Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CCN1 (cancer-related)
Jia H, Xu M, Bo Y, et al.Ras-ERK1/2 signaling accelerates the progression of colorectal cancer via mediation of H2BK5ac.
Life Sci. 2019; 230:89-96 [PubMed
] Related Publications
AIMS: Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) is a key downstream gene of Ras pathway. Activation of Ras-ERK1/2 has been testified to be linked to the progression of diverse cancers. Nonetheless, whether Ras-ERK1/2-tumorigenic pathway is mediated by epigenetic factors remains indistinct. The purpose of the research attempted to disclose the functions of H2BK5ac in Ras-ERK1/2-evoked CRC cell phenotypes.
MATERIALS AND METHODS: Western blot assay was implemented for exploration of the relevancy between Ras-ERK1/2 and H2BK5ac. H2BK5Q was established and its functions in cell viability, colony formation and migration were appraised via utilizing MTT, soft-agar colony formation and Transwell assays. The mRNA and transcription of ERK1/2 downstream genes were estimated via RT-qPCR and ChIP assays. HDAC2 functions in SW48 cell phenotypes were evaluated after co-transfection with pEGFP-Ras
KEY FINDINGS: H2BK5ac expression was evidently repressed by Ras-ERK1/2 pathway in SW48 cells. Moreover, Ras-ERK1/2-elevated cell viability, the number of colonies and migration were both impeded by H2BK5ac. The mRNA and transcriptions of CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16 were both mediated by H2BK5ac. Additionally, HDAC2 silence overtly recovered H2BK5ac expression inhibited by Ras-ERK1/2, meanwhile abated Ras-ERK1/2-affected SW48 cell phenotypes. Beyond that, restrained H2BK5ac induced by Ras-ERK1/2 was concerned with MDM2-mediated ATF2 degradation.
SIGNIFICANCE: These investigations testified that Ras-ERK1/2 pathway affected SW48 cell phenotypes through repressing H2BK5ac expression. Otherwise, declined H2BK5ac might be linked to MDM2-mediated ATF2 degradation.
BACKGROUND: Primary cutaneous malignant melanoma is a cancer of the pigment cells of the skin, some of which are accompanied by BRAF mutation. Melanoma incidence and mortality rates have been rising around the world. As the current knowledge about pathogenesis, clinical and genetic features of cutaneous melanoma is not very clear, we aim to use bioinformatics to identify the potential key genes involved in the expression and mutation status of BRAF.
METHODS: Firstly, we used UCSC public hub datasets of melanoma (Lin et al., Cancer Res 68(3):664, 2008) to perform weighted genes co-expression network analysis (WGCNA) and differentially expressed genes analysis (DEGs), respectively. Secondly, overlapping genes between significant gene modules and DEGs were screened and validated at transcriptional levels and overall survival in TCGA and GTEx datasets. Lastly, the functional enrichment analysis was accomplished to find biological functions on the web-server database.
RESULTS: We performed weighted correlation network and differential expression analyses, using gene expression data in melanoma samples. We identified 20 genes whose expression was correlated with the mutation status of BRAF. For further validation, three of these genes (CYR61, DUSP1, and RNASE4) were found to have similar expression patterns in skin tumors from TCGA compared with normal skin samples from GTEx. We also found that weak expression of these three genes was associated with worse overall survival in the TCGA data. These three genes were involved in the nucleic acid metabolic process.
CONCLUSION: In this study, CYR61, DUSP1, and RNASE4 were identified as potential genes of interest for future molecular studies in melanoma, which would improve our understanding of its causes and underlying molecular events. These candidate genes may provide a promising avenue of future research for therapeutic targets in melanoma.
Gao H, Yin FF, Guan DX, et al.Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of β-catenin/TCF/LEF signalling.
Cell Prolif. 2019; 52(3):e12583 [PubMed
] Related Publications
OBJECTIVES: Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive.
MATERIALS AND METHODS: The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting.
RESULTS: The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of β-catenin to the nucleus by activating glycogen synthase kinase-3β (GSK3β). Moreover, constitutively active β-catenin blocked the suppressive effects of WISP3 on HCC.
CONCLUSIONS: Our study showed that WISP3 suppressed the progression of HCC by negative regulation of β-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.
BACKGROUND: Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells.
METHODS: Modified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC.
RESULTS: CYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rβ levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rβ/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities.
CONCLUSIONS: Taken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway.
Cao Y, Wu C, Song Y, et al.Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation.
Int J Mol Med. 2019; 43(2):1011-1020 [PubMed
] Related Publications
Elevated Cyr61 levels have been reported in various malignancies. Elevation of Cyr61 protein levels contributes to the proliferation, metastasis, and chemotherapy resistance of malignant cells. Previously, it was discovered that Cyr61 is elevated in both the plasma and the bone marrow supernatants of patients with acute lymphoblastic leukemia (ALL), promoting ALL cell survival. However, the role of Cyr61 in the chemotherapeutic resistance of ALL cells remains unknown. The aim of the current study was to investigate the role of Cyr61 in regulating ALL cell chemosensitivity to Ara‑C. It was found that Cyr61 is overexpressed in bone marrow mononuclear cells from patients with ALL. Increased Cyr61 effectively decreased Ara‑C‑induced apoptosis of ALL cells, and its function was blocked by the use of the anti‑Cyr61 monoclonal antibody 093G9. Furthermore, Cyr61 increased the level of Bcl‑2 in Ara‑C‑treated ALL cells. Mechanistically, it was shown that Cyr61 affected ALL cell resistance to Ara‑C partially via the NF‑κB pathway. Taken together, the present study is the first, to the best of our knowledge, to reveal that Cyr61 is involved in ALL cell resistance through the NF‑κB pathway. The findings support a functional role for Cyr61 in promoting chemotherapy resistance, suggesting that targeting Cyr61 directly or its relevant effector pathways may improve the clinical responses of patients with ALL.
