Gene Summary

Gene:FOXC1; forkhead box C1
Summary:This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein C1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (51)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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

  • siRNA
  • Staging
  • Messenger RNA
  • DNA Methylation
  • Apoptosis
  • Transcriptional Activation
  • Synovial Sarcoma
  • Lung Cancer
  • Biomarkers, Tumor
  • Chromosome 6
  • Single Nucleotide Polymorphism
  • Transcription
  • Cell Proliferation
  • Signal Transduction
  • RT-PCR
  • Gene Knockdown Techniques
  • Promoter Regions
  • Mutation
  • Up-Regulation
  • Neoplasm Invasiveness
  • beta Catenin
  • Cancer Gene Expression Regulation
  • Epithelial-Mesenchymal Transition
  • Forkhead Transcription Factors
  • Drug Resistance
  • Nuclear Proteins
  • Protein Binding
  • Survival Rate
  • RNA Interference
  • Neoplasm Metastasis
  • Neoplastic Cell Transformation
  • Breast Cancer
  • Prostate Cancer
  • Gene Expression Profiling
  • Cell Movement
  • Gene Regulatory Networks
  • MicroRNAs
  • Down-Regulation
  • Triple Negative Breast Cancer
  • Immunohistochemistry
  • Oligonucleotide Array Sequence Analysis
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: FOXC1 (cancer-related)

Cao Q, Wang X, Shi Y, et al.
FOXC1 silencing inhibits the epithelial‑to‑mesenchymal transition of glioma cells: Involvement of β‑catenin signaling.
Mol Med Rep. 2019; 19(1):251-261 [PubMed] Free Access to Full Article Related Publications
Glioma is a type of malignant brain tumor. Forkhead box C1 (FOXC1) is a conserved transcription factor that is involved in tumorigenesis; however, the function of FOXC1 in glioma remains unclear. The present study aimed to investigate the effects of FOXC1 silencing on the epithelial‑to‑mesenchymal transition (EMT) of glioma cells. FOXC1‑specific small interfering RNAs were employed to downregulate the expression levels of FOXC1 in glioma cells. The proliferation, migration and invasion of glioma cells were assessed by MTT assay, wound healing assay and Transwell assay. Western blot analysis was performed to reveal the effects of FOXC1 on EMT‑associated proteins and β‑catenin signaling. The results revealed that, following FOXC1 silencing, the proliferation, migration and invasion of glioma cells were decreased. The expression levels of EMT‑associated proteins were also affected. Further examination demonstrated that β‑catenin signaling was involved in the effects of FOXC1 on glioma cells. Previous results suggested that overexpression of β‑catenin reversed the effects of FOXC1 silencing on glioma cells. The present study demonstrated that FOXC1 may regulate the EMT of glioma cells, potentially via β‑catenin signaling. Therefore, FOXC1 may be a potential therapeutic target for the treatment of glioma.

Khoury H, He R, Schimmer A, et al.
Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia.
Chemotherapy. 2018; 63(4):225-237 [PubMed] Related Publications
Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50-70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi-voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

Raeisi F, Abolfathi M, Ahmadi-Naji R, et al.
ARA lncRNA, is upregulated in liver and breast tumor tissues.
Mol Biol Rep. 2019; 46(1):77-82 [PubMed] Related Publications
Important regulatory roles of long non-coding RNAs (lncRNAs) have been recently found, and reported as useful biomarkers in cancer. To identify a potential expression of the new discovered lncRNA (ARA), during promotes cell proliferation, apoptosis inhibit, migration and cell cycle arrest, we firstly evaluate its expression in two cancer tissues (breast cancer and liver cancer) and then compared its variability expression in tumor versus non-tumor samples. Expression profile of ARA lncRNA was evaluated using qRT-PCR in paired tumor and marginal non-tumor samples collected from patients who had been referred to the Shiraz General. After RNA extraction from tissue samples, cDNA synthesis and RT-qPCR method were performed according to the protocols. ARA lncRNA expression level was calculated using 2

