

Feng Y, Gao Y, Yu J, et al.
CCDC85B promotes non-small cell lung cancer cell proliferation and invasion.
Mol Carcinog. 2019; 58(1):126-134 [PubMed] Related Publications
Coiled-coil domain containing 85 B (CCDC85B) is involved in diverse biological processes; however, its expression patterns and functions in human cancers are yet unknown. The present study demonstrated that the expression of CCDC85B in the cytoplasm of the non-small cell lung cancer (NSCLC) tumor cells was significantly higher compared to adjacent normal lung tissues (P < 0.05). Furthermore, CCDC85B expression correlated with advanced TNM stage (P = 0.004) and positive regional lymph node metastasis (P = 0.009) of NSCLC. In addition, in A549 and H1299 lung cancer cell lines, the overexpression of CCDC85B promoted cell proliferation and invasion, while siRNA-mediated CCDC85B knockdown exhibited opposite effects. CCDC85B promoted AKT and GSK3β phosphorylation and upregulated the levels of active β-catenin, Wnt targets c-myc, cyclin D1, and MMP7. Besides, the CCDC85B-induced upregulation of phosphorylated GSK3β and active β-catenin was rescued following the treatment with PI3 K inhibitor, LY294002. In conclusion, CCDC85B was associated with NSCLC progression as it promoted the proliferation and invasion of lung cancer cells through activated AKT/GSK3β/β-catenin oncogenic signaling pathway. Therefore, CCDC85B might serve as a novel target for NSCLC treatment.

Wang Z, Wang Z, Liu J, Yang H
Long non-coding RNA SNHG5 sponges miR-26a to promote the tumorigenesis of osteosarcoma by targeting ROCK1.
Biomed Pharmacother. 2018; 107:598-605 [PubMed] Related Publications
BACKGROUND: Osteosarcoma (OS) is one of the most common invasive malignancies of the bone. The long non-coding RNA (lncRNA) SNHG5 (small nucleolar RNA host gene 5) has been consistently shown to be involved in many cancers, although its precise function in osteosarcoma remains poorly understood. In this study, we investigated the role of SNHG5 in OS progression and the underlying mechanism.
METHODS: SNHG5 expression in 32 OS tissues and 4 OS cell lines was measured by quantitative real-time PCR (qRT-PCR). Migration, invasion, proliferation and cell cycle profiles were analyzed by established assays to determine the biological functions of SNHG5 and miR-26a in OS cells. The binding sites of miR-26a in SNHG5 and ROCK1 were predicted by the RNAhybrid 2.2 program. Luciferase reporter assay was then used to validate the direct targeting of SNHG5 with miR-26a and of Rho-associated coiled coil-containing protein kinase 1 (ROCK1) with miR-26a. The effect of SNHG5 on the ROCK signaling pathway was assessed by western blotting.
RESULTS: Elevated expression of SNHG5 was correlated with poor clinical outcome and prognosis in OS patients. SNHG5 functioned as a sponge for miR-26a and promoted proliferation, invasion and migration, and accelerated G1 to S phase transition in OS cells. SNHG5 functioned as a competing endogenous RNA (ceRNA) for miR-26a and activated the ROCK signaling pathway through the miR-26a-ROCK1 axis.
CONCLUSION: SNHG5 acts as an oncogene in OS via the SNHG5-miR-26a-ROCK1 axis and is therefore a potential novel therapeutic target for OS treatment.