Huang Y, Zhang J, Shao H, et al.miR-33a Mediates the Anti-Tumor Effect of Lovastatin in Osteosarcoma by Targeting CYR61.
Cell Physiol Biochem. 2018; 51(2):938-948 [PubMed
] Related Publications
BACKGROUND/AIMS: Preventing cell metastasis is an effective therapeutic strategy to treat osteosarcoma and improve prognosis. Statins have been found to have anticancer effects in addition to their cholesterol-lowering action. As a new target of statins, cysteine-rich 61 (CYR61) was recently identified to promote cell migration and metastasis in osteosarcoma. However, the underlying mechanisms mediating the regulation of CYR61 expression by statins remain unknown.
METHODS: Human osteosarcoma cell lines MG63 and SaOS2 were used to clarify the effect of lovastatin on CYR61 expression. Real-time PCR was performed to detect mRNA or microRNA (miRNA) levels and western blot was performed to detect protein levels. Cell invasive ability was determined using Transwell assays. Lentivirus encoding CYR61 cDNA or sterol regulatory element-binding protein 2 (SREBP-2) shRNA was used to upregulate CYR61 expression or downregulate SREBP-2 expression. Binding of the CYR61 3' untranslated region (UTR) and miR-33a was analyzed by luciferase reporter assay.
RESULTS: We found that lovastatin treatment decreased CYR61 expression, inhibited cell invasion and altered epithelial-to-mesenchymal-transition (EMT)-related protein expression, while CYR61 overexpression abolished the effect of lovastatin. Moreover, lovastatin increased the expression of SREBP-2 and miR-33a, which were then downregulated by SREBP-2 silencing. Bioinformatics analysis indicated that the CYR61 3'UTR harbored a potential miR-33a binding site and luciferase reporter assay demonstrated that CYR61 was a target of miR-33a in osteosarcoma cells. Furthermore, miR-33a could inhibit cell invasion and alter EMT-related protein expression. SREBP-2 silencing or miR-33a inhibitor upregulated CYR61 expression and reversed the effects of lovastatin on cell invasion and EMT-related proteins.
CONCLUSION: Our findings suggest lovastatin suppresses osteosarcoma cell invasion through the SREBP-2/miR-33a/CYR61 pathway.
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a high incidence and high mortality in East Asia. Identifying biomarkers and clarifying the regulatory mechanisms of HCC are of great importance. Herein, we report the role and mechanism of activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors in HCC.
METHODS: ATF3 overexpression vector and shRNAs were transfected into HCC cancer cells to upregulate or downregulate ATF3 expression. In vitro and in vivo assays were performed to investigate the functional role of ATF3 in hepatocellular carcinoma. RNA-Seq was performed to screen the differentially expressed genes downstream of ATF3. The dual-luciferase reporter assay, chromatin immunoprecipitation (Ch-IP) analysis and functional rescue experiments were used to confirm the target gene regulated by ATF3. Tissue microarrays (TMAs) comprising 236 human primary HCC tissues were obtained and immunohistochemical staining were carried out to analyze the clinical significance of ATF3.
RESULTS: The results indicate that ATF3 significantly inhibited the proliferation and mobility of HCC cells both in vitro and in vivo. Cysteine-rich angiogenic inducer 61 (CYR61) is a key target for transcriptional regulation by ATF3. Both ATF3 and CYR61 were consistently downregulated in human HCC tissues, and their expression levels were significantly and positively correlated with each other.
CONCLUSIONS: Our findings indicate that ATF3 functions as a tumor suppressor in HCC through targeting and regulating CYR61.
Yan J, Yang B, Lin S, et al.Downregulation of miR-142-5p promotes tumor metastasis through directly regulating CYR61 expression in gastric cancer.
Gastric Cancer. 2019; 22(2):302-313 [PubMed
] Related Publications
BACKGROUND: Recurrence is a primary cause of gastric cancer (GC)-related deaths. We reported previously that low expression of miR-142-5p could predict recurrence in GC. The present study aimed to investigate the function and mechanism of miR-142-5p in metastasis of GC.
METHODS: MiR-142-5p expression was detected in 101 GC samples by qRT-PCR. Its clinical significance was statistically analyzed. The roles of miR-142-5p and its candidate target gene CYR61 in metastasis were determined both in vivo and in vitro.