Rassidakis GZ, Herold N, Myrberg IH, et al.
Low-level expression of SAMHD1 in acute myeloid leukemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens.
Blood Cancer J. 2018; 8(11):98 [PubMed] Free Access to Full Article Related Publications
Sterile alpha motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) limits the efficacy of cytarabine (ara-C) used in AML by hydrolyzing its active metabolite ara-CTP and thus represents a promising therapeutic target. SAMHD1 has also been implicated in DNA damage repair that may impact DNA damage-inducing therapies such as anthracyclines, during induction therapy. To determine whether SAMHD1 limits ara-C efficacy during induction or consolidation therapy, SAMHD1 protein levels were assessed in two patient cohorts of de novo AML from The University of Texas MD Anderson Cancer Center (USA) and the National University Hospital (Singapore), respectively, using immunohistochemistry and tissue microarrays. SAMHD1 was expressed at a variable level by AML blasts but not in a broad range of normal hematopoietic cells in reactive bone marrows. A sizeable patient subset with low SAMHD1 expression (<25% of positive blasts) was identified, which was significantly associated with longer event-free (EFS) and overall (OS) survival in patients receiving high-dose cytarabine (HDAC) during consolidation. Therefore, evaluation of SAMHD1 expression level in AML blasts at diagnosis, may stratify patient groups for future clinical trials combining HDAC with novel SAMHD1 inhibitors as consolidation therapy.

Yan B, Chen Q, Shimada K, et al.
Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia.
Leukemia. 2019; 33(4):931-944 [PubMed] Related Publications
Chemoresistance may be due to the survival of leukemia stem cells (LSCs) that are quiescent and not responsive to chemotherapy or lie on the intrinsic or acquired resistance of the specific pool of AML cells. Here, we found, among well-established LSC markers, only CD123 and CD47 are correlated with AML cell chemosensitivities across cell lines and patient samples. Further study reveals that percentages of CD123

Cao S, Wang Z, Gao X, et al.
FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC.
J Exp Clin Cancer Res. 2018; 37(1):220 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidence suggests that cancer stem cells (CSCs) play a critical role in tumor initiation, progression and therapy, and recent studies have indicated that Forkhead box C1 (FOXC1) is strongly associated with CSCs. This study investigates the regulatory effects of FOXC1 on CSC-like properties in non-small cell lung cancer (NSCLC).
METHODS: We analyzed FOXC1 expression in NSCLC using the Cancer Genome Atlas (TCGA) database on UALCANC and performed survival analyses of NSCLC patients on Human Protein Atlas. CSC-like properties were analyzed based on CSC marker-positive cell population, self-renewal ability, stemness-related gene expression, tumorigenicity and drug resistance. The percentage of CD133
RESULTS: FOXC1 expression was found to be elevated in NSCLC tissues and negatively correlated with patient survival. FOXC1 knockdown reduced CD133
CONCLUSIONS: This study demonstrates that FOXC1 induces CSC-like properties in NSCLC by promoting beta-catenin expression. The findings indicate that FOXC1 is a potential molecular target for anti-CSC-based therapies in NSCLC.

Li Q, Wei P, Wu J, et al.
The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect.
Oncogene. 2019; 38(4):483-496 [PubMed] Related Publications
Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC.

Tang C, Li MH, Chen YL, et al.
Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia.
J Exp Clin Cancer Res. 2018; 37(1):204 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear.
METHODS: We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry.
RESULTS: The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs.
CONCLUSIONS: Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.

Li J, Choi PS, Chaffer CL, et al.
An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation of distinct protein products with diverse functions. In a genome-scale expression screen for inducers of the epithelial-to-mesenchymal transition (EMT), we found a striking enrichment of RNA-binding proteins. We validated that QKI and RBFOX1 were necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity. Using RNA-seq and eCLIP analysis, we found that QKI and RBFOX1 coordinately regulated the splicing and function of the actin-binding protein FLNB, which plays a causal role in the regulation of EMT. Specifically, the skipping of FLNB exon 30 induced EMT by releasing the FOXC1 transcription factor. Moreover, skipping of FLNB exon 30 is strongly associated with EMT gene signatures in basal-like breast cancer patient samples. These observations identify a specific dysregulation of splicing, which regulates tumor cell plasticity and is frequently observed in human cancer.