Sheng L, Hao SL, Yang WX, Sun Y
The multiple functions of kinesin-4 family motor protein KIF4 and its clinical potential.
Gene. 2018; 678:90-99 [PubMed] Related Publications
Human KIF4 is a member of Kinesin-4 kinesin family. The highly conserved structure contains an N-terminal motor region, coiled-coil region and C-terminal loading region. KIF4 plays important roles in DNA repair and DNA replication, which maintains genetic stability. KIF4 is also essential for regulation of mitosis and meiosis. KIF4 cooperates with condensin I and TopoIIα to help with chromosomal condensation, and binds to a plethora of cell-cycle proteins to regulate spindle organization and cytokinesis. Additionally, KIF4 plays roles in germ plasm aggregation and radial order in germ cells. In neuronal cells, KIF4 promotes proper axon growth by transporting substrates P0 and L1 to their proper location. Interestingly, KIF4 is abnormally expressed in a variety of cancers, where KIF4 is often up-regulated but can also be down-regulated in some cancers. This suggests distinctive regulatory mechanisms for different cancers. Recent studies support important roles for KIF4 in cancers such as the promotion of drug resistance or inhibition of apoptosis. Previous studies showed that by inhibiting or enhancing the expression of KIF4, the proliferation of cancer cells can be significantly reduced. Therefore KIF4 has potential as a therapeutic target for cancer therapy. Moreover, the misregulation of KIF4 is related to viral infection and neural system diseases like Alzheimer. We believe better understanding of this protein will help us develop better therapies for the diseases mentioned above. Here, we summarize KIF4 functions in normal cells and in various cancers, and provide an overview on the association between KIF4 disorders and disease progression.

Best SA, Harapas CR, Kersbergen A, et al.
FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium.
Oncogene. 2018; 37(46):6096-6104 [PubMed] Free Access to Full Article Related Publications
Structural rearrangements of the genome can drive lung tumorigenesis through the generation of fusion genes with oncogenic properties. Advanced genomic approaches have identified the presence of a genetic fusion between fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3 (TACC3) in non-small cell lung cancer (NSCLC), providing a novel target for FGFR inhibition. To interrogate the functional consequences of the FGFR3-TACC3 fusion in the transformation of lung epithelial cells, we generated a novel transgenic mouse model that expresses FGFR3-TACC3 concomitant with loss of the p53 tumor suppressor gene. Intranasal delivery of an Ad5-CMV-Cre virus promoted seromucinous glandular transformation of olfactory cells lining the nasal cavities of FGFR3-TACC3 (LSL-F3T3) mice, which was further accelerated upon loss of p53 (LSL-F3T3/p53). Surprisingly, lung tumors failed to develop in intranasally infected LSL-F3T3 and LSL-F3T3/p53 mice. In line with these observations, we demonstrated that intranasal delivery of Ad5-CMV-Cre induces widespread Cre-mediated recombination in the olfactory epithelium. Intra-tracheal delivery of Ad5-CMV-Cre into the lungs of LSL-F3T3 and LSL-F3T3/p53 mice, however, resulted in the development of lung adenocarcinomas. Taken together, these findings provide in vivo evidence for an oncogenic function of FGFR3-TACC3 in respiratory epithelium.

Wang Y, Ding X, Hu H, et al.
Long non-coding RNA lnc-PCTST predicts prognosis through inhibiting progression of pancreatic cancer by downregulation of TACC-3.
Int J Cancer. 2018; 143(12):3143-3154 [PubMed] Related Publications
Pancreatic cancer (PC), which is one of the most lethal of malignancies and a major health burden, is associated with a dismal prognosis despite current therapeutic advances. Numerous long noncoding RNAs (lncRNA) have shown to be essential for PC tumorigenesis and progression. Nevertheless, the exact expression pattern of lnc-PCTST and its clinical significance still remain unclear. This study investigates the expression pattern of lnc-PCTST and its associated mRNA in three paired PC tissues and adjacent non-tumor tissues by Microarray-coarray approach. Briefly, our data demonstrated that lnc-PCTST expression is down-regulated in PC tissues. Also, lnc-PCTST has shown to be negatively correlated with transforming acidic coiled-coil 3 (TACC-3) expression. This expression pattern was further confirmed following qRT-PCR validation of 34 out of 48 paired cancer tissues. Furthermore, lnc-PCTST overexpression in PC cell lines inhibited cell proliferation and invasion in vitro, and tumorigenesis in vivo (using nude mice as animal model), but did not altered cell migration. Moreover, lnc-PCTST overexpression increased E-cadherin and repressed vimentin expression in vitro. Additionally, TACC-3 knockdown simulated the inhibiting effect of lnc-PCTST overexpression on PC cell lines, and the impaired proliferation, invasion effect and E-cadherin, vimentin expression on lnc-PCTST over-expressed cell lines can be rescued by overexpressed TACC-3. Significantly, the expression of lnc-PCTST was closely associated with its genomic neighboring gene TACC-3 and inhibited its promoter activity. In conclusion, lnc-PCTST is a potential tumor suppressor in PC, which inhibits cell proliferation, invasion, tumorigenesis and EMT by modulating TACC-3.

