Research IndicatorsGraph generated 02 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 02 September, 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).
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: FOXM1 (cancer-related)
Dusek J, Skoda J, Holas O, et al.Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
Toxicol Lett. 2019; 313:1-10 [PubMed
] Related Publications
The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.
Emerging evidence has demonstrated that microRNAs (miRNAs/miRs) have various biological functions in the development of human epidermal growth factor receptor 2 (HER2) positive breast cancer. The aim of the present study is to reveal the mechanism of miR‑193a‑3p inhibiting the progress of HER2 positive breast cancer. The expression of miR‑193a‑3p was evaluated by quantitative polymerase chain reaction (PCR). The methylation status of miR‑193a‑3p was evaluated by PCR and pyrosequencing analysis. Overexpression of miR‑193a‑3p and growth factor receptor bound protein 7 (GRB7) combined with in vitro tumorigenic assays were conducted to determine the carcinostatic capacities of miR‑193a‑3p in HER2 positive breast cancer cells. The association between miR‑193a‑3p and GRB7 was determined by luciferase reporter assay. Protein level was evaluated using western blot analysis. miR‑193a‑3p was downregulated in HER2 positive breast cancer cells and clinical tissues. Methylation‑mediated silencing led to decreased expression of miR‑193a‑3p in HER2 positive breast cancer. Overexpression of miR‑193a‑3p could inhibit proliferation, migration and invasion of breast cancer cells. Overexpression of GRB7 could abolish this effect. miR‑193a‑3p could directly target the 3' untranslated region of GRB7. miR‑193a‑3p could directly or indirectly target extracellular signal‑regulated kinase 1/2 (ERK1/2) and forkhead box M1 (FOXM1) signaling. In conclusion, it was identified that silencing of miR‑193a‑3p through hypermethylation can promote HER2 positive breast cancer progress by targeting GRB7, ERK1/2 and FOXM1 signaling. The function of miR‑193a‑3p in HER2 positive breast cancer implicates its potential application in therapy.
Sun L, Wang Y, Wang L, et al.Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP.
J Exp Clin Cancer Res. 2019; 38(1):170 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Cancer stem cells (CSCs) require stromal signals for maintaining pluripotency and self-renewal capacities to confer tumor metastasis. Resolvin D1 (RvD1), an endogenous anti-inflammatory lipid mediator, has recently been identified to display anti-cancer effects by acting on stroma cells. Our previous study reveals that hepatic stellate cells (HSCs)-derived cartilage oligomeric matrix protein (COMP) contributes to hepatocellular carcinoma (HCC) progression. However, whether RvD1 inhibits paracrine of cancer-associated fibroblasts (CAFs)-derived COMP to prevent epithelial-mesenchymal transition (EMT) and cancer stemness in HCC remains to be elucidated.
METHODS: CAFs were isolated from HCC tissues. Direct and indirect co-culture models were established to analyze the interactions between HCC cells and CAFs in the presence of RvD1 in vitro. The transwell and tumor sphere formation assays were used to determine invasion and stemness of HCC cells. The subcutaneous tumor formation and orthotopic liver tumor models were established by co-implantation of CAFs and HCC cells to evaluate the role of RvD1 in vivo. To characterize the mechanism of RvD1 inhibited paracrine of COMP in CAFs, various signaling molecules were analyzed by ELISA, western blotting, reactive oxygen species (ROS) detection, immunofluorescence staining, dual luciferase reporter assay and chromatin immunoprecipitation assay.
RESULTS: Our data revealed that RvD1 treatment can impede the CAFs-induced cancer stem-like properties and the EMT of HCC cells under co-culture conditions. In vivo studies indicated that RvD1 intervention repressed the promoting effects of CAFs on tumor growth and metastasis of HCC. Furthermore, RvD1 inhibited CAF-induced EMT and stemness features of HCC cells by suppressing the secretion of COMP. Mechanistically, formyl peptide receptor 2 (FPR2) receptor mediated the suppressive effects of RvD1 on COMP and forkhead box M1 (FOXM1) expression in CAFs. Notably, RvD1 impaired CAF-derived COMP in a paracrine manner by targeting FPR2/ROS/FOXM1 signaling to ultimately abrogate FOXM1 recruitment to the COMP promoter.
CONCLUSION: Our results indicated that RvD1 impaired paracrine of CAFs-derived COMP by targeting FPR2/ROS/FOXM1 signaling to repress EMT and cancer stemness in HCC. Thus, RvD1 may be a potential agent to promote treatment outcomes in HCC.