Chen P, Zhu KW, Zhang DY, et al.
Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens.
J Transl Med. 2018; 16(1):197 [PubMed] Free Access to Full Article Related Publications
BACKGROUNDS: UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver.
METHODS: UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated.
RESULTS: After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10
CONCLUSION: Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

Zuo H, Yang Q
The potential pathway of FOXC1 high expression in regulating the proliferation, migration, cell cycle and epithelialmesenchymal transition of basal-like breast cancer and in vivo imaging.
J BUON. 2018 May-Jun; 23(3):720-728 [PubMed] Related Publications
PURPOSE: To investigate the role of high forkhead box C1 (FOXC1) expression in basal-like breast cancer (BLBC) cells in vitro and in vivo, as well as its potential regulatory pathway.
METHODS: Stable MDA-MB-231 cells, a type of BLBC cells, with high FOXC1 expression and luciferase (FOXC1) were established. The parental MDA-MB-231 cells with luciferase served as the control group. Proliferation, migratory capabilities and the cell cycle were evaluated. The tumorigenicity and the spontaneous pulmonary metastasis were measured in mice in vivo. In vivo imaging was also performed. Histopathology, immunohistochemical analysis and microarray processing were evaluated. Paired Student's t-test was used.
RESULTS: The proliferation and migratory ability of FOXC1- MDA-MB-231 cells were enhanced significantly (p<0.05). Spontaneous pulmonary metastases were observed in 2 out of 5 mice, but no pulmonary metastases were observed in control animals. There were more FOXC1 cells in the G1 phase compared to the control (p<0.05), but there were also significant reductions of cells in the S and G2 phases (p<0.05). The CD31 and endoglin (CD105) expression in the FOXC1 tumor was higher than in the control, especially CD105 (p<0.05). The total fluorescence expression quantity of FOXC1 was higher than in the control cells (p<0.05), and the apparent diffusion coefficient (ADC) values were lower compared with the control (p<0.05). One pathway with the most gene enrichment (p38 MAPK signalling) may play a key role in regulating BLBC cell proliferation, migration, cell cycle and epithelial-mesenchymal transition (EMT) through the interaction of related critical regulatory genes (IL-6 and FOXC1).
CONCLUSION: High FOXC1 enhanced the proliferation, migratory ability and EMT of BLBC cells. This function may be regulated by IL-6 and FOXC1 through the p38 MAPK signalling pathway.

Hirukawa A, Smith HW, Zuo D, et al.
Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program.
Nat Commun. 2018; 9(1):2547 [PubMed] Free Access to Full Article Related Publications
Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. Here we report that genetic or pharmacological targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behaviour in both a mouse model of breast cancer and patient-derived xenografts reflective of the Luminal B subtype. We further define a subtype-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, anti-invasive transcriptional program. We demonstrate that higher FOXC1 is predictive of favourable outcome specifically in Luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in Luminal B breast cancer, where options for targeted therapy are limited.

Liu J, Zhang Z, Li X, et al.
Forkhead box C1 promotes colorectal cancer metastasis through transactivating ITGA7 and FGFR4 expression.
Oncogene. 2018; 37(41):5477-5491 [PubMed] Related Publications
Metastatic colorectal cancer (CRC) is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying CRC metastasis remains unknown. Using an integrated approach, we identified forkhead box C1 (FOXC1) as a novel regulator of CRC metastasis. Elevated expression of FOXC1 is significantly correlated with metastasis, recurrence and reduced survival. FOXC1 overexpression promotes CRC invasion and lung metastasis, whereas FOXC1 knockdown has the opposite effect. In addition, FOXC1 directly binds its target genes integrin α7 (ITGA7) and fibroblast growth factor receptor 4 (FGFR4) and activates their expression. Genetic epistasis analysis confirmed that ITGA7 and FGFR4 act downstream of FOXC1. Furthermore, pharmaceutical inhibition of FGFR4 can reverse CRC metastasis mediated by FOXC1 overexpression. These results suggest that FOXC1 is a prognostic biomarker in CRC patients and targeting the FGFR4 signaling pathway may provide a promising strategy for the treatment of FOXC1-driven CRC metastasis.