Shakya M, Zhou A, Dai D, et al.
High expression of TACC2 in hepatocellular carcinoma is associated with poor prognosis.
Cancer Biomark. 2018; 22(4):611-619 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Transforming acidic coiled-coil protein 2 (TACC2) is a member of TACC family proteins which is mainly involved in the stabilization of spindles and regulation of microtubule dynamics through interactions with molecules involved in centrosomes/microtubules. TACC2 is involved in tumorigenesis of variety of cancers but the clinical significance of TACC2 protein in hepatocellular carcinoma (HCC) is still unclear.
OBJECTIVE: This study aims to investigate the expression of TACC2 in HCC and determine if clinical significance and prognostic relevance exists.
METHODS: We performed quantitative PCR (qPCR) and western blot to examine TACC2 mRNA and protein expression in paired HCC tissues and matched adjacent non-cancerous tissues. Immunohistochemistry was performed in 106 postoperative HCC samples.
RESULTS: There was higher expression of TACC2 protein and mRNA in HCC tissue. Immunohistochemistry analysis showed high expression of TACC2 in HCC tissue and was significantly associated with the capsular extension, tumor recurrence and shortened overall and disease free survival. The Cox regression analysis suggested that a high expression of TACC2 was an independent prognostic factor for HCC patients.
CONCLUSION: This finding suggests that TACC2 may be a useful tool as a candidate biomarker to predict the recurrence and prognosis of HCC.

Zhu QD, Zhou QQ, Dong L, et al.
MiR-199a-5p Inhibits the Growth and Metastasis of Colorectal Cancer Cells by Targeting ROCK1.
Technol Cancer Res Treat. 2018; 17:1533034618775509 [PubMed] Free Access to Full Article Related Publications
Mounting evidence indicates that microRNAs play important roles in the development of various cancers. Aberrant expression of microRNA-199a-5p has been frequently reported in cancer studies; however, the mechanistic details of the role of microRNA-199a-5p in colorectal cancer still remain unclear. Our study aimed to explore the role of microRNA-199a-5p in colorectal cancer cells by targeting Rho-associated coiled coil-containing protein kinase 1. Here, we showed that microRNA-199a-5p was significantly downregulated in colorectal cancer cell lines and tissue samples and was associated with a poor prognostic phenotype. MicroRNA-199a-5p suppressed colorectal cancer cell proliferation, migration, and invasion and induced cell apoptosis. Moreover, we identified Rho-associated coiled coil-containing protein kinase 1 as the direct target of microRNA-199a-5p using luciferase and Western blot assays. Importantly, Rho-associated coiled coil-containing protein kinase 1 overexpression rescued the microRNA-199a-5p-induced suppression of proliferation, migration, and invasion of colorectal cancer cells. Furthermore, the overexpression of microRNA-199a-5p inhibited tumor growth and metastasis by inactivating the phosphoinositide 3-kinase/AKT and Janus kinase 1/signal transducing activator of transcription signaling pathways through downregulation of Rho-associated coiled coil-containing protein kinase 1. Altogether, microRNA-199a-5p/Rho-associated coiled coil-containing protein kinase 1 may be a potential therapeutic target for colorectal cancer therapy.