Pituitary adenoma is one of the most common tumors in the neuroendocrine system. This study investigated the effects of long non-coding RNAs (lncRNAs) highly up-regulated in liver cancer (HULC) on rat secreting pituitary adenoma GH3 cell viability, migration, invasion, apoptosis, and hormone secretion, as well as the underlying potential mechanisms. Cell transfection and qRT-PCR were used to change and measure the expression levels of HULC, miR-130b, and FOXM1. Cell viability, migration, invasion, and apoptosis were assessed using trypan blue staining assay, MTT assay, two-chamber transwell assay, Guava Nexin assay, and western blotting. The concentrations of prolactin (PRL) and growth hormone (GH) in culture supernatant of GH3 cells were assessed using ELISA. The targeting relationship between miR-130b and FOXM1 was verified using dual luciferase activity. Finally, the expression levels of key factors involved in PI3K/AKT/mTOR and JAK1/STAT3 pathways were evaluated using western blotting. We found that HULC was highly expressed in GH3 cells. Overexpression of HULC promoted GH3 cell viability, migration, invasion, PRL and GH secretion, as well as activated PI3K/AKT/mTOR and JAK1/STAT3 pathways. Knockdown of HULC had opposite effects and induced cell apoptosis. HULC negatively regulated the expression of miR-130b, and miR-130b participated in the effects of HULC on GH3 cells. FOXM1 was a target gene of miR-130b, which was involved in the regulation of GH3 cell viability, migration, invasion, and apoptosis, as well as PI3K/AKT/mTOR and JAK1/STAT3 pathways. In conclusion, HULC tumor-promoting roles in secreting pituitary adenoma might be via down-regulating miR-130b, up-regulating FOXM1, and activating PI3K/AKT/mTOR and JAK1/STAT3 pathways.
Gao F, Feng J, Yao H, et al.LncRNA SBF2-AS1 promotes the progression of cervical cancer by regulating miR-361-5p/FOXM1 axis.
Artif Cells Nanomed Biotechnol. 2019; 47(1):776-782 [PubMed
] Related Publications
Long non-coding RNAs (lncRNAs) have been identified as critical players in tumorigenesis. Previous studies revealed that lncRNA SBF2-AS1 was involved in tumor progression. However, the role and underlying mechanism of SBF2-AS1 in cervical cancer (CC) remain unknown. In the present study, our data showed that SBF2-AS1 expression was significantly increased in CC. High SBF2-AS1 expression was associated with advanced FIGO stage and lymph node metastasis of CC patients. Function assays showed that SBF2-AS1 inhibition significantly reduced CC cells proliferation both in vitro and in vivo. Mechanistically, we showed that SBF2-AS1 upregulation restrained the activity of miR-361-5p and led to overexpression of FOXM1 in CC cells. Furthermore, we found that miR-361-5p inhibitors could rescue the effects of SBF2-AS1 inhibition on CC cells proliferation. Taken together, we demonstrated that the SBF2-AS1/miR-361-5p/FOXM1 axis might play an important role in CC progression. SBF2-AS1 might serve as a potential therapeutic target for CC treatment.
Colorectal cancer (CRC) is the third most commonly occurring cancer worldwide and the fourth most frequent cause of death having an oncological origin. It has been found that transcription factors (TF) dysregulation, leading to the significant expression modifications of genes, is a widely distributed phenomenon regarding human malignant neoplasias. These changes are key determinants regarding tumour's behaviour as they contribute to cell differentiation/proliferation, migration and metastasis, as well as resistance to chemotherapeutic agents. The forkhead box (FOX) transcription factor family consists of an evolutionarily conserved group of transcriptional regulators engaged in numerous functions during development and adult life. Their dysfunction has been associated with human diseases. Several FOX gene subgroup transcriptional disturbances, affecting numerous complex molecular cascades, have been linked to a wide range of cancer types highlighting their potential usefulness as molecular biomarkers. At least 14 FOX subgroups have been related to CRC pathogenesis, thereby underlining their role for diagnosis, prognosis and treatment purposes.This manuscript aims to provide, for the first time, a comprehensive review of FOX genes' roles during CRC pathogenesis. The molecular and functional characteristics of most relevant FOX molecules (FOXO, FOXM1, FOXP3) have been described within the context of CRC biology, including their usefulness regarding diagnosis and prognosis. Potential CRC therapeutics (including genome-editing approaches) involving FOX regulation have also been included. Taken together, the information provided here should enable a better understanding of FOX genes' function in CRC pathogenesis for basic science researchers and clinicians.
The comprehensive screening of intracellular and extracellular microRNAs was performed to identify novel tumor suppressors. We found that miR-8073 was present in exosome and predominantly exported from colorectal cancer cells. Treatment with a synthetic miR-8073 mimic resulted in a dramatic decrease in the proliferation of various types of cancer cells, which was not observed in similarly treated normal cells. As little is known about the biological functions of miR-8073, its target mRNAs were analyzed by both mRNA expression and in silico sequence analyses, leading to five probable target candidates (FOXM1, MBD3, CCND1, KLK10, and CASP2) that enhance survival during the regulation of the cell cycle, cell proliferation, and apoptosis. We experimentally confirmed that miR-8073 binds the 3'-UTR of each of these mRNA target candidates and that the introduction of a synthetic miR-8073 mimic into cancer cells reduced levels of protein expression. Finally, the antiproliferative effects of miR-8073 were validated in vivo: the subcutaneous injection of a synthetic miR-8073 mimic suppressed colorectal tumor volume to 43% in tumor-bearing xenografted mice. These results suggest that because miR-8073 binds, and thus reduces the levels of, these oncogenic targets, cancer cells must actively downregulate miR-8073 as a survival mechanism. The introduction of miR-8073 into tumors could thus inhibit tumor growth, indicating its great potential for cancer therapeutics.