Forma E, Jóźwiak P, Ciesielski P, et al.
Impact of OGT deregulation on EZH2 target genes FOXA1 and FOXC1 expression in breast cancer cells.
PLoS One. 2018; 13(6):e0198351 [PubMed] Free Access to Full Article Related Publications
Enhancer of zest homolog 2 (EZH2) is a histone methyltransferase which plays a crucial role in cancer progression by regulation of genes involved in cellular processes such as proliferation, invasion and self-renewal. Activity and biological function of EZH2 are regulated by posttranslational modifications. It is suggested that EZH2 stability may be regulated by O-GlcNAc transferase (OGT), which is an enzyme catalyzing the addition of GlcNAc moieties to target proteins. In this study, we determined the impact of OGT on expression of EZH2 target genes FOXA1 and FOXC1, that are involved in breast cancer progression. The results of chromatin immunoprecipitation experiments showed that both EZH2 and OGT are targeted to the promoter regions of FOXA1 and FOXC1 and knockdown of EZH2 or OGT affects expression of studied genes in breast non-malignant (MCF10A) and cancer cells (MCF7, T47D and MDA-MB-231). The results showed that OGT silencing affects EZH2 binding to FOXC1 promoter but the effect is cell-context dependent. Despite the slight decrease in EZH2 protein level in cells with OGT depletion, EZH2 binding to FOXC1 was increased. Moreover, OGT binding to promoter regions of FOXA1 and FOXC1 was increased in cells with knockdown of EZH2. Increased expression of FOXA1 and FOXC1 in cells with OGT deregulation was associated with increased acetylation level of histone H3. The results suggest that OGT is involved in regulation of FOXA1 and FOXC1 expression but its role is not associated with regulation of EZH2 protein stability.

Ortea I, González-Fernández MJ, Ramos-Bueno RP, Guil-Guerrero JL
Proteomics Study Reveals That Docosahexaenoic and Arachidonic Acids Exert Different In Vitro Anticancer Activities in Colorectal Cancer Cells.
J Agric Food Chem. 2018; 66(24):6003-6012 [PubMed] Related Publications
Two polyunsaturated fatty acids, docosahexaenoic acid (DHA) and arachidonic acid (ARA), as well as derivatives, such as eicosanoids, regulate different activities, affecting transcription factors and, therefore, DNA transcription, being a critical step for the functioning of fatty-acid-derived signaling. This work has attempted to determine the in vitro anticancer activities of these molecules linked to the gene transcription regulation of HT-29 colorectal cancer cells. We applied the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test along with lactate dehydrogenase and caspase-3 assays; proteome changes were assessed by "sequential windowed acquisition of all theoretical mass spectra" quantitative proteomics, followed by pathway analysis, to determine the affected molecular mechanisms. In all assays, DHA inhibited cell proliferation of HT-29 cells to a higher extent than ARA and acted primarily by downregulating proteasome particles, while ARA presented a dramatic effect on all six DNA replication helicase particles. The results indicated that both DHA and ARA are potential chemopreventive agent candidates.