Liu Y, Wang Y, Fu X, Lu Z
Long non-coding RNA NEAT1 promoted ovarian cancer cells' metastasis through regulation of miR-382-3p/ROCK1 axial.
Cancer Sci. 2018; 109(7):2188-2198 [PubMed] Free Access to Full Article Related Publications
Long non-coding RNA (lncRNA) are extensively involved in various malignant tumors, including ovarian cancer (OC). In the present study, we focused on the expression and function of nuclear enriched abundant transcript 1 (NEAT1) in OC cells' metastasis. We demonstrated that NEAT1 was upregulated in OC tissue specimens and cell lines. In addition, we revealed that depression of NEAT1 inhibited OC cells' metastasis and the expression of Rho associated coiled-coil containing protein kinase 1 (ROCK1), which is a metastasis-related gene. Using online predictive software and a series of luciferase assays, we demonstrated that both NEAT1 and ROCK1 were the targets of microRNA-382-3p (miR-382-3p) and share similar microRNA responding elements (MRE). Furthermore, we illustrated that NEAT1 and miR-382-3p inhibited each other in a reciprocal manner. Finally, through antisense experiments we demonstrated that NEAT1 promoted ROCK1-mediated metastasis by functioning as a ceRNA of miR-382-3p. In summary, the findings of this study revealed that NEAT1 promoted OC cells' metastasis through regulating the miR-382-3p/ROCK1 axial. The present study might provide a new target for treating OC.

Wang Y, Zeng X, Wang N, et al.
Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma.
Mol Cancer. 2018; 17(1):89 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidences indicate that non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as crucial regulators in osteosarcoma (OS). Previously, we reported that Rho associated coiled-coil containing protein kinase 1 (ROCK1), a metastatic-related gene was negatively regulated by microRNA-335-5p (miR-335-5p) and work as an oncogene in osteosarcoma. Whether any long non-coding RNAs participate in the upstream of miR-335-5p/ROCK1 axial remains unclear.
METHODS: Expression of differentiation antagonizing non-protein coding RNA (DANCR) and miR-335-5p/miR-1972 in osteosarcoma tissues were determined by a qRT-PCR assay and an ISH assay. Osteosarcoma cells' proliferation and migration/invasion ability changes were measured by a CCK-8/EDU assay and a transwell assay respectively. ROCK1 expression changes were checked by a qRT-PCR assay and a western blot assay. Targeted binding effects between miR-335-5p/miR-1972 and ROCK1 or DANCR were verified by a dual luciferase reporter assay and a RIP assay. In vivo experiments including a nude formation assay as well as a CT scan were applied to detect tumor growth and metastasis changes in animal level.
RESULTS: In the present study, an elevated DNACR was found in osteosarcoma tissue specimens and in osteosarcoma cell lines, and the elevated DNACR was closely correlated with poor prognosis in clinical patients. Functional experiments illustrated that a depression of DANCR suppressed ROCK1-mediated proliferation and metastasis in osteosarcoma cells. The results of western blot assays and qRT-PCR assays revealed that DANCR regulated ROCK1 via crosstalk with miR-335-5p and miR-1972. Further cellular behavioral experiments demonstrated that DNACR promoted ROCK1-meidated proliferation and metastasis through decoying both miR-335-5p and miR-1972. Finally, the outcomes of in vivo animal models showed that DANCR promoted tumor growth and lung metastasis of osteosarcoma.
CONCLUSIONS: LncRNA DANCR work as an oncogene and promoted ROCK1-mediated proliferation and metastasis through acting as a competing endogenous RNA (ceRNA) in osteosarcoma.