RESULTS: MiR-142-5p downregulation was significantly associated with the recurrence (P = 0.031) and poor prognosis of GC (P = 0.043). MiR-142-5p inhibited cancer cell migration and invasion both in vitro and in vivo. CYR61 was identified as a novel direct target of miR-142-5p by bioinformatics analysis of target prediction and luciferase reporter assay. The re-expression and knockdown of CYR61 could, respectively, rescue the effects induced by miR-142-5p overexpression and knockdown. MiR-142-5p attenuated GC cell migration and invasion, at least partially, by inactivation of the canonical Wnt/β-catenin signaling pathway through CYR61.
CONCLUSIONS: The newly identified miR-142-5p-CYR61-Wnt/β-catenin axis partially illustrates the molecular mechanism of GC recurrence and represents a novel prognosis biomarker for GC.
The CCN protein family is composed of six matricellular proteins, which serve regulatory roles rather than structural roles in the extracellular matrix. First identified as secreted proteins which are induced by oncogenes, the acronym CCN came from the names of the first three members: CYR61, CTGF, and NOV. All six members of the CCN family consist of four cysteine-rich modular domains. CCN proteins are known to regulate cell adhesion, proliferation, differentiation, and apoptosis. In addition, CCN proteins are associated with cardiovascular and skeletal development, injury repair, inflammation, and cancer. They function either through binding to integrin receptors or by regulating the expression and activity of growth factors and cytokines. Given their diverse roles related to the pathology of certain diseases such as fibrosis, arthritis, atherosclerosis, diabetic nephropathy, retinopathy, and cancer, there are many emerging studies targeting CCN protein signaling pathways in attempts to elucidate their potentials as therapeutic targets. [BMB Reports 2018; 51(10): 486-493].
It was demonstrated in previous studies that cysteine-rich angiogenic inducer 61 (Cyr61) plays vital roles in hematological disorders, and we have already reported that the Cyr61 protein is a tumor promoter in acute myeloid leukemia (AML). Here, we investigated the association between CYR61 gene polymorphisms and susceptibility to AML.We genotyped 2 single-nucleotide polymorphisms (rs2297141 and rs6576776) in the region of the CYR61 gene by improved multiplex ligase detection reaction genotyping assays in a total of 275 samples, including samples from 137 AML patients and 138 healthy controls. Chi-squared tests and logistic regression analysis were performed to compare the different distributions of the genotypes and alleles between patients and healthy controls.The rs2297141 A allele was associated with lower risk of AML compared with the G allele (odds ratio [OR] = 0.704, 95% confidence interval [CI] = 0.503-0.985, P = .04) in both the dominant (OR = 0.447, 95% CI = 0.22-0.909, P = .025, AA vs GG) and recessive inheritance models (OR = 0.419, 95% CI = 0.23-0.763, P = .004, AA vs GA + GG). Although the distribution of the rs6576776 alleles was not different between patients with AML and normal controls, the CC genotype significantly increased the risk of AML in the dominant inheritance model (OR = 6.064, 95% CI = 1.303-28.216, P = .01, CC vs GG) and the recessive inheritance model (OR = 5.937, 95% CI = 1.291-27.306, P = .01, CC vs GC + GG). Additionally, it was shown that the rs2297141 and rs6576776 genotypes were associated with AML-M5 and AML-M2, respectively.Our findings indicated that genetic polymorphisms in the CYR61 gene may be considered potential AML risk factors in the Han Chinese population.
Ji Y, Jia L, Zhang Y, et al.Antitumor activity of the plant extract morin in tongue squamous cell carcinoma cells.
Oncol Rep. 2018; 40(5):3024-3032 [PubMed
] Related Publications
Morin is a naturally occurring bioflavonoid originally isolated from members of the Moraceae family of flowering plants and it possesses antitumor activity in various human cancer cells. The present study explored the antitumor effects of morin in tongue squamous cell carcinoma (TSCC) cells in vitro and investigated the underlying molecular events. A TSCC cell line was treated with different doses of morin for up to 48 h. Analyses of cell viability, using Cell Counting Kit‑8 (CCK‑8), EdU incorporation, colony formation, flow cytometric analysis of cell cycle distribution and apoptosis, wound healing assay, western blot analysis and qRT‑PCR assays, were then performed. The data revealed that morin treatment reduced Cal27 cell proliferation and reduced the migration capacity of tumor cells in a dose‑dependent manner. Morin treatment also significantly upregulated mammalian sterile 20‑like 1 (MST1) and MOB kinase activator 1 (MOB1) phosphorylation in CAL27 cells, but suppressed nuclear translocation of yes‑associated protein (YAP) through the induction of YAP phosphorylation in Cal27 cells. Moreover, the expression of YAP‑targeting genes, such as CTGF, CYR61 and ANKRD, was downregulated in morin‑treated TSCC cells, indicating that morin was able to activate the Hippo signaling pathway to inhibit YAP nuclear translocation and YAP‑related transcriptional activity in TSCC cells. In conclusion, the data from the present study demonstrated that morin produces anti‑TSCC activity in vitro through activation of the Hippo signaling pathway and the downstream suppression of YAP activity in TSCC cells. Future studies should assess the clinical antitumor effects of morin.
Vastrad C, Vastrad BBioinformatics analysis of gene expression profiles to diagnose crucial and novel genes in glioblastoma multiform.