Wu J, Jiang Z, Chen C, et al.
CircIRAK3 sponges miR-3607 to facilitate breast cancer metastasis.
Cancer Lett. 2018; 430:179-192 [PubMed] Related Publications
As a class of endogenous noncoding RNAs, circular RNAs (circRNAs) have been recently identified to regulate tumourigenesis and progression in multiple malignancies. However, the expression profiles and function of circRNAs in breast cancer metastasis are largely unknown. Here, we determined that the expression of a novel circRNA, which we named circIRAK3, was increased in metastatic breast cancer (BC) cells and predictive of BC recurrence. Gain-of-function and loss-of-function studies in BC cells demonstrated that circIRAK3 promoted cell migration, invasion and metastasis in vitro and in vivo but did not affect cell proliferation, colony formation or cell cycle progression. Using circIRAK3 in vivo precipitation and luciferase reporter assays, we identified miR-3607 as a circIRAK3-associated miRNA. Furthermore, RNA sequencing and bioinformatics analysis showed that forkhead box C1 (FOXC1), the target of miR-3607, was downregulated in circIRAK3-silenced cells and mediated circIRAK3-induced BC cell migration. Intriguingly, FOXC1 could, in turn, bind to the IRAK3 promoter, triggering a positive-feedback loop that perpetuated the circIRAK3/miR-3607/FOXC1 signaling axis. Collectively, our findings indicated that circIRAK3 may exert regulatory roles in BC metastasis and may be a potential target for metastatic BC therapy.

Guo W, Jin J, Pan J, et al.
The change of nuclear LC3 distribution in acute myeloid leukemia cells.
Exp Cell Res. 2018; 369(1):69-79 [PubMed] Related Publications
Making sure the change of nuclear LC3 distribution in the autophagy of acute myeloid leukemia (AML) cell and finding out the regulation mechanism may lead to a breakthrough for killing AML cells. Western blots were performed to assess the expression of autophagy proteins. Changes in the LC3 distribution were monitored by immunofluorescence assays together with western blots, and the expression levels of Sirt1, DOR, Beclin1, HMGB1, and AMPK mRNA were detected via fluorescent quantitative PCR. The effects of Sirt1 and DOR on cell proliferation and survival were analyzed by MTT, flow cytometry, and western blotting assays. We found that treating AML cells with Ara-c or Sorafenib resulted in autophagy enhancement, and when autophagy was enhanced, nuclear LC3 moved into the cytoplasm. Notably, when autophagy was inhibited by blocking the nuclear LC3 shift, the cytotoxicity of drugs was enhanced. Our results also identified Sirt1 and DOR as regulatory molecules for the observed nuclear LC3 shift, and these molecules further affected the expression of Beclin1, HMGB1, and AMPK. Our results suggest the distribution of nuclear LC3 can be a novel way for further studying death of AML cells,and the regulatory molecules may be new targets for treating AML.

Xu XF, Cheng RB, Zhang XJ, Gao RL
Total Saponins of Rubus Parvifolius L. Exhibited Anti-Leukemia Effect in vivo through STAT3 and eIF4E Signaling Pathways.
Chin J Integr Med. 2018; 24(12):920-924 [PubMed] Related Publications
OBJECTIVE: To investigate the anti-leukemia effect of total saponins of Rubus parvifolius L. (TSRP) on K562 cell xenografts in nude mice and the mechanisms of action.
METHODS: The K562 cell xenografts in nude mice were established, and then randomly divided into 5 groups, the control group, the cytosine arabinoside group(Ara-c) and 3 TSRP groups (20, 40 and 100 mg/kg). The tumor volume and mass of each group of nude mice were measured and the anti-tumor rates of TSRP were calculated subsequently. The apoptosis status of tumor cells was detected by hematoxylin-eosin (HE) and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining analysis. Finally, the activities of apoptosis related signaling of signal transducer and activator of transcription 3 (STAT3), eukaryotic initiation factor 4E (eIF4E) and B-cell lymphoma-2 (bcl-2) were determined with immunohistochemistry tests.
RESULTS: Subcutaneous injection of K562 cells induced tumor formation in nude mice, and the TSRP treated group showed a signifificant inhibitory effect on tumor formation. The nude mice treated with TSRP showed a signifificant decrease in tumor growth rate and tumor weight in comparison to the control group (all P<0.05). The HE staining and TUNEL assay showed that TSRP induced cell death by apoptosis. The immunohistochemical assay showed down-regulation of the bcl-2 gene in the TSRP treated cells. The phosphorylation levels of eIF4E and STAT3 were decreased obviously after the treatment of TSRP.
CONCLUSION: TSRP had an excellent tumor-suppressing effect on K562 cells in the nude mice xenograft model, suggesting that TSPR can be developed as a promising anti-chronic myeloide leukemia drug.