Huang L, Wang ZY, Pan DDPenicillin‑binding protein 1A mutation‑positive Helicobacter pylori promotes epithelial‑mesenchymal transition in gastric cancer via the suppression of microRNA‑134.
Int J Oncol. 2019; 54(3):916-928 [PubMed
] Free Access to Full Article Related Publications
Evidence suggests that Helicobacter pylori (H. pylori) is not only the main cause of gastric cancer (GC), but is also closely associated with its metastasis. One of the major virulence factors in H. pylori is the cytotoxin‑associated gene A (CagA). With the growing proportion of amoxicillin‑resistant H. pylori strains, the present study aimed to explore the effects of CagA‑ and penicillin‑binding protein 1A (PBP1A) mutation‑positive H. pylori (H. pyloriCagA+/P+) on GC cells, and its clinical significance. The clinical significance of H. pyloriCagA+/P+ infection was analyzed in patients with GC. In vitro, GC cells were infected with H. pyloriCagA+/P+ to investigate whether it was involved in the epithelial‑mesenchymal transition (EMT) of SGC‑7901 cells using immunofluorescence and western blot analysis. The results of clinical analysis demonstrated that, although CagA‑negative H. pylori infection had no significant association with the characteristics of patients with GC, H. pyloriCagA+/P+ infection was significantly associated with various clinicopathological parameters, including invasion depth, lymphatic metastasis and distant metastasis. In vitro, the results indicated that H. pyloriCagA+/P+ promoted proliferation, invasion and EMT of SGC‑7901 cells. MicroRNA (miR)‑134 was downregulated in H. pyloriCagA+/P+ infected tissues compared with in those with H. pyloriCagA+/P‑ infection. miR‑134 overexpression significantly reversed H. pyloriCagA+/P+ infection‑associated cell proliferation, invasion and EMT. Furthermore, the results revealed that Forkhead box protein M1 (FoxM1) was a direct target of miR‑134, and FoxM1 knockdown impeded H. pyloriCagA+/P+‑induced EMT. In conclusion, the present study demonstrated that miR‑134 may suppress the proliferation, invasion and EMT of SGC‑7901 cells by targeting FoxM1, and may serve a protective role in the process of H. pyloriCagA+/P+‑induced GC. These findings may lead to an improved understanding of H. pyloriCagA+/P+‑associated poor clinical characteristics in patients with GC.
Wang Y, Yang Q, Cheng Y, et al.Myosin Heavy Chain 10 (MYH10) Gene Silencing Reduces Cell Migration and Invasion in the Glioma Cell Lines U251, T98G, and SHG44 by Inhibiting the Wnt/β-Catenin Pathway.
Med Sci Monit. 2018; 24:9110-9119 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND The myosin heavy chain 10 or MYH10 gene encodes non-muscle myosin II B (NM IIB), and is involved in tumor cell migration, invasion, extracellular matrix (ECM) production, and epithelial-mesenchymal transition (EMT). This study aimed to investigate the effects of the MYH10 gene on normal human glial cells and glioma cell lines in vitro, by gene silencing, and to determine the signaling pathways involved. MATERIAL AND METHODS The normal human glial cell line HEB, and the glioma cell lines, U251, T98G, and SHG44 were studied. Plasmid transfection silenced the MYH10 gene. The cell counting kit-8 (CCK-8) assay evaluated cell viability. Cell migration and invasion were evaluated using scratch and transwell assays. Western blot measured the protein expression levels, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels, for MYH10, metastasis-associated protein 1 (MTA-1), matrix metalloproteinase (MMP)-1, MMP-9, tissue inhibitor of metalloproteinases 2 (TIMP2), collagen 1, E-cadherin, vimentin, Wnt3a, β-catenin, and cyclin D1. RESULTS The MYH10 gene was overexpressed in U251, T98G, and SHG44 cells. MYH10 expression was down-regulated following siMYH10 plasmid interference, which also inhibited glioma cell migration and invasion. MYH10 gene silencing resulted in reduced expression of MTA-1, MPP-2, MMP-9 and vimentin, and increased expression of TIMP-2, E-cadherin and collagen 1 at the protein and mRNA level, and inhibited the Wnt/β-catenin pathway. CONCLUSIONS In human glioma cell lines, silencing the MYH10 gene reduced cell migration and invasion, by inhibiting the Wnt/β-catenin pathway, which may regulate the ECM and inhibit EMT in human glioma.
Liu B, Su F, Lin R, et al.Overexpression of forkhead box M1 is associated poor survival in patients with nonsmall cell lung cancer.
J Cancer Res Ther. 2018; 14(Supplement):S1121-S1123 [PubMed
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Aims: The association between forkhead box M1 (FOXM1) and survival of nonsmall cell lung cancer (NSCLC) has been extensively investigated. However, the results were conflicted and inconclusive. Therefore, we performed this meta-analysis to precisely estimate the association between FOXM1 and survival of NSCLC.
Materials and Methods: Studies were searched using the PubMed and EMBASE. The strength of the association was calculated with the hazard ratios (HRs) and respective 95% confidence intervals (CIs).