Pathol Res Pract. 2018; 214(9):1395-1461 [PubMed
] Related Publications
Therefore, the current study aimed to diagnose the genes associated in the pathogenesis of GBM. The differentially expressed genes (DEGs) were diagnosed using the limma software package. The ToppFun was used to perform pathway and Gene Ontology (GO) enrichment analysis of the DEGs. Protein-protein interaction (PPI) networks, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network were used to obtain insight into the actions of DEGs. Survival analysis for DEGs carried out. A total of 701 DEGs, including 413 upregulated and 288 downregulated genes, were diagnosed between U1118MG cell line (PK 11195 treated with 1 h exposure) and U1118MG cell line (PK 11195 treated with 24 h exposure). The up-regulated genes were enriched in superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis, cell cycle, cell cycle process and chromosome. The down-regulated genes were enriched in folate transformations I, biosynthesis of amino acids, cellular amino acid metabolic process and vacuolar membrane. The current study screened the genes in PPI network, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network with higher degrees as hub genes, which included MYC, TERF2IP, CDK1, EEF1G, TXNIP, SLC1A5, RGS4 and IER5L Survival suggested that low expressed NR4A2, SLC7 A5, CYR61 and ID1 in patients with GBM was linked with a positive prognosis for overall survival. In conclusion, the current study could improve our understanding of the molecular mechanisms in the progression of GBM, and these crucial as well as new molecular markers might be used as therapeutic targets for GBM.
Liu M, Jiang K, Lin G, et al.Ajuba inhibits hepatocellular carcinoma cell growth via targeting of β-catenin and YAP signaling and is regulated by E3 ligase Hakai through neddylation.
J Exp Clin Cancer Res. 2018; 37(1):165 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Aberrant activation of β-catenin and Yes-associated protein (YAP) signaling pathways has been associated with hepatocellular carcinoma (HCC) progression. The LIM domain protein Ajuba regulates β-catenin and YAP signaling and is implicated in tumorigenesis. However, roles and mechanism of Ajuba expression in HCC cells remain unclear. The E3 ligase Hakai has been shown to interact with other Ajuba family members and whether Hakai interacts and regulates Ajuba is unknown.
METHODS: HCC cell lines stably depleted of Ajuba or Hakai were established using lentiviruses expressing shRNAs against Ajuba or Hakai. The effects of Ajuba on HCC cells were determined by a number of cell-based analyses including anchorage-independent growth, three dimension cultures and trans-well invasion assay. In vivo tumor growth was determined in a xenograft model and Ajuba expression in tumor sections was examined by immunohistochemistry. Co-immunoprecipitation, confocal microscopy and immunoblot assay were used to examine the expression and interaction between Ajuba and Hakai.
RESULTS: Depletion of Ajuba in HCC cells significantly enhanced anchorage-independent growth, invasion, the formation of spheroids and tumor growth in a xenograft model, suggesting a tumor suppressor function for Ajuba in HCC. Mechanistically, Ajuba depletion triggered E-cadherin loss and β-catenin translocation with increased Cyclin D1 levels. In addition, depletion of Ajuba upregulated the levels of YAP and its target gene CYR61. Furthermore, siRNA-mediated knockdown of either β-catenin or YAP attenuated the pro-tumor effects by Ajuba depletion on HCC cells. Notably, Ajuba stability in HCC cells was regulated by Hakai, an E3 ligase for E-cadherin. Hakai interacted with Ajuba via its HYB domain and induced Ajuba neddylation, which was antagonized by the neddylation inhibitor, MLN4924, but not MG132. We further show that overexpression of Hakai in HCC cells markedly increased anchorage-independent growth, spheroid-formation ability and tumor growth in xenografts whereas Hakai depletion resulted in these opposite effects, indicating an oncogenic role for Hakai in HCC. Hakai also induced β-catenin translocation with increased levels of Cyclin D1.
CONCLUSIONS: Our data suggest a role for Ajuba and Hakai in HCC, and uncover the mechanism underlying the regulation of Ajuba stability.
Jin D, Wu Y, Shao C, et al.Norcantharidin reverses cisplatin resistance and inhibits the epithelial mesenchymal transition of human non‑small lung cancer cells by regulating the YAP pathway.
Oncol Rep. 2018; 40(2):609-620 [PubMed
] Free Access to Full Article Related Publications
Non‑small cell lung cancer (NSCLC) accounts for >80% of all lung cancer cases, which are the leading cause of cancer‑related mortality worldwide. The clinical efficacy of available therapies for NSCLC is often limited due to the development of resistance to anticancer drugs, particularly to cisplatin (DDP). Norcantharidin (NCTD) is a traditional Chinese medicine used in the treatment of many types of cancer, to which patients do not develop resistance. The aim of the present study was to examine the potential synergistic effects of NCTD and DPP on the viability of the the DDP‑resistant NSCLC cell line, A549/DDP. We further explored the potential underlying mechanisms by examining the expression of the oncogene, Yes-associated protein 1 (YAP), whose activation was recently found to be associated with drug resistance. We further examined a series of human lung cancer cell lines and tissues from patients with lung cancer, which revealed that YAP activation contributed to lung cancer initiation, progression and metastasis, and was associated with a poor prognosis, and confering resistance against targeted therapies. Moreover, YAP expression was evaluated in the A549/DDP cells treated with NCTD, DDP, or both drugs. The combined treatment significantly sensitized the A549/DDP cells to DDP‑induced growth inhibition by reducing YAP promoter activity (based on transcriptional expression) and the expression of its target genes, connective tissue growth factor (CTGF) and cysteine rich angiogenic inducer 61 (CYR61). Furthermore, compared to the individual treatments, combined treatment increased cell apoptosis and senescence, and decreased epithelial‑to‑mesenchymal transition and the cell migratory and invasive ability. On the whole, our data indicate that the application of NCTD with reverses DDP resistance and thus, this combined treatment may have promising prospects for use in improving the outcome of patients with NSCLC.