Zhu KW, Chen P, Zhang DY, et al.
Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML).
J Transl Med. 2018; 16(1):90 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP.
METHODS: A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed.
RESULTS: Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients.
CONCLUSION: Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

Fanciullino R, Farnault L, Donnette M, et al.
CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine.
Blood Adv. 2018; 2(5):462-469 [PubMed] Free Access to Full Article Related Publications
Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the

Huang M, Inukai T, Miyake K, et al.
Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression.
Cancer Med. 2018; 7(4):1297-1316 [PubMed] Free Access to Full Article Related Publications
Cytosine arabinoside (Ara-C) is one of the key drugs for the treatment of acute myeloid leukemia. It is also used for consolidation therapy of acute lymphoblastic leukemia (ALL). Ara-C is a deoxyadenosine analog and is phosphorylated to form cytosine arabinoside triphosphate (Ara-CTP) as an active form. In the first step of the metabolic pathway, Ara-C is phosphorylated to Ara-CMP by deoxycytidine kinase (DCK). However, the current cumulative evidence in the association of the Ara-C sensitivity in ALL appears inconclusive. We analyzed various cell lines for the possible involvement of DCK in the sensitivities of B-cell precursor ALL (BCP-ALL) to Ara-C. Higher DCK expression was associated with higher Ara-C sensitivity. DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced marked resistance to Ara-C, but not to vincristine and daunorubicin, indicating the involvement of DCK expression in the Ara-C sensitivity of BCP-ALL. DCK gene silencing due to the hypermethylation of a CpG island and reduced DCK activity due to a nonsynonymous variant allele were not associated with Ara-C sensitivity. Clofarabine is a second-generation deoxyadenosine analog rationally synthesized to improve stability and reduce toxicity. The IC50 of clofarabine in 79 BCP-ALL cell lines was approximately 20 times lower than that of Ara-C. In contrast to Ara-C, although the knockout of DCK induced marked resistance to clofarabine, sensitivity to clofarabine was only marginally associated with DCK gene expression level, suggesting a possible efficacy of clofarabine for BCP-ALL that shows relative Ara-C resistance due to low DCK expression.

Peng J, Fu B, Fu G, et al.
Effect of NPM1 type B mutation on the proliferation, invasion and chemosensitivity of THP-1 leukemia cells.
Pharmazie. 2017; 72(10):608-613 [PubMed] Related Publications
Acute myeloid leukemia (AML) is the most malignant myeloid disorder in adults. AML with mutated nucleophosmin (NPM1) is regarded as an independent leukemia subtype. According to previous studies, the role of NPM1 gene A mutation in AML has been well established; however, another major type, NPM1 gene B type mutation (NPM1 MutB) has been rarely reported. In the present study, we found that overexpression of NPM1 MutB enhanced the proliferation and invasion of THP-1 AML cells through the regulation of TIMP-2, MMP-2, Ang-1, c-myc and CCND1; led to no significant change of apoptosis rate with the absence of chemotherapy agents, while enhanced the chemosensitivity of THP-1 AML cells to chemotherapy agents DNR and Ara-C through the regulation of Bax, Bcl-2 and caspase-3. Further, we revealed that NPM1 MutB overexpression reduced the NF-κB activity of THP-1 cells upon drug treatment. Taken together, we demonstrated the detailed functions of NPM1MutB in THP-1 proliferation, invasion, apoptosis and chemo-sensitivity. We provided a novel understanding of prognosis of patients carrying the NPM1 B mutation.