Results: Result of this meta-analysis showed that high expression of FOXM1 was significantly associated with shorter overall survival (OS) of NSCLC (HR = 1.82; 95% CI 1.45-2.29). In the stratified analysis by country, we found that the expression of FOXM1 was significantly associated with shorter OS in Chinese NSCLC patients (HR = 1.82; 95% CI 1.45-2.29). In addition, high expression of FOXM1 decreased the OS in patients with surgery (HR = 1.88; 95% CI 1.37-2.58). Furthermore, the results were still positive in both large sample size studies and small sample size studies.
Conclusions: This meta-analysis showed that overexpression of FOXM1 might be associated with shorter OS of NSCLC patients.
Zhou Y, Wang Q, Chu L, et al.FOXM1c promotes oesophageal cancer metastasis by transcriptionally regulating IRF1 expression.
Cell Prolif. 2019; 52(2):e12553 [PubMed
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OBJECTIVES: We aimed to elucidate the role and molecular mechanisms of FOXM1 in regulating metastasis in oesophageal squamous cell carcinoma (ESCC) as well as its clinical implications.
MATERIALS AND METHODS: The expression levels of four isoforms of FOXM1 were analysed by real-time PCR. Next, genetically modification using overexpression and RNAi systems and transwell were employed to examine FOXM1c function in invasion and migration. Dual luciferase and ChIP assays were performed to decipher the underlying mechanism for transcriptional regulation. The expression levels of FOXM1 and IRF1 were determined by immunohistochemistry staining in ESCC specimens.
RESULTS: The FOXM1c was predominantly overexpressed in ESCC cell lines compared to the other FOXM1 isoforms. Ectopic expression of FOXM1c promoted invasion and migration of ESCC cells lines, whereas downregulation of FOXM1c inhibited these processes. Moreover, FOXM1c expression was positively correlated with IRF1 expression in ESCC cell lines and tumour specimens. IRF1 is, at least in part, responsible for FOXM1c-mediated invasion and migration. Mechanistically, we identified IRF1 as a transcriptional target of FOXM1c and found a FOXM1c-binding site in the IRF1 promoter region. Furthermore, high expression levels of both FOXM1c and IRF1 were positively associated with low survival rate and predicted a poor prognosis of oesophageal cancer patients.
CONCLUSION: FOXM1c promotes the metastasis by transcriptionally targeting IRF1 and may serve as a potential prognostic predictor for oesophageal cancer.
BACKGROUND: Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox).
METHODS: FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1
RESULTS: Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1
CONCLUSIONS: These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1
BACKGROUND: Prognostic biomarkers are needed in clinical setting to predict outcome after resection for early-stage lung adenocarcinoma. The goal of this study is to validate tumor-based single-gene expression biomarkers with demonstrated prognostic value in order to move them along the clinical translation pipeline.
METHODS: Prognostic genes were selected from the literature and the best candidates measured by quantitative real-time polymerase chain reaction (qPCR) in tumors of 233 patients with stage I adenocarcinoma. Significant prognostic genes were then validated in an independent set of 210 patients matching the first set in terms of histology, stage, and clinical data.
RESULTS: Eleven genes with demonstrated prognostic value were selected from the literature. Complementary analyses in public databases and our own microarray dataset led to the investigation of six genes associated with good (BTG2, SELENBP1 and NFIB) or poor outcome (RRM1, EZH2 and FOXM1). In the first set of patients, EZH2 and RRM1 were significantly associated with better survival on top of age, sex and pathological stage (EZH2 p = 3.2e-02, RRM1 p = 5.9e-04). The prognostic values of EZH2 and RRM1 were not replicated in the second set of patients. A trend was observed for both genes in the joint analyses (n = 443) with higher expression associated with worse outcome.
CONCLUSION: Adenocarcinoma-specific mRNA expression levels of EZH2 and RRM1 are associated with poor post-surgical survival in the first set of patients, but not replicated in a clinically and pathologically matched independent validation set. This study highlights challenges associated with clinical translation of prognostic biomarkers.
Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.
Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.
Liu A, Zeng S, Lu X, et al.Overexpression of G2 and S phase-expressed-1 contributes to cell proliferation, migration, and invasion via regulating p53/FoxM1/CCNB1 pathway and predicts poor prognosis in bladder cancer.
Int J Biol Macromol. 2019; 123:322-334 [PubMed
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Bladder cancer is one of the most common urogenital tumors worldwide. The specific function and molecular mechanism of GTSE1 in bladder cancer remain unknown. In the present study, real-time quantitative polymerase chain reaction and Western blotting were used to identify GTSE1 expression in bladder cancer tissues and cells, and immunohistochemical assays were conducted to investigate GTSE1 expression in tissue microarray. Regression analyses explored the relationship between GTSE1 expression and pathological characteristics. A series of functional tests were performed to observe the effects of GTSE1 knockdown or overexpression, and the related mechanism was also performed. GTSE1 expression was significantly higher in bladder cancer tissues; overexpression of GTSE1 was positively associated with disease recurrence history, lymph node invasion, and progression. Patients with higher GTSE1 expression were more likely to experience shorter survival time, and GTSE1 expression served as a prognostic factor for the disease progression. Knockdown of GTSE1 obviously suppressed the proliferation, migration, and invasion capacity whereas increasing GTSE1 led to the opposite trend, which suggested that GTSE1 could serve as a potential therapeutic target for bladder cancer. GTSE1 overexpression in bladder cancer might participate in the regulation of FoxM1/CCNB1 expression via the induction of the transfer of p53 to cytoplasm.