Li R, Dong B, Wang Z, et al.
MicroRNA-361-5p inhibits papillary thyroid carcinoma progression by targeting ROCK1.
Biomed Pharmacother. 2018; 102:988-995 [PubMed] Related Publications
MicroRNAs function as key regulators in various human cancers, including papillary thyroid cancer (PTC). MiR-361-5p has been proved to be a tumor suppressor in multiple cancers. However, the function of miR-361-5p in PTC remains unknown. In this study, we aimed to determine the function of miR-361-5p in PTC progression, and elaborate the mechanism by which miR-361-5p acts in PTC. Here, we report that miR-361-5p expression levels were significantly downregulated in PTC tissues and cell lines, as detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) analysis. Functional analysis revealed that overexpression of miR-361-5p significantly inhibited cell proliferation, migration, invasion in vitro, as well as suppressed tumor growth in vivo. Bioinformatic analysis showed that Rho-associated coiled-coil kinase 1 (ROCK1) was a predicted target of miR-361-5p, which was further validated by the dual-luciferase reporter assay, qRT-PCR, and western blot analysis. In addition, an inverse expression pattern was also observed between miR-361-5p and ROCK1 in a cohort of PTC tissues. Rescue experiments showed that restoration of ROCK1 expression significantly reversed the suppressive effect of miR-361-5p on cell proliferation, migration, and invasion in PTC cells. Taken together, these findings suggest that miR-361-5p is a novel potential therapeutic target for thyroid cancer.

Ji DG, Guan LY, Luo X, et al.
Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKα/NF-κB pathway.
Biochem Biophys Res Commun. 2018; 501(1):33-40 [PubMed] Related Publications
Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in tumor cell growth process. However, its role and molecular mechanism in liver cancer is still not fully understood. In this study, we found that MALAT1 was significantly expressed in liver cancer cell lines. And knockdown of MALAT1 suppressed proliferation, migration and invasion of HepG2 cells, accompanied with decrease of Rho-associated coiled-coil-forming protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), N-cadherin, Vimentin and TWIST. Significantly, MALAT1 deletion sensitized HepG2 cells to 5-FU-induced cell cycle arrest in G1 phase, as evidenced by the significant reduction in Cyclin D1 and CDK4 and increase in p53, p21 and p27 protein levels. In addition, MALAT1 knockdown triggered 5-FU induced apoptosis in HepG2 cells by inducing intrinsic apoptosis-related signals, including Cyto-c, Apaf-1, cleaved Caspase-9/-7/-3 and poly (ADP-ribose) polymerase (PARP). Furthermore, phosphorylated nuclear factor-κB (p-NF-κB) was also down-regulated by MALAT1 silence. Importantly, suppression of IKKα/NF-κB significantly elevated apoptosis and reduced liver cancer cell viability in MALAT1-knockdown cells with 5-FU incubation. The nude mice transplantation model also confirmed the promoted sensitivity of MALAT1-silenced HepG2 cells to 5-FU by blocking tumor cell proliferation and inducing apoptosis. Therefore, our data supplied a potential mechanism by which knockdown of MALAT1 might play an important role in augmenting sensitivity of HepG2 cells to 5-FU in therapeutic approaches, demonstrating suppressing of MALAT1 may serve as a combination with chemotherapeutic agents in liver cancer treatment.

Tang Y, He Y, Zhang P, et al.
LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis.
Mol Cancer. 2018; 17(1):77 [PubMed] Free Access to Full Article Related Publications
Some of the key steps in cancer metastasis are the migration and invasion of tumor cells; these processes require rearrangement of the cytoskeleton. Actin filaments, microtubules, and intermediate filaments involved in the formation of cytoskeletal structures, such as stress fibers and pseudopodia, promote the invasion and metastasis of tumor cells. Therefore, it is important to explore the mechanisms underlying cytoskeletal regulation. The ras homolog family (Rho) and Rho-associated coiled-coil containing protein serine/threonine kinase (ROCK) signaling pathway is involved in the regulation of the cytoskeleton. Moreover, long noncoding RNAs (lncRNAs) have essential roles in tumor migration and guide gene regulation during cancer progression. LncRNAs can regulate the cytoskeleton directly or may influence the cytoskeleton via Rho/ROCK signaling during tumor migration. In this review, we focus on the regulatory association between lncRNAs and the cytoskeleton and discuss the pathways and mechanisms involved in the regulation of cancer metastasis.