Huang X, Xiang L, Li Y, et al.Snail/FOXK1/Cyr61 Signaling Axis Regulates the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.
Cell Physiol Biochem. 2018; 47(2):590-603 [PubMed
] Related Publications
BACKGROUND/AIMS: Metastasis is the primary cause of colorectal cancer (CRC)-related death. However, the molecular mechanisms underlying metastasis in CRC remain unclear.
METHODS: We evaluated mRNA and protein expression levels by quantitative real-time reverse transcription PCR, western blotting, immunofluorescence, tissue microarrays, and immunohistochemistry assays. We also assessed the migration and invasion abilities of CRC cells in vitro by wound healing assays, invasion and migration assays, western blot analysis, and immunofluorescence. Tumor metastasis was evaluated in nude mice in vivo.
RESULTS: A positive correlation was observed between the expression patterns of Forkhead box k1 (FOXK1) and Snail in CRC. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Snail directly bound to and activated the human FOXK1 gene promoter. Moreover, the Snail-FOXK1 axis promote epithelial mesenchymal transition (EMT)-mediated CRC cell invasion and metastasis. FOXK1 and Snail expression levels were correlated with tumor progression and served as significant predictors of overall survival in patients with CRC. Furthermore, overexpression of FOXK1 induced the EMT by upregulating the expression of cysteine-rich angiogenic inducer 61 (Cyr61). Luciferase assays showed that Cyr61 was a direct transcriptional target of FOXK1. Down regulation of Cyr61 decreased FOXK1-enhanced "CRC cell" migration, invasion, and metastasis. Additionally, FOXK1 expression was positively correlated with Cyr61 expression and was associated with poor prognosis.
CONCLUSIONS: The Snail/FOXK1/Cyr61 signaling axis regulates the EMT and metastasis of CRC.
Maity G, Haque I, Ghosh A, et al.The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF-ERK signaling.
J Biol Chem. 2018; 293(12):4334-4349 [PubMed
] Free Access to Full Article Related Publications
Myc-associated zinc-finger protein (MAZ) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression is associated with the progression of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of action of MAZ in PDAC progression is largely unknown. Here, we present evidence that MAZ mRNA expression and protein levels are increased in human PDAC cell lines, tissue samples, a subcutaneous tumor xenograft in a nude mouse model, and spontaneous cancer in the genetically engineered PDAC mouse model. We also found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis indicated that MAZ depletion in PDAC cells inhibits invasive phenotypes such as the epithelial-to-mesenchymal transition, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we detected no direct effects of MAZ on the expression of K-Ras mutants, but MAZ increased the activity of CRAF-ERK signaling, a downstream signaling target of K-Ras. The MAZ-induced activation of CRAF-ERK signaling was mediated via p21-activated protein kinase (PAK) and protein kinase B (AKT/PKB) signaling cascades and promoted PDAC cell invasiveness. Moreover, we found that the matricellular oncoprotein cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) regulates MAZ expression via Notch-1-sonic hedgehog signaling in PDAC cells. We propose that Cyr61/CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells not through direct K-Ras activation but instead through the activation of CRAF-ERK signaling. Collectively, these results highlight key molecular players in PDAC invasiveness and may help inform therapeutic strategies to improve clinical management and outcomes of PDAC.
Cysteine-rich angiogenic inducer 61 (CYR61) is an extracellular matrix-associated protein involved in survival, tumorigenesis, and drug resistance. Therefore, we examined the effects of flavones against CYR61-overexpressing human gastric adenocarcinoma AGS (AGS-cyr61) cells, which show remarkable resistance to 5-fluorouracil (5-FU), adriamycin (ADR), tamoxifen (TAM), paclitaxel (PAC), and docetaxel (DOC). Among the tested flavones, quercetin had the lowest 50% inhibitory concentration (IC
Xu Y, Chu H, Zhou Y, et al.miR-365 functions as a tumor suppressor by directly targeting CYR61 in osteosarcoma.