Wang L, Lu J, Zhang H, et al.MicroRNA‑876‑5p inhibits the progression of glioblastoma multiforme by directly targeting Forkhead box M1.
Oncol Rep. 2019; 41(1):702-710 [PubMed
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Considerable evidence has suggested that microRNAs (miRNAs) are dysregulated in glioblastoma multiforme (GBM), and their dysregulation may modulate the aggressiveness of GBM. Therefore, miRNAs with dysregulated expression are potential therapeutic targets for the treatment of GBM. miRNA‑876‑5p (miR‑876‑5p) has recently been identified to be aberrantly expressed and serve an important role in hepatocellular carcinoma and lung cancer. However, its expression pattern and functional significance in GBM remains largely unknown. Therefore, the present study detected miR‑876‑5p expression in GBM, examined the biological roles of miR‑876‑5p in GBM progression and explored its underlying mechanism. The present study demonstrated that miR‑876‑5p expression was significantly downregulated in GBM tissues and cell lines. Overexpression of miR‑876‑5p restricted the proliferation, induced the apoptosis and reduced the migration and invasion capabilities of GBM cells. In GBM cells, Forkhead box M1 (FOXM1) was identified as a direct target of miR‑876‑5p. FOXM1 was overexpressed in clinical GBM tissues, and its overexpression was inversely correlated with miR‑876‑5p level. Small interfering RNA‑mediated knockdown of FOXM1 exhibited effects similar to those of miR‑876‑5p overexpression in GBM cells. The tumour suppressive roles of miR‑876‑5p overexpression in GBM cells were significantly reversed by FOXM1 reintroduction. Overall, the present results revealed that miR‑876‑5p may inhibit the development of GBM by directly targeting FOXM1, suggesting that this miRNA may be a potential therapeutic target in patients, for the management of GBM.
The present study aimed to identify the therapeutic role of the forkhead box M1 (FOXM1)‑associated pathway in triple‑negative breast cancer (TNBC). Using a Cancer Landscapes‑based analysis, a gene regulatory network model was constructed. The present results demonstrated that FOXM1 occupies a key position in gene networks and is a critical regulatory gene in breast cancer. Using breast carcinoma gene expression data from The Cancer Genome Atlas, it was identified that FOXM1 expression was increased in the basal‑like breast cancer subtype compared with other breast cancer subtypes. RNA‑sequencing analysis of MDA‑MB‑231 cells treated with 4 and 10 µl/ml Thiostrepton identified 662 and 5,888 significantly differentially expressed genes, respectively. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that FOXM1 was highly associated with multiple biological processes and was markedly associated with metabolic pathways in TNBC. The use of Search Tool for the Retrieval of Interacting Genes/Proteins provided a critical assessment and integration of protein‑protein interactions, and demonstrated the multiple important functions of FOXM1 in TNBC. Real‑time cell analysis, reverse transcription‑quantitative polymerase chain reaction and immunofluorescence staining were used to assess the anti‑tumor activity of Thiostrepton in TNBC cells in vitro. The present results identified that suppression of FOXM1 using Thiostrepton inhibited MDA‑MB‑231 cell proliferation and the expression of cell cycle‑associated genes, including cyclin A2, cyclin B2, checkpoint kinase 1, centrosomal protein 55 and polo like kinase 1. Immunofluorescence staining analysis demonstrated that vimentin, filamentous actin and zinc finger E‑box‑binding homeobox 1 were all decreased following treatment with Thiostrepton. Furthermore, a BALB/C nude mouse subcutaneous xenograft model was used to verify the function of FOXM1 in vivo. The present results demonstrated that FOXM1 inhibition significantly suppressed MDA‑MB‑231 cell tumorigenesis in vivo. Overall, the present results suggested that FOXM1 is a key gene that serves important roles in multiple biological processes in TNBC and that it may serve as a novel therapeutic target in TNBC.
Kang MK, Chen W, Park NHRegulation of Epithelial Cell Proliferation, Differentiation, and Plasticity by Grainyhead-Like 2 During Oral Carcinogenesis.
Crit Rev Oncog. 2018; 23(3-4):201-217 [PubMed
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Grainyhead-Like 2 (GRHL2) was originally described as one of the three mammalian isoforms with sequence homology to Grainyhead (GRH) in Drosophila, which determines the cuticle formation in fruit flies. Earlier studies characterized GRHL2 as an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Using a high-throughput proteomic approach, we discovered GRHL2 as a novel trans-regulator of the hTERT gene, which codes for the catalytic subunit of the human telomerase. GRHL2 was found to be necessary and sufficient for hTERT expression and telomerase activity in human oral squamous cell carcinomas (OSCCs) and in primary normal human keratinocytes. Subsequently, we found numerous other direct transcription targets of GRHL2, including p63, microRNA (miR)-200 family genes, FoxM1, and epidermal differentiation complex (EDC) genes. These target molecules mediate the phenotypic effects of GRHL2 on epithelial cell proliferation, differentiation, and epithelial plasticity. The pro-carcinogenic role of GRHL2 was implicated by its aberrant overexpression in OSCC cells and tissues, although several other studies also suggested the tumor suppressive effects of GRHL2. Using the novel Grhl2 cKO model, we recently reported the first genetic study in which Grhl2 knockout completely abolished oral carcinogenesis induced by a potent carcinogen, 4-nitroquinoline N-oxide (NQO). In this review, we discuss the mechanistic insights underlying the phenotypic effects of GRHL2 on epithelial cell proliferation and differentiation, as well as possibly mechanisms by which GRHL2 may promote oral carcinogenesis.
