RhoC over-expression has been reported in ductal pancreatic adenosarcoma (Suwa, 1998) and in inflammatory breast cancers (van Golen, 1999). RhoC is also implicated in the spread of metastastic disease (Clarke, 2000).
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 (6)
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: RHOC (cancer-related)
BACKGROUND: Damage-regulated autophagy modulator 2(DRAM2) is associated with autophagy processes. However, the role of DRAM2 in the progression of human neoplasms is still unknown. Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC).
METHODS: Tumor specimens from 259 NSCLC patients were collected and analyzed. Transwell migration, cell cycle analysis, MTT and colony formation assays were performed to determine the effect of DRAM2 overexpression and knockdown on NSCLC-cell migration and proliferation. Western blotting confirmed the expression of DRAM2, p53, and the other involved proteins.
RESULTS: DRAM2 was preferentially upregulated in NSCLC tissues and higher expression of DRAM2 in NSCLC correlated with tumor node metastases stage and lymph node metastasis. Additionally, DRAM2 overexpression promoted cell metastasis and proliferation in vitro, while knockdown of DRAM2 expression yielded opposite result. Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. DRAM2 overexpression also increased proteins CDK4, CyclinD3, and decreased p27 expression, all of which are cell cycle-related factors. Consistently knocked down DRAM2 had the opposite effect. We also found that DRAM2 expression was negatively correlated to p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. Finally, absence of p53 did not influence the function of DRAM2 in NSCLC, but overexpression of p53 repressed its function.
CONCLUSIONS: DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Therefore, DRAM2 may act as an oncogene in NSCLC and could serve as a prognostic factor and potential target for NSCLC treatment.
BACKGROUND: To examine the influence of HOXD10 on the metabolism and growth of colon carcinoma cells by suppressing the RHOC/AKT/MAPK pathway.
METHODS: Thirty-seven paired colon cancer and its adjacent samples from The Cancer Genome Atlas (TCGA) were analyzed. Chip Analysis Methylation Pipeline (ChAMP) analysis was employed for differential methylated points (DMPs) and the differential methylation regions (DMRs) screening. The HOXD10 mRNA expression and DNA methylation levels were detected by RT-PCR. The Cell proliferation, migration, invasion and apoptosis were respectively measured by MTT assay, transwell assay, wound healing assay and flow cytometry assay in carcinoma cell lines after treated with 5-aza-2'-deoxycytidine (5-Aza-dC) or transfected with HOXD10-expressing plasmid. The expression of HOXD10 and RHOC was revealed by immunohistochemistry in disparate differentiation colon carcinoma tissues, and the dephosphorylation of AKT and MAPK pathways were detected by RT-PCR and western blot.
RESULTS: The bioinformatics analysis demonstrated that HOXD10 was hypermethylated and low-expressed in colorectal cancer tissues. The detection of RT-PCR indicated the similar results in colorectal cancer cell lines and tissues. The induction of demethylation was recovered by treatment with 5-Aza-dC and the HOXD10 in colorectal cancer cell lines was re-expressed by transfection with a HOXD10 expression vector. The demethylation or overexpression of HOXD10 suppressed proliferation, migration, invasion and promoted apoptosis in colorectal cancer cells. HXOD10 suppressed the tumor growth and detected an opposite trend of protein RHOC. AKT and MAPK pathways were notably inactivated after the dephosphorylation due to the overexpression of HOXD10.
CONCLUSIONS: HOXD10 was suppressed in colon adenocarcinoma cells, which down-regulated RHOC/AKT/MAPK pathway to enhance colon cancer cells apoptosis and constrain the proliferation, migration and invasion.
Schipper L, Kanber D, Steenpass LGeneration of heterozygous and homozygous hESC H9 sublines carrying inactivating mutations in RB1.
Stem Cell Res. 2018; 33:41-45 [PubMed
] Related Publications
Inactivation of the tumor suppressor gene RB1 is causal for development of retinoblastoma, a tumor of the neural retina arising in children under the age of five. In addition, secondary RB1 mutations are found in many other tumor types. To investigate retinoblastoma formation in vitro, stem cells with inactivated RB1 can be differentiated into neural retina. To enable such studies, two sublines of hESC line H9 carrying mutations in RB1 exon 3 in heterozygous or homozygous state were generated and characterized. Homozygous mutation led to loss of RB1 protein expression. Resource table.
Cao Y, Xu J, Wen J, et al.Generation of a Urine-Derived Ips Cell Line from a Patient with a Ventricular Septal Defect and Heart Failure and the Robust Differentiation of These Cells to Cardiomyocytes via Small Molecules.
Cell Physiol Biochem. 2018; 50(2):538-551 [PubMed
] Related Publications
BACKGROUND/AIMS: Ventricular septal defects (VSDs) are one of the most common types of congenital heart malformations. Volume overload resulting from large VSDs can lead to heart failure (HF) and constitutes a major cause of pediatric HF with a series of often-fatal consequences. The etiology of VSD with HF is complex, and increasing evidence points toward a genetic basis. Indeed, we identified an L2483R mutation in the ryanodine receptor type 2 (RyR2) in a 2-month-old male patient with VSD with HF.