Zhang H, Zhou B, Qin S, et al.
Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.
Genes Dev. 2018; 32(5-6):341-346 [PubMed] Free Access to Full Article Related Publications
The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (

Campo L, Breuer EK
Inhibition of TACC3 by a small molecule inhibitor in breast cancer.
Biochem Biophys Res Commun. 2018; 498(4):1085-1092 [PubMed] Related Publications
Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied. In this study, we show that a small molecule TACC3 inhibitor, KHS101, suppresses cell growth, motility, epithelial-mesenchymal transition (EMT), and breast cancer cell stemness while it induces apoptotic cell death. Quantitative multiplexed proteomic analysis using tandem mass tags (TMTs) revealed that KHS101 alters multiple biological processes and signaling pathways, and significantly reduces the expression of mitotic kinases Aurora A and Polo-like kinase 1 (PLK1), which are closely associated with TACC3. Our findings therefore provide a new insight into the potential mechanisms of the action of KHS101 and suggest its possible use as a dual or multi-targeting mitotic inhibitor in breast cancer.

Wang H, Zhang M, Sun G
Long non-coding RNA NEAT1 regulates the proliferation, migration and invasion of gastric cancer cells via targeting miR-335-5p/ROCK1 axis.
Pharmazie. 2018; 73(3):150-155 [PubMed] Related Publications
This study aimed to elucidate the roles of long non-coding RNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) in gastric cancer. The expression of NEAT1 in gastric cancer tissues and cells was determined. NEAT1 was then overexpressed and suppressed in BGC-823 cells in vitro to further explore the effects of NEAT1 on cell proliferation, migration, and invasion. In addition, the regulatory relationship among NEAT1, miR-335-5p and Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) was investigated. LncRNA NEAT1 was upregulated in gastric cancer tissues and cells. Upregulated NEAT1 significantly promoted the proliferation, migration and invasion of BGC-823 cells, while suppression of NEAT1 exhibited contrary results. In addition, lncRNA NEAT1 inhibited the expression of miR-335-5p, and miR-335-5p targeted ROCK1 in BGC-823 cells. miR-335-5p overexpression significantly inhibited cell proliferation, migration and invasion, which was counteracted by ROCK1 overexpression concurrently. Our findings indicate that upregulation of NEAT1 may promote proliferation, migration and invasion of gastric cancer cells via targeting miR-335-5p/ROCK1 axis. NEAT1-miR-335-5p-ROCK1 axis may be a potential therapeutic strategy for gastric cancer therapy.