Biomed Pharmacother. 2018; 98:531-537 [PubMed
] Related Publications
Increasing evidence indicates that microRNAs(miRNAs) are often aberrantly expressed in osteosarcoma (OS) and play critical roles in OS tumorigenesis. Therefore, the discovery of miRNAs may provide a new and powerful tool for understanding the mechanismof OS initiation and development. The aim of this study was to investigate the functional significance of miR-365 and identify its possible mechanism in OS cells. Here, wefound that the expression level of miR-365 is significantly downregulated in OS tissues and cell lines, and its expression isassociated with the clinical stage, distant metastasis, tumor grade, and poor overall survival rate. The overexpression of miR-365 is able to inhibit cell proliferation, migration, and invasion in Saos-2 and MG-63 cells. Moreover, the cysteine-rich angiogenic inducer 61 (CYR61) has been identified as a target of miR-365 in OS cells, and its expression is found to be significantly increased in OS tissues, which is negatively correlated with miR-365. Furthermore, CYR61 overexpression significantly attenuated the suppressive effects of miR-365 on the proliferation, migration, and invasion of Saos-2 and MG-63 cells. Therefore, we consider that miR-365 acts as a tumor suppressor in OS, partly, by targeting CYR61 expression.
Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)‑producing cells in liver fibrosis. Activated HSCs stimulate the proliferation and migration of hepatocellular carcinoma (HCC) cells. Cysteine‑rich 61 (CCN1/Cyr61) is an ECM protein. Our previous studies demonstrated that the expression of CCN1 was significantly higher in benign hepatic cirrhosis tissue and cancer‑adjacent hepatic cirrhosis tissues. CCN1 is a target gene of β‑catenin in HCC and promotes the proliferation of HCC cells. The present study aimed to examine whether CCN1 can activate HSCs and affect the function of activated HSCs in promoting the progression of HCC. CCN1 expression was determined during the progression of liver fibrosis in a mouse model. LX‑2 cells, which were infected with adenoviruses AdCCN1 or AdRFP, and HepG2 cells were co‑cultured or subcutaneously co‑implanted into in nude mice. MTT assay, Crystal Violet staining, Boyden chamber, matrigel invasion and monolayer scratch assays were used to analyze the proliferation, migration and invasion capability of HepG2 cells. Xenograft sizes were measured and histological analyses were performed by hematoxylin and eosin, immunohistochemical, immunefluorescence and Sirius Red staining. It was demonstrated that the expression of CCN1 was continually increased in liver fibrosis and the that expression may be correlated with the progression of liver fibrosis. CCN1 affected the function of LX‑2 and enhanced the effect of LX‑2 on promoting the viability, migration and invasion of HepG2 cells in vitro. CCN1 enhanced the effect of LX‑2 on promoting the growth of HepG2 xenografts in vivo. CCN1 also affected the function of activated HSCs and regulated the formation of the xenograft microenvironment, including fibrogenesis and angiogenesis, which are beneficial for the progression of HCC. These findings demonstrated that CCN1 may be involved in the progression of the hepatic cirrhosis‑HCC axis through regulating HSCs.
Cysteine‑rich angiogenic inducer 61 (CCN1/Cyr61) is a prompt response transcription product activated by growth factors. As a member of the CCN family, it mediates cell survival, proliferation, differentiation, migration, adhesion and synthesis of the extracellular matrix by binding directly to the integrins and heparin sulfate proteoglycans or activating multiple signaling transduction pathways. It has previously been demonstrated that CCN1/Cyr61 exhibits an important role in the female reproductive system during embryogenesis and tumorigenesis. However, the functions of CCN1/Cyr61 in the female reproductive system have not been systematically investigated, therefore, the primary aim of the present review is to introduce the role and function of CCN1/Cyr61 in the female reproductive system. The current review presents the molecular structure and biological function of CCN1/Cyr61 and provides detailed data on its expression pattern and contribution to the female reproductive system, including the role in embryogenesis and tumorigenesis.
Wang R, Wei B, Wei J, et al.Cysteine-rich 61-associated gene expression profile alterations in human glioma cells.
Mol Med Rep. 2017; 16(4):5561-5567 [PubMed
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The present study aimed to investigate gene expression profile alterations associated with cysteine‑rich 61 (CYR61) expression in human glioma cells. The GSE29384 dataset, downloaded from the Gene Expression Omnibus, includes three LN229 human glioma cell samples expressing CYR61 induced by doxycycline (Dox group), and three control samples not exposed to doxycycline (Nodox group). Differentially expressed genes (DEGs) between the Dox and Nodox groups were identified with cutoffs of |log2 fold change (FC)|>0.5 and P<0.05. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for DEGs were performed. Protein‑protein interaction (PPI) network and module analyses were performed to identify the most important genes. Transcription factors (TFs) were obtained by detecting the TF binding sites of DEGs using a Whole Genome rVISTA online tool. A total of 258 DEGs, including 230 (89%) upregulated and 28 (11%) downregulated DEGs were identified in glioma cells expressing CYR61 compared to cells without CYR61 expression. The majority of upregulated DEGs, including interferon (IFN)B1, interferon‑induced (IFI)44 and interferon regulatory factor (IRF)7, were associated with immune, defense and virus responses, and cytokine‑cytokine receptor interaction signaling pathways. Signal transducer and activator of transcription 1 (STAT1) and DEAD‑box helicase 58 (DDX58) were observed to have high connection degrees in the PPI network. A total of seven TFs of the DEGs, including interferon consensus sequence‑binding protein and IFN‑stimulated gene factor‑3 were additionally detected. In conclusion, IFNB1, genes encoding IFN‑induced proteins (IFI16, IFI27, IFI44 and IFITM1), IRFs (IRF1, IRF7 and IRF9), STAT1 and DDX58 were demonstrated to be associated with CYR61 expression in glioma cells; thus, they may be critical for maintaining the role of CYR61 during cancer progression.