METHODS: We generated integration-free induced pluripotent stem cells from urine samples (UiPSCs) of this patient using Sendai virus containing the Yamanaka factors and characterized these cells based on alkaline phosphatase activity, pluripotency marker expression, and teratoma formation. Then, we induced the derived UiPSCs to rapidly and efficiently differentiate into functional cardiomyocytes through temporal modulation of canonical Wnt signaling with small molecules. Real-time PCR and immunofluorescence were used to verify the expression of myocardium-specific markers in the differentiated cardiomyocytes. The ultrastructure of the derived myocardial cells was further analyzed by using transmission electron microscopy.
RESULTS: The established UiPSC lines were positive for alkaline phosphatase activity, retained the RyR2 mutation, expressed pluripotency markers, and displayed differentiation potential to three germ layers in vivo. The UiPSC-derived cells showed hallmarks of cardiomyocytes, including spontaneous contraction and strong expression of cardiac-specific proteins and genes. However, compared with cardiomyocytes derived from H9 cells, they had a higher level of autophagy, implying that autophagy may play an important role in the development of VSD with HF.
CONCLUSION: The protocol described here yields abundant myocardial cells and provides a solid platform for further investigation of the pathogenesis, pharmacotherapy, and gene therapy of VSD with HF.
Glioblastoma multiforme (GBM) is the most common type of malignant brain tumors in adults and has a dismal prognosis. The highly aggressive invasion of malignant cells into the normal brain parenchyma renders complete surgical resection of GBM tumors impossible, increases resistance to therapeutic treatment, and leads to near-universal tumor recurrence. We have previously demonstrated that TROY (TNFRSF19) plays an important role in glioblastoma cell invasion and therapeutic resistance. However, the potential downstream effectors of TROY signaling have not been fully characterized. Here, we identified PDZ-RhoGEF as a binding partner for TROY that potentiated TROY-induced nuclear factor kappa B activation which is necessary for both cell invasion and survival. In addition, PDZ-RhoGEF also interacts with Pyk2, indicating that PDZ-RhoGEF is a component of a signalsome that includes TROY and Pyk2. PDZ-RhoGEF is overexpressed in glioblastoma tumors and stimulates glioma cell invasion via Rho activation. Increased PDZ-RhoGEF expression enhanced TROY-induced glioma cell migration. Conversely, silencing PDZ-RhoGEF expression inhibited TROY-induced glioma cell migration, increased sensitivity to temozolomide treatment, and extended survival of orthotopic xenograft mice. Furthermore, depletion of RhoC or RhoA inhibited TROY- and PDZ-RhoGEF-induced cell migration. Mechanistically, increased TROY expression stimulated Rho activation, and depletion of PDZ-RhoGEF expression reduced this activation. Taken together, these data suggest that PDZ-RhoGEF plays an important role in TROY signaling and provides insights into a potential node of vulnerability to limit GBM cell invasion and decrease therapeutic resistance.
The present study tested the effect of a bacterial lactone N-(3-oxododecanoyl)-homoserine lactone (C12-HSL) on the cytoskeletal and transcriptional genes and proteins in prostate adenocarcinoma (PA) cells (DU145 and LNCaP) and prostate small cell neuroendocrine carcinoma (SCNC) PC3 cells including their cellular viability and apoptosis. Our data indicate that cell migration and colony formation were affected in the presence of C12-HSL. C12-HSL induced apoptosis and altered viability of both PA and SCNC cells in a concentration dependent manner as measured by fluorescence and chemiluminescence assays. Compared to PCa cells, noncancerous prostate epithelial cells (RWPE1) were resistant to modification by C12-HSL. Further, the viability of PC3 cells in 3D matrix was suppressed by C12-HSL treatment as detected using calcein AM fluorescence in situ. C12-HSL treatment induced cytoskeletal associated protein expression of vinculin and RhoC, which may have implications in cancer cell motility, adhesion, and metastasis. IQGAP protein expression was reduced in DU145 and RWPE1 cells in the presence of C12-HSL. C12-HSL decreased STAT3 phosphorylation in DU145 cells but increased STAT1 protein phosphorylation in PC3 and LNCaP cells. Overall, these studies indicate that C12-HSL can trigger changes in transcription factors and cytoskeletal proteins and thereby modulate growth and migration properties of PCa cells.
Meng C, He Y, Wei Z, et al.MRTF-A mediates the activation of COL1A1 expression stimulated by multiple signaling pathways in human breast cancer cells.