Wang YT, Yuan B, Chen HD, et al.
Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression.
Cancer Sci. 2018; 109(3):821-831 [PubMed] Free Access to Full Article Related Publications
With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46-71.78-fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi-treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6-8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

Wang X, Hu Y, Cui J, et al.
Coordinated targeting of MMP-2/MMP-9 by miR-296-3p/FOXCUT exerts tumor-suppressing effects in choroidal malignant melanoma.
Mol Cell Biochem. 2018; 445(1-2):25-33 [PubMed] Related Publications
Choroidal melanoma is the most common intraocular tumor in adults, and overexpression of matrix metalloproteinase-2 or matrix metalloproteinase-9 (MMP-2/MMP-9) is associated with angiogenesis and tumor metastasis of the choroidal malignant melanoma (CMM). This study aims to investigate the functions and mechanisms of microRNA or long non-coding RNA-targeted MMP-2/MMP-9 in CMM. We demonstrated that expressions of MMP-2/MMP-9 were increased in CMM tissues and C918 cells in comparison with normal choroidal melanocytes. Bio-informatics prediction and our experiments validated that MMP-2 and MMP-9 were simultaneously targeted by miR-296-3p and FOXC1 promoter upstream transcript (FOXCUT); the latter two exerted tumor-suppressing effects on CMM cells by inhibiting cell proliferation, cell cycle progression, migration, invasion, and induction of cell apoptosis. Furthermore, significant downregulations of miR-296-3p and FOXCUT were found in C918 cells compared with choroidal melanocytes from the unaffected eyes, and a positive correlation was observed between their levels in three cases of eye malignant melanomas. Our data indicated that MMP-2/MMP-9 was coordinately targeted by two non-coding RNAs, miR-296-3p and FOXCUT, which were decreased, and tumor-suppressing factors in CMM. Further study will show the possibility of developing them as therapeutic candidates for CMM.

Han B, Zhou B, Qu Y, et al.
FOXC1-induced non-canonical WNT5A-MMP7 signaling regulates invasiveness in triple-negative breast cancer.
Oncogene. 2018; 37(10):1399-1408 [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancer (TNBC) has high rates of local recurrence and distant metastasis, partially due to its high invasiveness. The Forkhead box C1 (FOXC1) transcription factor has been shown to be specifically overexpressed in TNBC and associated with poor clinical outcome. How TNBC's high invasiveness is driven by FOXC1 and its downstream targets remains poorly understood. In the present study, pathway-specific PCR array assays revealed that WNT5A and matrix metalloproteinase-7 (MMP7) were upregulated by FOXC1 in TNBC cells. Interestingly, WNT5A mediates the upregulation of MMP7 by FOXC1 and the WNT5A-MMP7 axis is essential for FOXC1-induced invasiveness of TNBC cells in vitro. Xenograft models showed that the lung extravasation and metastasis of FOXC1-overexpressing TNBC cells were attenuated by knocking out WNT5A, but could be restored by MMP7 overexpression. Mechanistically, FOXC1 can bind directly to the WNT5A promoter region to activate its expression. Engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), coupled with mass spectrometry, identified FOXC1-interacting proteins including a group of heterogeneous nuclear ribonucleoproteins involved in WNT5A transcription induction. Finally, we found that WNT5A activates NF-κB signaling to induce MMP7 expression. Collectively, these data demonstrate a FOXC1-elicited non-canonical WNT5A signaling mechanism comprising NF-κB and MMP7 that is essential for TNBC cell invasiveness, thereby providing implications toward developing an effective therapy for TNBC.