Tian B, Li J, Pang R, et al.Gold Nanoparticles Biosynthesized and Functionalized Using a Hydroxylated Tetraterpenoid Trigger Gene Expression Changes and Apoptosis in Cancer Cells.
ACS Appl Mater Interfaces. 2018; 10(43):37353-37363 [PubMed
] Related Publications
Understanding the synthetic mechanisms and cell-nanoparticle interactions of biosynthesized and functionalized gold nanoparticles (AuNPs) using natural products is of great importance for developing their applications in nanomedicine. In this study, we detailed the biotransformation mechanism of Au(III) into AuNPs using a hydroxylated tetraterpenoid deinoxanthin (DX) from the extremophile Deinococcus radiodurans. During the process, Au(III) was rapidly reduced to Au(I) and subsequently reduced to Au(0) by deprotonation of the hydroxyl head groups of the tetraterpenoid. The oxidized form, deprotonated 2-ketodeinoxanthin (DX3), served as a surface-capping agent to stabilize the AuNPs. The functionalized DX-AuNPs demonstrated stronger inhibitory activity against cancer cells compared with sodium citrate-AuNPs and were nontoxic to normal cells. DX-AuNPs accumulated in the cytoplasm, organelles, and nuclei, and induced reactive oxygen species generation, DNA damage, and apoptosis within MCF-7 cancer cells. In the cells treated with DX-AuNPs, 374 genes, including RRAGC gene, were upregulated; 135 genes, including the genes encoding FOXM1 and NR4A1, were downregulated. These genes are mostly involved in metabolism, cell growth, DNA damage, oxidative stress, autophagy, and apoptosis. The anticancer activity of the DX-AuNPs was attributed to the alteration of gene expression and induction of apoptosis. Our results provide significant insight into the synthesis mechanism of AuNPs functionalized with natural tetraterpenoids, which possess enhanced anticancer potential.
Li CF, Li YC, Wang Y, Sun LBThe Effect of LncRNA H19/miR-194-5p Axis on the Epithelial-Mesenchymal Transition of Colorectal Adenocarcinoma.
Cell Physiol Biochem. 2018; 50(1):196-213 [PubMed
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BACKGROUND/AIMS: Since the combined actions of lncRNAs and miRNAs have been considered to be involved in the occurrence and development of various neoplasms, the main purpose of this study was to discover whether and how lncRNA H19 and miR-194 influenced the epithelial-mesenchymal transition (EMT) process of colorectal adenocarcinoma (CRA).
METHODS: Totally 214 pairs of CRA and adjacent normal tissues were collected, and 5 human CRA cell lines (i.e. HCT116, HT-29, RKO SW280 and Lovo) were purchased. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was adopted to quantify the H19 and miR-194-5p expressions in cells and tissues. The expressions of FoxM1, E-cadherin, vimentin, N-cadherin were determined using western blot. On the side, si-H19, si-NC, miR-194-5p mimic, miR-194-5p inhibitor and negative control (NC) were transfected into CRA cell lines. Meanwhile, the invasive, migratory and proliferative conditions of the cells were assessed through transwell, wound healing and colony-forming experiments, with final verification of the relationship between H19 and miR-194-5p employing dual-luciferase reporter gene assay.
RESULTS: Highly-expressed H19, lowly-expressed miR-194-5p, low-grade differentiation and lymph node metastasis appeared as the independent predictors of unfavorable prognosis in CRA patients' (all P< 0.05). It indicated that FoxM1 expression displayed positive correlations with H19 expression, yet negative associations with miR-194-5p expression within CRA tissues (P< 0.05). In addition, transfection of H19-siRNA and miR-145-5p mimic triggered a conspicuous increase in E-cadherin expression, as well as an evidently down-regulation in vimentin and N-cadherin expressions within HT29 and RKO cells (P< 0.05). On the other hand, the invasive and migratory capacities of CRA cells were significantly hindered (P< 0.05). Moreover, the luciferase reporter gene assay confirmed that H19 modified miR-194-5p expression through directly targeting at it (P< 0.05). Ultimately, FoxM1 could reverse the role of miR-194-5p in inhibiting invasion, migration and EMT of CRA cells (P< 0.05).
CONCLUSION: LncRNA H19/miR-194/FoxM1 axis could serve as a profound target for the diagnosis and treatment of CRA.
Seyedabadi S, Saidijam M, Najafi R, et al.Assessment of CEP55, PLK1 and FOXM1 expression in patients with bladder cancer in comparison with healthy individuals.