Biomed Pharmacother. 2018; 104:718-728 [PubMed
] Related Publications
Deposition of type I collage in ECM is an important property of various fibrotic diseases including breast cancer. The excessive expression of type I collagen contributes to the rigidity of cancer tissue and increases the mechanical stresses which facilitate metastasis and proliferation of cancer cells via the activation of TGF-β signaling pathway. The increased mechanical stresses also cause the compression of blood vessels and result in hypoperfusion and impaired drug delivery in cancer tissue. Additionally, type I collage functions as the ligand of α2β1-integrin and DDR1/2 receptors on the membrane of cancer cells to initiate signal transduction leading to metastasis. The expression of type I collage in cancer cells is previously shown to be inducible by TGF-β however the detailed mechanism by which the synthesis of type I collagen is regulated in breast cancer cells remains unclear. Herein, we report that MRTF-A, a co-activator of SRF, is important for the regulation of type I collagen gene COL1A1 in breast cancer cells. MRTF-A physically interacted with the promoter of COL1A1 to facilitate histone acetylation and RNA polymerase II recruitment. The RhoC-ROCK signaling pathway which controls the nuclear localization of MRTF-A regulated the transcription of COL1A1 in human breast cancer cells. TGF-β and Wnt signaling increased the expression of both MRTF-A and COL1A1. Furthermore, depletion of MRTF-A abolished the upregulation of COL1A1 in response to the TGF-β or Wnt signaling, indicating the importance of MRTF-A in the synthesis of type I collagen in breast cancer. Given the crucial roles of type I collagen in the formation of metastasis-prone and hypoperfusion microenvironment, MRTF-A would be a potential target for the development of anti-breast cancer activities.
Zacharopoulou N, Tsapara A, Kallergi G, et al.The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells.
Cell Physiol Biochem. 2018; 47(1):368-377 [PubMed
] Related Publications
BACKGROUND/AIMS: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells.
METHODS: We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins.
RESULTS: We report here that KDM2B regulates EZH2 and BMI1 in HCT116 colon tumor cells. Knockdown of this epigenetic factor induced potent up-regulation of the protein levels of the epithelial markers E-cadherin and ZO-1, while the mesenchymal marker N-cadherin was downregulated. On the other hand, KDM2B overexpression downregulated the levels of both epithelial markers and upregulated the mesenchymal marker, suggesting control of EMT by KDM2B. In addition, RhoA, RhoB and RhoC protein levels diminished upon KDM2B-knockdown, while all three small GTPases became upregulated in KDM2B-overexpressing HCT116 cell clones. Interestingly, Rac1 GTPase level increased upon KDM2B-knockdown and diminished in KDM2B-overexpressing HCT116 colon tumor- and DU-145 prostate cancer cells.
CONCLUSIONS: These results establish a clear functional role of the epigenetic factor KDM2B in the regulation of EMT and small-GTPases expression in colon tumor cells and further support the recently postulated oncogenic role of this histone demethylase in various tumors.
Nomikou E, Livitsanou M, Stournaras C, Kardassis DTranscriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases.
Cell Mol Life Sci. 2018; 75(12):2111-2124 [PubMed
] Related Publications
Rho GTPases are highly conserved proteins that play critical roles in many cellular processes including actin dynamics, vesicular trafficking, gene transcription, cell-cycle progression, and cell adhesion. The main mode of regulation of Rho GTPases is through guanine nucleotide binding (cycling between an active GTP-bound form and an inactive GDP-bound form), but transcriptional, post-transcriptional, and post-translational modes of Rho regulation have also been described. In the present review, we summarize recent progress on the mechanisms that control the expression of the three members of the Rho-like subfamily (RhoA, RhoB, and RhoC) at the level of gene transcription as well as their post-transcriptional regulation by microRNAs. We also discuss the progress made in deciphering the mechanisms of cross-talk between Rho proteins and the transforming growth factor β signaling pathway and their implications for the pathogenesis of human diseases such as cancer metastasis and fibrosis.
Lung cancer remains the leading cause of cancer-related death worldwide. Previous studies have shown that the novel KIAA0247 gene potentially targeted by the tumor suppressor p53 may inhibit the development of several cancers. However, the exact function of KIAA0247 in non-small-cell lung cancer (NSCLC) is unknown. The purpose of the present study was to clarify the role of KIAA0247 in NSCLC. KIAA0247 expression was evaluated in tumors and adjacent normal tissues of 197 NSCLC patients by immunohistochemistry and real-time PCR and analyzed for association with clinicopathological parameters. Results indicated that KIAA0247 levels positively correlated with cell differentiation (P < .001) and patient survival (P < .0001) and negatively correlated with lymph node metastasis (P < .001) and advanced p-TNM stage (P < .001). In cultured NSCLC cell lines, KIAA0247 overexpression inhibited cell migration, invasion, and proliferation and downregulated the expression of Jagged1, Notch1 intracellular domain (NICD), Snail, cyclin D1, RhoA, RhoC, and MMP9, while upregulating that of E-cadherin and p21. The Notch inhibitor DAPT reduced the biological effects of KIAA0247 knockdown, suggesting that KIAA0247 decreased the carcinogenic activity of NSCLC cells through downregulation of Notch signaling. Our results indicate that KIAA0247 inhibits NSCLC progression by reducing the metastatic potential of cancer cells through downregulation of the Notch pathway, which may underlie the association of KIAA0247 expression with favorable clinicopathological characteristics of NSCLC patients. These findings suggest that KIAA0247 is a candidate prognostic biomarker and potential therapeutic target in NSCLC.
Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by β-arrestin1 (β-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of β-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENAΔv6 isoforms through β-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of β-arr1 with hMENA/hMENAΔv6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of β-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ET
Chen S, Wang LL, Sun KX, et al.The role of the long non-coding RNA TDRG1 in epithelial ovarian carcinoma tumorigenesis and progression through miR-93/RhoC pathway.
Mol Carcinog. 2018; 57(2):225-234 [PubMed
] Related Publications
As one of the most frequently diagnosed cancers in women, the development and progression of epithelial ovarian carcinoma (EOC) remains an open area of research. The role of long non-coding RNAs (lncRNAs) in EOC is an emerging field of study. We found that LncRNA TDRG1 (human testis development-related gene 1) was highly expressed in EOC tissues than in normal ovarian tissues, and expression differed significantly with differentiation. LncRNA TDRG1 downregulation suppressed EOC cell proliferation, migration, and invasion, while its overexpression had the opposite effect. Bioinformatic predictions and dual-luciferase reporter assays showed that LncRNA TDRG1 has possible miRNA-93 (miR-93) binding sites. LncRNA TDRG1 downregulation upregulated miR-93 expression, while its overexpression reduced miR-93 expression. In addition, TDRG1 downregulation reduced the expression of Ras homolog gene family member C (RhoC), P70 ribosomal S6 kinase (P70S6 K), Bcl-xL, and matrix metalloproteinase 2 (MMP2) protein, which are regulated by miR-93, while its upregulation induced RhoC, P70S6 K, Bcl-xL, and MMP2 protein expression. In vivo, LncRNA TDRG1 overexpression induced tumor development and RhoC expression. Taken together, our results demonstrated for the first time that LncRNA TDRG1 may be a new and important diagnostic and therapeutic target in EOC.
Zhou X, Guo X, Chen M, et al.HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC-ROCK1 Signaling Pathway.
Mol Cancer Res. 2018; 16(1):124-134 [PubMed
] Related Publications
Hypoxia contributes to pancreatic cancer progression and promotes its growth and invasion. Previous research principally focused on hypoxia-inducible factor-1 alpha (HIF-1α) and HIF-2α (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3α (HIF3A) has not been investigated. Therefore, HIF-1α, HIF-2α, and HIF-3α expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3α expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3α expression on cell invasion and migration was investigated
Jiang L, Wang WJ, Li ZW, Wang XZDownregulation of Piwil3 suppresses cell proliferation, migration and invasion in gastric cancer.
Cancer Biomark. 2017; 20(4):499-509 [PubMed
] Related Publications
BACKGROUND: Gastric cancer is one of the most common malignancies worldwide. Recent studies reported that Piwil3 was overexpressed in various cancers, including gastric cancer (GC). This study was intended to investigate its function and mechanism in GC progress.
METHODS: Quantitative real time PCR(RT-PCR) and western blotting assays were utilized to measure mRNA and protein expression levels, respectively. SiRNA transfection was performed to suppress the expression of Piwil3. CCK-8 assay, cell invasion and migration assays were used to determine the cell proliferative, cell invasive and migratory ability.
RESULTS: The expression of Piwil3 was significantly increased in GC tissues compared with matched normal tissues. The specific siRNA significantly inhibited the protein and mRNA expressions of Piwil3, and effectively inhibited the proliferation and induced G0/G1 phase arrest in GC cells. Downregulation of Piwil3 significantly suppressed the migration and invasion of GC cells. Moreover, the downregulation of Piwil3 also significantly suppressed the tumor volumes in nude mice. Mechanism investigation showed that the downregulation of Piwil3 significantly decreased the mRNA and protein expressions of metastasis-related genes, including RhoC, MTA1, MMP2 and MMP9, and also modulated the phosphorylation levels of JAK2 and STAT3 but not their protein levels.
CONCLUSIONS: These findings indicate that overexpression of Piwil3 promotes the proliferation, migration and invasion of GC cells partially through JAK2/STAT3 signal pathway.
Liu Y, Zong ZH, Guan X, et al.The role of long non-coding RNA PCA3 in epithelial ovarian carcinoma tumorigenesis and progression.
Gene. 2017; 633:42-47 [PubMed
] Related Publications
OBJECTIVES: Ovarian carcinoma is one of the highest incidence of tumors in women, and the generation, development and prognosis of epithelial ovarian carcinoma (EOC) remains an open field of study. The role of long non-coding RNAs (lncRNAs) in epithelial ovarian carcinoma is an emerging area of research.
MATERIALS AND METHODS: LncRNA PCA3 expression was determined in EOC and normal ovarian tissues by RT-PCR. Phenotypes indicative of tumor progression and aggressiveness, including cell proliferation, migration, invasion, and expression of related molecules, were analysed in EOC cell following knockdown of lncRNA PCA3 by transfection with small interfering RNA (siRNA).