Despite therapeutic advances, glioblastoma represents a lethal brain tumor. Recently, research to identify prognostic markers for glioblastoma has intensified. Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression. To understand the molecular mechanisms that regulate CCN1 expression, we examined 147 tumour samples from 80 patients with glioblastoma and 67 patients with lower grade glioma. Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma. This mutation was also detected in corresponding blood samples. In multivariate analysis, high CCN1 expression and PIK3R1Met326Ile in glioblastoma patients were prognostic factors for OS [HR = 2.488 (1.298-4.769), p = 0.006] and [HR = 2.089 (1.020-4.277), p = 0.0439], respectively. Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.
In this paper, we introduce a novel computational method for constructing protein networks based on reverse phase protein array (RPPA) data to identify complex patterns in protein signaling. The method is applied to phosphoproteomic profiles of basal expression and activation/phosphorylation of 76 key signaling proteins in three breast cancer cell lines (MCF7, LCC1, and LCC9). Temporal RPPA data are acquired at 48h, 96h, and 144h after knocking down four genes in separate experiments. These genes are selected from a previous study as important determinants for breast cancer survival. Interaction networks are constructed by analyzing the expression levels of protein pairs using a multivariate analysis of variance model. A new scoring criterion is introduced to determine relevant protein pairs. Through a network topology based analysis, we search for wiring patterns to identify key proteins that are associated with significant changes in expression levels across various experimental conditions.
The aim of this study is to clarify whether YAP/TAZ is involved in the pathogenesis and proliferative growth of keratocystic odontogenic tumor (KCOT). The expression levels of YAP/TAZ and downstream proteins and genes in normal oral mucosa (OM) and KCOT were determined and compared by immunohistochemistry and real-time quantitative PCR. The results showed that the expression of YAP/TAZ and downstream proteins (Cyr61, CTGF) was significantly upregulated in KCOT with upregulation of Ki-67 compared to OM. Importantly, the mRNA levels of transcription factors (TEAD1, TEAD4, and RUNX2) and cell cycle related genes (CDK2, PCNA), which interact with the transcriptional coactivators YAP/TAZ, are also upregulated in the KCOT. In addition, the results from Spearman rank correlation test revealed the close relationship between YAP/TAZ and Ki-67, which was further evidenced by double-labelling immunofluorescence that revealed a synchronous distribution for YAP/TAZ with Ki-67 in KCOT samples. All the data suggested YAP/TAZ might be involved in the proliferative behavior of KCOT.
Epithelial ovarian carcinomas account for more than 90% of human ovarian cancers and have become the primary cause of death for gynecological malignancies. Unlimited cell proliferation and resistance to cell apoptosis contribute to the development of ovarian cancers. However, the underlying mechanisms involved in these processes in epithelial ovarian carcinomas are yet poorly understood. In the present study, we examined the Hippo signaling gene expression and investigated the effects of Sphingosine 1-phosphate (S1P) on cell proliferation and the underlying mechanisms in human ovarian cancer cell lines, OVCAR3 and SKOV3. Our results demonstrate that S1P disrupts Hippo signaling by reducing YAP phosphorylation and increasing the expression of CCN1 and CCN2 in both ovarian cancer cells. Furthermore, the increase in CCN1/CCN2 expression contributes to the S1P-induced increase in cancer cell proliferation.
Lau HK, Wu ER, Chen MK, et al.Effect of genetic variation in microRNA binding site in WNT1-inducible signaling pathway protein 1 gene on oral squamous cell carcinoma susceptibility.
PLoS One. 2017; 12(4):e0176246 [PubMed
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BACKGROUND: Oral squamous cell carcinoma (OSCC), which is the most common head and neck cancer, accounts for 1%-2% of all human malignancies and is characterized by poor prognosis and reduced survival rates. WNT1-inducible signaling pathway protein 1 (WISP1), a cysteine-rich protein belonging to the Cyr61, CTGF, Nov (CCN) family of matricellular proteins, has many developmental functions and may be involved in carcinogenesis. This study investigated WISP1 single-nucleotide polymorphisms (SNPs) to elucidate OSCC susceptibility and clinicopathologic characteristics.
METHODOLOGY/PRINCIPAL FINDINGS: Real-time polymerase chain reaction was used to analyze 6 SNPs of WISP1 in 900 OSCC patients and 1200 cancer-free controls. The results showed that WISP1 rs2929970 polymorphism carriers with at least one G allele were susceptible to OSCC. Moreover, compared with smokers, non-smoker patients with higher frequencies of WISP1 rs2929970 (AG + GG) variants had a late stage (stages III and IV) and a large tumor size. In addition, OSCC patients who were betel quid chewers and carried WISP1 rs16893344 (CT + TT) variants had a low risk of lymph node metastasis.
CONCLUSION: Our results demonstrate that a joint effect of WISP1 rs2929970 with smoking as well as WISP1 rs16893344 with betel nut chewing causally contributes to the occurrence of OSCC. WISP1 polymorphism may serve as a marker or a therapeutic target in OSCC.