Cancer Invest. 2018; 36(8):407-414 [PubMed
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This case/control study is aimed at investigating the expression of CEP55, PLK1 and FOXM1 in bladder cancer tissues and comparing it with healthy tissue and their relationship with clinicopathological features of BC. Total RNA was extracted; then, gene expression was performed using real-time PCR relative to 18 s rRNA. 2
Bian D, Wu Y, Song GNovel circular RNA, hsa_circ_0025039 promotes cell growth, invasion and glucose metabolism in malignant melanoma via the miR-198/CDK4 axis.
Biomed Pharmacother. 2018; 108:165-176 [PubMed
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Malignant melanoma, a tumor derived from melanocytes, shows severe drug resistance and prompt metastasis, causing a serious threat to human health. Circular RNAs (circRNAs) are widely expressed in mammals and have been indicated to play important roles in tumorigenesis. In the present study, we analyzed the variability of circRNAs in malignant melanoma by microarray and identified six differentially expressed circRNAs. In particular, we found that hsa_circ_0025039, which is formed by FOXM1 exons, is significantly upregulated in melanoma. In vitro, the knockdown of circ_0025039 inhibited cell proliferation, colony formation ability, invasion and glucose metabolism in melanoma cells. Additionally, we identified miR-198 as a direct target of hsa_circ_0025039. Furthermore, we demonstrated that hsa_circ_0025039 regulates CDK4 expression by sponging miR-198. In vivo study indicated that the silencing of hsa_circ_0025039 inhibits melanoma tumor formation and downregulates miR-198 and CDK4 expression. Taken together, our data showed that circ_0025039 promotes cell growth, invasion and glucose metabolism in malignant melanoma by sponging miR-198 and regulating CDK4.
He ZJ, Li W, Chen H, et al.miR-1306-3p targets FBXL5 to promote metastasis of hepatocellular carcinoma through suppressing snail degradation.
Biochem Biophys Res Commun. 2018; 504(4):820-826 [PubMed
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This study aimed to elucidate the effect of miR-1306-3p on metastasis of hepatocellular carcinoma (HCC) and potential mechanism involved. miR-1306-3p promoted migration and invasion of HCC in vivo and in vitro. Moreover, miR-1306-3p inhibited snail to enhance its expression via directly targeting FBXL5, thus inducing the epithelial-mesenchymal transition (EMT) in HCC. Intriguingly, miR-1306-3p expression was transcriptionally enhanced by FoxM1. Consistently, miR-1306-3p was upregulated in HCC compared with paracarcinoma and correlated with poor prognosis of HCC patients. Our researches suggest that miR-1306-3p is a tumor enhancer in regulating of HCC metastasis, and miR-1306-3p may be clinically utilized as a factor for the clinical diagnosis and prognosis of HCC.
FOXM1 (forkhead box protein M1) is a critical proliferation-associated transcription factor that is widely spatiotemporally expressed during the cell cycle. It is closely involved with the processes of cell proliferation, self-renewal, and tumorigenesis. In most human cancers, FOXM1 is overexpressed, and this indicates a poor prognosis for cancer patients. FOXM1 maintains cancer hallmarks by regulating the expression of target genes at the transcriptional level. Due to its potential role as molecular target in cancer therapy, FOXM1 was named the Molecule of the Year in 2010. However, the mechanism of FOXM1 dysregulation remains indistinct. A comprehensive understanding of FOXM1 regulation will provide novel insight for cancer and other diseases in which FOXM1 plays a major role. Here, we summarize the transcriptional regulation, post-transcriptional regulation and post-translational modifications of FOXM1, which will provide extremely important implications for novel strategies targeting FOXM1.
Pérez-Peña J, Győrffy B, Amir E, et al.Epigenetic modulation of FOXM1-gene interacting network by BET inhibitors in breast cancer.
Breast Cancer Res Treat. 2018; 172(3):725-732 [PubMed
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INTRODUCTION: FOXM1 is a transcription factor that has been implicated in the genesis of several tumors by regulating the expression of genes involved in the mitotic process.
METHODS: Transcriptomic enrichment analysis was performed to evaluate deregulated pathways in breast cancer, and relapse-free survival associated with the upregulated genes of FOXM1 signature was explored using the KM Plotter online tool. Treatment with bromodomain and extraterminal (BET) inhibitor JQ1 was explored in breast cancer cell lines to evaluate FOXM1 by qPCR and proliferation by MTT colorimetric assays.
RESULTS: The FOXM1 gene signature was clearly deregulated in breast cancer patients, particularly in the basal-like subgroup where it was linked with detrimental prognosis. Treatment with the BET inhibitor JQ1 reduced the expression of FOXM1, decreasing cell proliferation in a panel of cell lines, being more active in the basal-like subtype, MDA-MB-231 and HS-578T. Knockdown of FOXM1 or treatment with JQ1 reduced genes included in the FOXM1 signature. Similarly, genes downregulated by the FOXM1 small interfering RNA approach were associated with detrimental outcome in breast cancer patients. Finally, we observed that FOXM1 was amplified in the triple-negative breast cancer subtype in around 15% of patients.
CONCLUSION: Our study demonstrates that activation of the FOXM1 pathway has a prognostic role in breast cancer. JQ1 can modulate the expression of the FOXM1-gene interacting network, opening the opportunity for the evaluation of this compound in breast cancer patients.