RESULTS: Expression of lncRNA PCA3 in epithelial ovarian cancer tissues was higher than in normal ovarian tissue. We discovered that knockdown of lncRNA PCA3 in EOC cells by siRNA transfection significantly suppressed cell proliferation, migration, and invasion. Bioinformatic predictions and dual-luciferase reporter assays indicate that the 3'UTR of PCA3 has potential binding sites for miR-106b-5p. Knockdown of the lncRNA PCA3 by siRNA resulted in up-regulated miR-106b expression. In addition, knockdown of PCA3 also reduced protein expression of Ras homolog gene family member C (RhoC), Bcl/xl, P70 ribosomal S6 kinase (P70S6K), and Matrix metallopeptidase 2 (MMP2), which are regulated by miR-106b.
CONCLUSIONS: Research results show that lncRNA PCA3 may coordinate EOC tumorigenesis through disrupting miR-106b regulated gene expression. PCA3 may be a novel and important diagnostic biomarker and a valuable marker for prediction in the clinical care of epithelial ovarian carcinoma.
BACKGROUND: There is increasing evidence in support of the role of lncRNAs in tumor cell proliferation, differentiation and apoptosis.
METHODS: We examined the expression of the lncRNA ABHD11-AS
RESULTS: Expression of the lncRNA ABHD11-AS
CONCLUSIONS: This is the first study to demonstrate the role of RhoC in the tumor-promoting effects of the lncRNA ABHD11-AS
Friedlander P, Wassmann K, Christenfeld AM, et al.Whole-blood RNA transcript-based models can predict clinical response in two large independent clinical studies of patients with advanced melanoma treated with the checkpoint inhibitor, tremelimumab.
J Immunother Cancer. 2017; 5(1):67 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions.
METHODS: Peripheral blood samples were collected in PAXgene® tubes from 210 treatment-naïve melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset). A central panel of radiologists determined objective response using RECIST criteria. Gene expression for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene pre-treatment response-predictive classifier model was identified. An independent population (N = 150) of refractory melanoma patients receiving tremelimumab after chemotherapy enrolled in a worldwide phase II study (validation dataset). The classifier model, using the same genes, coefficients and constants for objective response and one-year survival after treatment, was applied to the validation dataset.
RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17, CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC, TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set. This model was validated in the validation set with AUCs of 0.62 (95% confidence interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year survival (95% confidence interval 0.59 to 0.75 p = 0.0002).
CONCLUSIONS: To our knowledge, this is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response. The data suggest that the model captures a biological signature representative of genes needed for a robust anti-cancer immune response. It also identifies non-responders to tremelimumab at baseline prior to treatment.
Fan FY, Deng R, Yi H, et al.The inhibitory effect of MEG3/miR-214/AIFM2 axis on the growth of T-cell lymphoblastic lymphoma.
Int J Oncol. 2017; 51(1):316-326 [PubMed
] Related Publications
T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy with poor prognosis and high recurrence rate. Long non-coding RNA (lncRNA)-MEG3 is an important tumor suppressor in various cancers. The present study investigated the potential role of maternally expressed gene 3 (MEG3) in the progression of T-LBL. Suppressed expression of MEG3 was detected in T-LBL tissues compared with adjacent histologically normal tissues. Down-regulated level of MEG3 was also found in three T-LBL cell lines (CCRF-CEM, Jurkat and SUP-T1) compared with human T-cell line H9. The proliferation of T-LBL cells was inhibited and cell apoptosis rate was largely promoted when MEG3 was upregulated by a lentiviral vector. Further research revealed that microRNA (miRNA)-214 is a direct target of MEG3. The expression of miR-214 was increased in T-LBL tissues and cell lines compared with control groups. Besides, decreased level of miR-214 was elevated adding miR-214 mimic in SUP-T1 cells transfected with LncRNA-MEG3. Similarly, upregulated level of miR-214 was downregulated adding miR-214 inhibitor in SUP-T1 cells transfected with MEG3 siRNA. Luciferase activity assay further confirmed the targeting relationship between MEG3 and miR-214. Moreover, AIFM2 protein was predicted as a target of miR-214. The expression of AIFM2 was increased by MEG3 and was downregulated by miR-214 mimic. miRNA-214 reversed the effect of MEG3 on inhibiting cell proliferation and inducing cell apoptosis and cell cycle arrest in SUP-T1 cells. Moreover, relative expression of AIFM2 had a positive correlation with the expression of MEG3 and was negatively affected by miR-214. In vivo, MEG3 effectively suppressed tumor growth and the expression of proliferation markers Ki-67 and proliferating cell nuclear antigen (PCNA). Taken together, our research revealed that MEG3 worked as an anti-oncogene in T-LBL, and the MEG3-miR-214-AIFM2 pathway regulated the growth of T-LBL, providing potential prognosis markers as well as new potential targets for T-LBL treatment.
Bora I, Shrivastava NABCs of RhoGTPases indicating potential role as oncotargets.