Cornillie SP, Bruno BJ, Lim CS, Cheatham TE
Computational Modeling of Stapled Peptides toward a Treatment Strategy for CML and Broader Implications in the Design of Lengthy Peptide Therapeutics.
J Phys Chem B. 2018; 122(14):3864-3875 [PubMed] Related Publications
The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia, and although several therapies exist to curb the aberrant kinase activity of Bcr-Abl through targeting of the Abl kinase domain, these therapies are rendered ineffective by frequent mutations in the corresponding gene. It has been demonstrated that a designed protein, known as CCmut3, is able to produce a dominant negative inactivating effect on Bcr-Abl kinase by preferentially oligomerizing with the N-terminal coiled-coil oligomerization domain of Bcr-Abl (Bcr-CC) to effectively reduce the oncogenic potential of Bcr-Abl. However, the sheer length of the CCmut3 peptide introduces a high degree of conformational variability and opportunity for targeting by intracellular proteolytic mechanisms. Here, we have examined the effects of introducing one or two molecular staples, or cross-links, spanning i, i + 7 backbone residues of the CCmut3 construct, which have been suggested to reinforce α-helical conformation, enhance cellular internalization, and increase resistance to proteolytic degradation, leading to enhanced pharmacokinetic properties. The importance of optimizing staple location along a highly tuned biological construct such as CCmut3 has been widely emphasized and, as such, we have employed in silico techniques to swiftly build, relax, and characterize a large number of candidates. This approach effectively allowed exploring each and every possible staple location along the peptide backbone so that every possible candidate is considered. Although many of the stapled candidate peptides displayed enhanced binding characteristics for Bcr-CC and improved conformational stability in the (Bcr-CC) bound form, simulations of the stapled peptides in the unbound form revealed widespread conformational variability among stapled candidates dependent on staple type and location, implicating the molecular replacement of helix-stabilizing residues with staple-containing residues in disrupting the native α-helical conformation of CCmut3, further highlighting a need for careful optimization of the CCmut3 construct. A candidate set has been assembled, which retains the native backbone α-helical integrity in both the bound and unbound forms while providing enhanced binding affinity for the Bcr-CC target, as research disseminated in this manuscript is intended to guide the development of a next-generation CCmut3 inhibitor peptide in an experimental setting.

Chen HQ, Zhao J, Li Y, et al.
Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells.
Toxicol Lett. 2018; 289:42-53 [PubMed] Related Publications
Microcystin (MC) is a cyclic heptapeptide compound which could lead to the development of hepatocellular carcinoma. However, the underlying epigenetic regulation mechanism is largely unknown. In this study, microcystin-LR (L: lysine, R: arginine, MC-LR) was used to induce the malignant transformation of human hepatocyte L02 cell line. The profile of gene expression, microRNA (miRNA) and DNA methylation were detected through high-throughput sequencing. Compared with control group, the expression of 826 genes and 187 miRNAs changed significantly in MC-LR treated group. DNA methylation sequencing analysis showed that 2592 CpG sites differentially methylated in promoter or the coding DNA sequence (CDS) of genes, while DNA methyltransferase 3 alpha (DNMT3a) and DNA methyltransferase 3 beta (DNMT3b) were dramatically up-regulated. Functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that significantly changed mRNAs and microRNAs were mainly involved in the formation of cancer, proliferation, invasion, migration and metabolism. MiRNA-mRNA network and mRNA-mRNA network analysis showed that hsa-miR-320a, hsa-miR-331-3p, hsa-miR-26a-5p, hsa-miR-196a-5p, hsa-miR-221-3p, coiled-coil domain containing 180 (CCDC180), melanoma antigen gene family member D1 (MAGED1), membrane spanning 4-domains A7 (MS4A7), hephaestin like 1 (HEPHL1), BH3 (Bcl-2 homology 3)-like motif containing, cell death inducer (BLID), matrix metallopeptidase 13 (MMP13), guanylate binding protein 5 (GBP5), adipogenesis regulatory factor (ADIRF), formin homology 2 domain containing 1 (FHDC1), protein kinase CAMP-dependent type II regulatory subunit beta (PRKAR2B), nodium leak channel, non-selective (NALCN), myosin light chain kinase 3 (MYLK3), epidermal growth factor receptor (EGFR) and zinc finger protein 704 (ZNF704) were key miRNAs and genes in the malignant transformation induced by MC-LR in L02 cells. Moreover, we found that expression of MYLK3, EGFR and ZNF704 were regulated by DNA methylation and miRNAs, and these genes affected the cell cycle and cell division. Our study suggested that characteristic gene alterations regulated by DNA methylation and miRNA could play an important role in environmental MC-LR induced hepatic carcinogenesis.