Hwang SM, Lee HJ, Jung JH, et al.Inhibition of Wnt3a/FOXM1/β-Catenin Axis and Activation of GSK3β and Caspases are Critically Involved in Apoptotic Effect of Moracin D in Breast Cancers.
Int J Mol Sci. 2018; 19(9) [PubMed
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Although Moracin D derived from
Fu Z, Cao X, Yang Y, et al.Upregulation of FoxM1 by MnSOD Overexpression Contributes to Cancer Stem-Like Cell Characteristics in the Lung Cancer H460 Cell Line.
Technol Cancer Res Treat. 2018; 17:1533033818789635 [PubMed
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Manganese superoxide dismutase promotes migration and invasion in lung cancer cells via upregulation of the transcription factor forkhead box M1. Here, we assessed whether upregulation of forkhead box M1 by manganese superoxide dismutase overexpression mediates the acquisition of cancer stem-like cell characteristics in non-small cell lung cancer H460 cells. The second-generation spheroids from H460 cells were used as lung cancer stem-like cells. The levels of manganese superoxide dismutase, forkhead box M1, stemness markers (CD133, CD44, and ALDH1), and transcription factors (Bmi1, Nanog, and Sox2) were analyzed by Western blot. Sphere formation in vitro and carcinogenicity of lung cancer stem-like cells were evaluated by spheroid formation assay and limited dilution xenograft assays. Knockdown or overexpression of manganese superoxide dismutase or/and forkhead box M1 by transduction with short hairpin RNA(shRNA) or complementary DNA were performed for mechanistic studies. We showed that manganese superoxide dismutase and forkhead box M1 amounts as well as the expression levels of stemness markers and transcription factors sphere formation in vitro, and carcinogenicity of lung cancer stem-like cells were higher than in monolayer cells. Lung cancer stem-like cells transduced with manganese superoxide dismutase shRNA or FoxM1 shRNA exhibited decreased sphere formation and lower amounts of stemness markers and transcription factors. Overexpression of manganese superoxide dismutase or FoxM1 in H460 cells resulted in elevated sphere formation rates and protein levels of stemness markers and transcription factors. Meanwhile, manganese superoxide dismutase knockdown or overexpression accordingly altered forkhead box M1 levels. However, forkhead box M1 knockdown or overexpression had no effect on manganese superoxide dismutase levels but inhibited or promoted lung cancer stem-like cell functions. Interestingly, forkhead box M1 overexpression alleviated the inhibitory effects of manganese superoxide dismutase knockdown in lung cancer stem-like cells. In a panel of non-small cell lung cancer cells, including H441, H1299, and H358 cells, compared to the respective monolayer counterparts, the expression levels of manganese superoxide dismutase and forkhead box M1 were elevated in the corresponding spheroids. These findings revealed the role of forkhead box M1 upregulation by manganese superoxide dismutase overexpression in maintaining lung cancer stem-like cell properties. Therefore, inhibition of forkhead box M1 upregulation by manganese superoxide dismutase overexpression may represent an effective therapeutic strategy for non-small cell lung cancer.
Long noncoding RNAs (lncRNAs) play an important role in the proliferation and metastasis of osteosarcoma. Identification of the pathogenesis of osteosarcoma and development of new therapeutic strategies against osteosarcoma are urgently needed. In this study, we evaluated the expression of TUG1 (Taurine Upregulated Gene 1) in osteosarcoma tissues and selected it as our target for further analyses. In vitro, we found that TUG1 was upregulated by FOXM1 (Forkhead Box M1) in osteosarcoma cells. TUG1 accelerated osteosarcoma proliferation, migration, and invasion by competitively sponging miR-219a-5p, leading to upregulation of Phosphatidylinositol-4, 5-Bisphosphate 3-Kinase Catalytic Subunit Alpha and activation of the protein kinase B (AKT) signaling pathway. In addition, the AKT pathway activation promoted TUG1 expression by upregulating the expression of FOXM1, forming a positive feedback loop in osteosarcoma. Furthermore, we designed and synthesized therapeutic locked nucleic acids targeting TUG1. The proliferation of osteosarcoma was significantly repressed. Hence, TUG1 may be a potential biomarker and therapeutic target for osteosarcoma.
An increasing body of evidence has indicated that microRNAs (miRNAs/miRs) may play an important role in tumourigenesis and tumour progression. Recent studies have demonstrated that miR‑320a is aberrantly expressed in a variety of different types of human cancer. The results of the present study confirmed that the expression of miR‑320a was decreased in clinical specimens and cell lines. Expression of miR‑320a inhibited the growth and invasive ability of ACHN and Caki‑1 cells. Bioinformatics analysis and a luciferase reporter assay demonstrated that forkhead box protein M1 (FoxM1) was directly regulated by miR‑320a. Rescue experiments in vitro revealed that the upregulation of FoxM1 antagonized the miR‑320a‑mediated malignant phenotype in renal cancer. Furthermore, experiments employing a xenograft mouse model revealed that the upregulation of miR‑320a inhibited the proliferation of renal cancer cells in nude mice when FoxM1 protein expression was reduced. Collectively, the present study demonstrated a novel molecular interaction regulated by miR‑320a, which may provide a novel insight into the treatments for renal cancer.