J Cancer Res Ther. 2017 Jan-Mar; 13(1):2-8 [PubMed
] Related Publications
RhoGTPases also known as molecular switches represent a family of GTP-binding proteins. They shuttle between "On" and "Off" states. In the "On" state, they activate plethora of molecules. These proteins perform a wide variety of functions involving cytoskeletal modeling, cell motility, migration, and mitosis. Members of this family are referred as master regulators of many cellular activities. Due to wide variety of portfolios attributed to RhoGTPases, their misbehavior leads to initiation and also progression of metastatic cancers. Many members of this family have been reported to be differentially regulated leading to spread of malignant cells from one site to other. These wandering cells find a comfortable site in accordance to Paget's soil and seed hypothesis and form secondary lesions. Out of multiple members of this family, RhoA and RhoC are important factors. RhoA is supposed to increase tumor proliferation when overexpressed while RhoC is responsible for tumor initiation. We searched publications on RhoGTPases, their functions and contribution in cancer development and metastasis on World Wide Web and PubMed. This review focuses on the role of Rac and Rho small GTPases in cell motility and granting the opportunistic motile behavior of aggressive cancer cells. To condense knowledge from existing literature about the roles played by these molecular switches, their structural and functional ramifications are introduced in the beginning followed by an account on their wrong behavior that leads to oncogenesis and oncoprogression. This piece of work highlights members of RhoGTPases as viable oncotargets.
Wang X, Liu S, Zhou Z, et al.A herpes simplex virus type 2-encoded microRNA promotes tumor cell metastasis by targeting suppressor of cytokine signaling 2 in lung cancer.
Tumour Biol. 2017; 39(5):1010428317701633 [PubMed
] Related Publications
Certain viruses use microRNAs to regulate the expression of their own genes, host genes, or both. A number of microRNAs expressed by herpes simplex virus type 2 have been confirmed by previous studies. However, whether these microRNAs play a role in the metastasis of lung cancers and how these viral microRNAs precisely regulated the tumor biological process in lung cancer bone metastasis remain obscure. We recently identified the high expression of an acutely and latently expressed viral microRNA, Hsv2-miR-H9-5p, encoded by herpes simplex virus type 2 latency-associated transcript through microarray and quantitative polymerase chain reaction analyses which compared the expression of microRNAs in bone metastasis from lung cancer with primary lung cancers. We now reported that Hsv2-miR-H9-5p was highly expressed in bone metastasis and closely associated with pathological and metastatic processes of lung cancers. The functions of Hsv2-miR-H9-5p were determined by overexpression which results in an increase in survival, migration, and invasion of lung cancer cells in vitro. We determined that Hsv2-miR-H9-5p directly targeted SOCS2 mechanistically by dual-luciferase reporter assay. Then, we investigated the functions of SOCS2 in the progress of lung cancers. Reduction of SOCS2 dosage by hsv2-miR-H9-5p induced increased migration and invasion of lung cancer cells. Overexpression of SOCS2 inverted these phenotypes generated by hsv2-miR-H9-5p, indicating the potential roles of SOCS2 in Hsv2-miR-H9-5p-driven metastasis in lung cancers. The results highlighted that Hsv2-miR-H9-5p regulated and contributed to bone metastasis of lung cancers. We proposed that Hsv2-miR-H9-5p could be used as a potential target in lung cancer therapy.
E2F1 (E2F transcription factor 1) can act as a tumor suppressor or oncogene. We report the molecular mechanism of E2F1 in ovarian carcinoma tumorigenesis and progression. E2F1 expression levels in ovarian carcinoma tissue were examined by immunohistochemistry. After E2F1 plasmid transfection and E2F1-microRNA-519d (miR-519d)/si-RhoC (Ras homolog gene family member C) co-transfection, ovarian cancer cell phenotypes and the related molecules were examined in vitro and in vivo. E2F1 was overexpressed in type I and type II ovarian carcinoma as compared to normal ovary tissues and normal fallopian tube tissues, respectively. E2F1 overexpression promoted cell proliferation, G1-S progression, survival, migration, and invasion in vitro; miR-519d or siRhoC co-transfection reversed E2F1 oncogenic effects. E2F1 overexpression promoted tumor growth in vivo; miR-519d overexpression inhibited it. E2F1 overexpression increased RhoC, Bcl-2, cyclin D1, survivin, MMP2 (matrix metalloproteinase 2), MMP9, STAT3 (signal transducer and activator of transcription 3), and HuR (ELAV-like RNA-binding protein 1) expression; miR-519d overexpression decreased their expression. E2F1 downregulated miR-519d directly and miR-519d downregulated RhoC directly. Conversely, miR-519d directly downregulated E2F1, There is a direct repressive regulatory loop between E2F1 and miR-519d. We provide evidence that E2F1/miR-519d/RhoC is a promising signaling pathway for diagnosing and treating ovarian carcinoma.
He H, Wei Z, Du F, et al.Transcription of HOTAIR is regulated by RhoC-MRTF-A-SRF signaling pathway in human breast cancer cells.