Zhou P, Wang C, Hu Z, et al.
Genistein induces apoptosis of colon cancer cells by reversal of epithelial-to-mesenchymal via a Notch1/NF-κB/slug/E-cadherin pathway.
BMC Cancer. 2017; 17(1):813 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genistein has been known to inhibit proliferation and induce apoptosis in several kinds of cancer cells. While knowledge of genistein in regulating epithelial mesenchymal transition (EMT) of colon cancer cells is unknown.
METHODS: To investigate the effects and mechanisms of genistein on EMT of colon cancer cells, HT-29 cells were used and treated by genistein and TNF-α in this paper. EMT was determined by cell invasion assays using a transwell chamber and the expression changes of EMT-related markers were confirmed by RT-PCR, Western blotting, and immunofluorescence staining.
RESULTS: Genistein inhibited cell migration at 200 μmol/L. Genistein reversed the EMT of colon cancer cells by upregulation of E-cadherin and downregulation of N-cadherin, accompanied by the suppression of EMT related makers, such as Snail2/slug, ZEB1, ZEB2, FOXC1, FOXC2 and TWIST1. Moreover, genistein can inhibit the expression of notch-1, p-NF-κB and NF-κB, while promote the expression of Bax/Bcl-2 and caspase-3 in HT-29 cells.
CONCLUSION: The present study demonstrated that genistein suppressed the migration of colon cancer cells by reversal the EMT via suppressing the Notch1/NF-κB/slug/E-cadherin pathway. Genistein may be developed as a potential antimetastasis agent to colon cancer.

Telerman A, Amson R
Introduction: How We Encountered TCTP and Our Purpose in Studying It.
Results Probl Cell Differ. 2017; 64:1-8 [PubMed] Related Publications
In this brief introduction, we describe our encounter with TCTP. Back in 2000, we discovered TCTP in two quite different ways: first, we looked at protein partners of TSAP6 and one of them was TCTP. Then, in collaboration with Sidney Brenner, we performed a high-throughput differential screening comparing the parental cancer cells with revertants. The results indicated that TCTP was of the most differentially expressed genes. These two approaches were carried out only months apart. They guided our research and led to the discoveries of drugs that inhibit the function of TCTP. Much of the preclinical data on sertraline as an inhibitor of TCTP in cancer were obtained with Judith Karp at Johns Hopkins. This drug is now given in combination with Ara-C to patients in a phase I clinical trial for Acute Myeloid Leukemia. We will here detail how all this happened in our lab while working around one central project: tumor reversion.

Cao HX, Miao CF, Yan L, et al.
Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients.
J Transl Med. 2017; 15(1):235 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene polymorphisms at microRNA-binding sites (poly-miRTS) may affect gene transcription and expression through miRNA regulation, which is associated with cancer susceptibility, sensitivity to chemotherapy and prognosis. This study investigated the association between poly-miRTS of Ara-C/anthracycline metabolic pathways genes and the outcome of acute myeloid leukemia (AML) in Chinese patients after Ara-C-based chemotherapy.
METHODS: A total of 17 poly-miRTS were selected from the SNPinfo Web Server and genotyped in 206 Chinese Han non-FAB-M3 AML patients using the SEQUENOM Mass-ARRAY system.
RESULTS: Among these 17 poly-miRTS, five Ara-C metabolic gene single nucleotide polymorphisms (SNPs, NT5C2 rs10786736 and rs8139, SLC29A1 rs3734703, DCTD rs7278, and RRM1 rs1042919) were identified to significantly associate with complete AML remission and/or overall and relapse-free survival (OS and RFS, respectively), and four anthracycline-metabolic gene SNPs (ABCC1 rs3743527, rs212091, and rs212090 and CBR1 rs9024) were significantly associated with chemotherapy-related toxicities. Moreover, SLC29A1 rs3734703 was shown to associate with both chemotherapy response and survival (adjusted OR 2.561 in the overdominant model; adjusted HR 2.876 for OS and 2.357 for RFS in the dominant model).
CONCLUSIONS: The data from the current study demonstrated that the poly-miRTS of Ara-C/anthracyclines metabolic genes predicted the sensitivity and side effects of AML to Ara-C-based chemotherapy and patient survival. Further study will confirm them as biomarkers for AML patients after Ara-C-based chemotherapy.

Cagnetta A, Soncini D, Orecchioni S, et al.
Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.
Haematologica. 2018; 103(1):80-90 [PubMed] Free Access to Full Article Related Publications
Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD

Deb S, Gorringe KL, Pang JB, et al.
BRCA2 carriers with male breast cancer show elevated tumour methylation.
BMC Cancer. 2017; 17(1):641 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs.
METHODS: 60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.
RESULTS: Tumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARβ methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival.
CONCLUSIONS: Increased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types.

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