We examined the impact of crosstalk between the insulin receptor and G protein-coupled receptor (GPCR) signaling pathways on the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in the context of human pancreatic ductal adenocarcinoma (PDAC). Stimulation of PANC-1 or MiaPaCa-2 cells with insulin and neurotensin, a potent mitogenic combination of agonists for these cells, promoted striking YAP nuclear localization and decreased YAP phosphorylation at Ser
Hussain SR, Ali S, Singh A, et al.Identification of the cysteine-rich 61 (CYR61) gene variations in osteosarcoma patients.
Turk J Med Sci. 2017; 47(1):287-294 [PubMed
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BACKGROUND/AIM: Osteosarcoma requires an angiogenesis process. CYR61 is one of the extracellular signaling molecules that promote angiogenesis, tumor growth, and the malignancy of osteosarcoma. In the present study, we investigate the CYR61 gene variations in osteosarcoma and their correlations with clinicopathological findings.
MATERIALS AND METHODS: We performed variation analysis of the CYR61 gene in 58 patients with osteosarcoma. With an aim to ascertain the variety of variations in exons 2, 3, 4, and 5 of the CYR61 gene in osteosarcoma, we did a PCR-SSCP followed by DNA sequencing.
RESULTS: In osteosarcoma the CYR61 gene variations found were 18.96% (11/58) in exon 2, 3.44% (2/58) in exon 3, 8.62% (5/58) in exon 4, and 15.51% (9/58) in exon 5. In our variation analysis, we detected one missense variation in exon 2 (Arg47Trp), one silent variation in exon 3 (Lys152Lys), one missense variation in exon 4 (Phe213Leu), and two missense variations in exon 5 (Gly315Arg and Asp339Asn). The overall CYR61 variation frequency in exons 2, 3, 4, and 5 was determined to be 46.55% (27/58).
CONCLUSION: Our study specifies the role of CYR61 gene variation in osteosarcoma. The result signifies that CYR61 might be used as a prognostic/diagnostic marker in osteosarcoma patients.
Liu H, Peng F, Liu Z, et al.CYR61/CCN1 stimulates proliferation and differentiation of osteoblasts in vitro and contributes to bone remodeling in vivo in myeloma bone disease.
Int J Oncol. 2017; 50(2):631-639 [PubMed
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Cysteine-rich 61 (CYR61/CCN1), a secreted protein in bone marrow (BM) microenvironment, has diverse effects on many cellular activities such as growth and differentiation. However, the effect of CCN1 on osteoblasts (OBs) in myeloma bone disease remains unclear. In our study, the level of CCN1 in multiple myeloma (MM) patients was detected by ELISA and RT-PCR. The proliferation and differentiation of OBs from MM patients were observed after stimulated by CCN1 in vitro. The myeloma cells transduced with CYR61 gene (RPMI‑8226/CYR61) were injected in a mouse model to evaluate the efficacy of CCN1 in vivo and compare with zoledronic acid. The results showed that CYR61/CCN1 levels in BM supernatant and OBs both elevated significantly in all newly diagnosed MM patients, especially in patients without bone disease (P=0.001 and P<0.001). After 30 ng/l CCN1 stimulation for 24 h, the quantity and mineralization of OBs increased significantly in vitro (P=0.046 and 0.048). The transcription factors of Wnt pathway, runt-related transcription factor 2 (Runx2) and β-catenin were upregulated in OBs after CCN1 stimulation (P=0.012 and 0.011). After injection of RPMI‑8226 cells, bone lesions were observed obviously by microCT and histochemistry at 7 weeks. Radiographic analysis of the bones showed decreased resorption in CCN1 overexpression group and zoledronic acid group, while severe resorption in negative control. Furthermore, trabecular bone volume in CCN1 overexpression group (1.7539±0.16949) was significantly higher than zoledronic acid group (1.2839±0.077) (P=0.012). In conclusion, CCN1 can stimulate the proliferation and differentiation of OBs in vitro and contribute to bone remodeling in vivo in MBD.
Epithelial-mesenchymal transition (EMT) is a critical step in the acquisition of the migratory and invasive capabilities associated with metastatic competence. Cysteine-rich protein 61 (CCN1/Cyr61) has been implicated as an important mediator in the proliferation and metastasis of breast cancer. Hence, Cyr61 and associated pathways are attractive targets for therapeutic interventions directed against the EMT. In the present study, we report that baicalein significantly inhibits the expression of Cyr61 and migration and invasion of MDA-MB231 human breast cancer cells. Exposure to baicalein led to increased E-cadherin expression, possibly due to the ubiquitination of Snail and Slug, which was mediated by the Cyr61/Akt/glycogen synthase kinase 3β (GSK3β) pathway. Further analysis revealed that baicalein inhibited the expression of lysyl oxidase like-2 (LOXL-2), which is a functional collaborator of Snail and Slug, and subsequently attenuated the direct interaction between LOXL-2 and Snail or Slug, thereby enhancing GSK3β-dependent Snail and Slug degradation. Our findings provide new insights into the antimetastatic mechanism of baicalein and may contribute to its beneficial use in breast cancer therapies.