Wei Y, Zhou F, Zhou H, et al.
Endothelial progenitor cells contribute to neovascularization of non-small cell lung cancer via histone deacetylase 7-mediated cytoskeleton regulation and angiogenic genes transcription.
Int J Cancer. 2018; 143(3):657-667 [PubMed] Related Publications
To supply tumor tissues with nutrients and oxygen, endothelial progenitor cells (EPCs) home to tumor sites and contribute to neovascularization. Although the precise mechanism of EPCs-induced neovascularization remains poorly understood in non-small cell lung cancer (NSCLC), histone deacetylase 7 (HDAC7) is considered as a critical regulator. To explore the function of HDAC7 in neovascularization induced by EPCs, tube formation assay, immunofluorescence, microarray, Western blot analysis and animal models were performed. In vitro, HDAC7 abrogation led to the activation of Rho-associated coiled-coil containing protein kinase/myosin light chain 2 pathway concomitant with ERK dephosphorylation, causing the instability of cytoskeleton and collapse of tube formation. In vivo, absence of HDAC7 impaired the vascular lumen integrity and decreased the functional blood perfusion, inhibiting the growth of tumor. At the level of transcription, HDAC7 silencing upregulated antiangiogenic genes and suppressed proangiogenic genes collectively, turning off the angiogenic switch during vessel formation. Taken together, HDAC7 plays a dual role in maintaining the structural and nonstructural functions of EPCs. Our work demonstrates the molecular mechanism by which HDAC7 contributes to the angiogenic property of EPCs and provides a rational basis for specific targeting of antiangiogenic strategies in lung cancer.

Lin ZR, Wang MY, He SY, et al.
TACC3 transcriptionally upregulates E2F1 to promote cell growth and confer sensitivity to cisplatin in bladder cancer.
Cell Death Dis. 2018; 9(2):72 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence has shown that transforming acidic coiled-coil 3 (TACC3) is deregulated in a broad spectrum of cancers. In the present study, we reported that TACC3 was markedly elevated in bladder cancer, especially in muscle-invasive bladder cancers (MIBCs). The upregulation of TACC3 was positively associated with tumor invasiveness, grade, T stage, and progression in patients with bladder cancer. Furthermore, a Kaplan-Meier survival analysis showed that patients with bladder cancer whose tumors had high TACC3 expression experienced a dismal prognosis compared with patients whose tumors had low TACC3 expression. Functional studies have found that TACC3 is a prerequisite for the development of malignant characteristics of bladder cancer cells, including cell proliferation and invasion. Moreover, TACC3 promoted G1/S transition, which was mediated via activation of the transcription of E2F1, eventually enhancing cell proliferation. Notably, the overexpression of TACC3 or E2F1 indicates a high sensitivity to cisplatin. Taken together, these findings define a tumor-supportive role for TACC3, which may also serve as a prognostic and therapeutic indicator in bladder cancers.

Kim JL, Ha GH, Campo L, Breuer EK
Negative regulation of BRCA1 by transforming acidic coiled-coil protein 3 (TACC3).
Biochem Biophys Res Commun. 2018; 496(2):633-640 [PubMed] Related Publications
In spite of the push to identify modifiers of BRCAness, it still remains unclear how tumor suppressor BRCA1 is lost in breast cancers in the absence of genetic or epigenetic aberrations. Mounting evidence indicates that the transforming acidic coiled-coil 3 (TACC3) plays an important role in the centrosome-microtubule network during mitosis and gene expression, and that deregulation of TACC3 is associated with breast cancer. However, the molecular mechanisms by which TACC3 contributes to breast cancer development have yet to be elucidated. Herein, we found that high levels of TACC3 in human mammary epithelial cells can cause genomic instability possibly in part through destabilizing BRCA1. We also found that high levels of TACC3 inhibited the interaction between BRCA1 and BARD1, thus subsequently allowing the BARD1-uncoupled BRCA1 to be destabilized by ubiquitin-mediated proteosomal pathway. Moreover, there is an inverse correlation between TACC3 and BRCA1 expression in breast cancer tissues. Overall, our findings provide a new insight into the role of TACC3 in genomic instability and breast tumorigenesis.

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