Cell Signal. 2017; 31:87-95 [PubMed
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HOTAIR is a long non-coding RNA highly expressed in cancer tissues and is a negative prognostic factor, whereas the mechanism by which HOTAIR expression is upregulated in cancers remains elusive. In the present study, the regulation of HOTAIR transcription was investigated in breast cancer cells MCF7 and T47D. We found that, when the RhoC-ROCK signaling was disturbed by specific siRNAs or chemical inhibitors, the expression of HOTAIR would be down-regulated. Further, MRTF-A and SRF were found to affect HOTAIR expression. HOTAIR promoter activity was demonstrated to be regulated by the RhoC-MRTF-A-SRF signaling in a CArG-box-dependent manner. Moreover, MRTF-A was identified to physically interact with HOTAIR promoter, and RNA polymerase II association on HOTAIR promoter was enhanced by MRTF-A overexpression. Taken together, our results suggest that HOTAIR is regulated by the RhoC-MRTF-A-SRF signaling pathway in breast cancer cells.
Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. All IBC patients have lymph node involvement and one-third of patients already have distant metastasis at diagnosis. This propensity for metastasis is a hallmark of IBC distinguishing it from less lethal non-inflammatory breast cancers (nIBC). Genetic profiling studies have been conducted to differentiate IBC from nIBC, but no IBC cancer-cell-specific gene signature has been identified. We hypothesized that a tumor-extrinsic factor, notably tumor-associated macrophages, promotes and contributes to IBC's extreme metastatic phenotype. To this end, we studied the effect of macrophage-conditioned media (MCM) on IBC. We show that two IBC cell lines are hyper-responsive to MCM as compared to normal-like breast and aggressive nIBC cell lines. We further interrogated IBC's hyper-responsiveness to MCM using a microfluidic migration device, which permits individual cell migration path tracing. We found the MCM "primes" the IBC cells' cellular machinery to become extremely migratory in response to a chemoattractant. We determined that interleukins -6, -8, and -10 within the MCM are sufficient to stimulate this enhanced IBC migration effect, and that the known metastatic oncogene, RhoC GTPase, is necessary for the enhanced migration response.
Epithelial to mesenchymal transition is a common event during tumour dissemination. However, direct epithelial to amoeboid transition has not been characterized to date. Here we provide evidence that cells from hepatocellular carcinoma (HCC), a highly metastatic cancer, undergo epithelial to amoeboid transition in physiological environments, such as organoids or three-dimensional complex matrices. Furthermore, the NADPH oxidase NOX4 inhibits this transition and therefore suppresses efficient amoeboid bleb-based invasion. Moreover, NOX4 expression is associated with E-cadherin levels and inversely correlated with invasive features. NOX4 is necessary to maintain parenchymal structures, increase cell-cell and cell-to-matrix adhesion, and impair actomyosin contractility and amoeboid invasion. Importantly, NOX4 gene deletions are frequent in HCC patients, correlating with higher tumour grade. Contrary to that observed in mesenchymal cell types, here NOX4 suppresses Rho and Cdc42 GTPase expression and downstream actomyosin contractility. In HCC patients, NOX4 expression inversely correlates with RhoC and Cdc42 levels. Moreover, low expression of NOX4 combined with high expression of either RhoC or Cdc42 is associated with worse prognosis. Therefore, loss of NOX4 increases actomyosin levels and favours an epithelial to amoeboid transition contributing to tumour aggressiveness.
RhoB is a Rho family GTPase that is highly similar to RhoA and RhoC, yet has distinct functions in cells. Its unique C-terminal region is subject to specific post-translational modifications that confer different localization and functions to RhoB. Apart from the common role with RhoA and RhoC in actin organization and cell migration, RhoB is also implicated in a variety of other cellular processes including membrane trafficking, cell proliferation, DNA-repair and apoptosis. RhoB is not an essential gene in mice, but it is implicated in several physiological and pathological processes. Its multiple roles will be discussed in this review.
Haak AJ, Appleton KM, Lisabeth EM, et al.Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma.
Mol Cancer Ther. 2017; 16(1):193-204 [PubMed
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Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed small-molecule inhibitor, CCG-203971, which at low micromolar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971-mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G
The RhoA and RhoC GTPases act via the ROCK1 and ROCK2 kinases to promote actomyosin contraction, resulting in directly induced changes in cytoskeleton structures and altered gene transcription via several possible indirect routes. Elevated activation of the Rho/ROCK pathway has been reported in several diseases and pathological conditions, including disorders of the central nervous system, cardiovascular dysfunctions and cancer. To determine how increased ROCK signalling affected gene expression in pancreatic ductal adenocarcinoma (PDAC) cells, we transduced mouse PDAC cell lines with retroviral constructs encoding fusion proteins that enable conditional activation of ROCK1 or ROCK2, and subsequently performed RNA sequencing (RNA-Seq) using the Illumina NextSeq 500 platform. We describe how gene expression datasets were generated and validated by comparing data obtained by RNA-Seq with RT-qPCR results. Activation of ROCK1 or ROCK2 signalling induced significant changes in gene expression that could be used to determine how actomyosin contractility influences gene transcription in pancreatic cancer.
Sang XB, Sun KX, Wang LL, et al.Effects and mechanism of RhoC downregulation in suppressing ovarian cancer stem cell proliferation, drug resistance, invasion and metastasis.
Oncol Rep. 2016; 36(6):3267-3274 [PubMed
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Cancer stem cells are considered to be the root cause of tumor initiation, metastasis, recurrence and therapeutic resistance. Recent studies have reported that RhoC plays a critical role in regulating cancer stem cells; however, its function in ovarian cancer stem cells (OCSCs) remains unknown. The ovarian cancer cell line A2780, and the paclitaxel-resistant A2780 cell line (A2780-PTX) were obtained. A2780 cells were used to isolate and identify the highly invasive A2780-PM cells, and A2780-PTX cells were used to isolate and identify the highly drug-resistant and highly invasive A2780-PTX-PM cells by Transwell assay. MTT, Transwell and wound healing assays were used to compare the differences in cell proliferation, invasion and migration ability among the four cell lines. Immunofluorescence was used to detect the expression of stem cell markers CD117 and CD133. OCSCs were sorted by flow cytometry. Following si-RhoC transfection of the OCSCs, cell proliferation, drug resistance, invasion and migration ability and RhoC, CD117 and CD133 expression levels were assayed. RT-PCR was used to assess RhoC, CD117, CD133 and matrix metalloproteinase 9 (MMP9) mRNA expression levels. A2780-PM and A2780‑PTX-PM cells exhibited higher cell proliferation, drug resistance, and invasion and migration ability than the A2780 and A2780-PTX cell lines. Furthermore, CD133 and CD117 expression levels were higher in the A2780-PM and A2780‑PTX-PM cells than levels in the A2780 and A2780-PTX cells. Transfection of si-RhoC in OCSCs suppressed the proliferation, drug resistance, invasion, migration and CD117 and CD133 expression levels. Furthermore, the expression levels of RhoC, CD117, CD133, MDR1, and MMP9 mRNA were downregulated in the transfected population. Taken together, our results demonstrated that RhoC downregulation may inhibit the proliferation, drug resistance, invasion and migration of OCSCs, and RhoC may play an important role in the formation of OCSCs.
According to recent research, Ras homolog gene family member C (RhoC) is confirmed to have a powerful regulatory effect on cell motility mediated by the cytoskeleton, and this process is closely associated with tumor invasion and metastasis. In addition, the epithelial-mesenchymal transition (EMT) process which causes cytoskeleton rearrangement, also plays a pivotal role in tumor invasion and metastasis.Consequently, in the present study, we aimed to ascertain whether RhoC has an effect on the EMT process induced by TGF-β1 in lung adenocarcinoma cells and whether RhoC promotes tumor invasion by mediating the occurrence of EMT. Based on the findings, we demonstrated that RhoC was an essential mediator of the EMT process in lung adenocarcinoma cell line A549 which was evaluated by observing the morphological characteristics of the cells and by assessing the expression levels of two EMT marker proteins: E-cadherin and vimentin. During the process of EMT in the A549 cells induced by TGF-β1 (5 ng/ml), upregulated RhoC protein and RhoC activity were detected, which was associated with the enhanced invasive capability of the cells in vitro. Conversely, downregulation of the expression of RhoC by shRNA markedly impeded EMT progression as well as the invasion of A549 cells. Our results may provide a novel target towards the prevention of metastasis in advanced lung adenocarcinoma.
Czapiewski P, Gorczynski A, Radecka K, et al.Expression of SOX11, PAX5, TTF-1 and ISL-1 in medulloblastoma.
Pathol Res Pract. 2016; 212(11):965-971 [PubMed
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The aim of our study was to evaluate the immunohistochemical expression of SOX11, PAX5, TTF-1 and ISL-1 in medulloblastoma (MB) to investigate their diagnostic usefulness.
METHODS: Immunohistochemical expression of PAX5 (two antibodies: Dako, DAK-Pax5; and BD, clone 24), TTF-1 (Dako, 8G7G3/1), SOX11 (CL0142; Abcam) and ISL-1 (1 H9, Abcam) was analyzed using the h-score and Remmele score in 25 cases of MB.
RESULTS: There were 18 MBs of classic and 7 of desmoplastic type. SOX11 was strongly expressed in all tumors. The expression of PAX5 was higher and more frequent in a case of DAK-Pax5 clone (25/25) than clone 24 (6/25). ISL-1 was positive in 11 (44%) and TTF-1 in 3 (12%) cases. ISL-1 expression correlated positively (p<0.001), while TTF-1 correlated negatively with the age of patients (p=0.039). PAX5 expression correlated with ISL-1 (p=0.039) and showed a trend toward higher expression in the desmoplastic subtype (p=0.069).
CONCLUSIONS: SOX11 is strongly and robustly expressed in MBs. PAX5 expression pattern differs substantially among two antibody clones. TTF-1 and ISL-1 is associated with the age of patients.