Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TXNIP (cancer-related)
BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is characterized by its unique morphology and frequent nodal metastasis. However, the mechanism for development of this unique subtype has not been clearly elucidated. The aim of this study was to obtain a better understanding of IMPC.
METHODS: Using representative cases of mixed IMPC, mRNA expression in the micropapillary area and usual invasive area was compared. Then, immunohistochemical analyses for 294 cases (76 invasive carcinomas with a micropapillary feature [ICMF] and 218 invasive carcinomas without a micropapillary feature [ICNMF]) were conducted. Clinicopathological analyses were also studied.
RESULTS: DNA microarray analyses for mixed IMPC showed that BC-1514 (C21orf118) was commonly upregulated in the micropapillary area. CAMK2N1, CD1d, PJA2, RPL5, SAMD13, TCF4, and TXNIP were commonly downregulated in the micropapillary area. Immunohistochemically, we confirmed that BC-1514 was more upregulated in ICMF than in ICNMF. CD1d and PJA2 were more downregulated in ICMF than ICNMF. All patients with cases of PJA2 overexpression survived without cancer recurrence during the follow-up period, although the differences for disease-free (p = 0.153) or overall survival (p = 0.272) were not significant.
CONCLUSIONS: The CD1d- and PJA2-related tumour microenvironment might be crucial for IMPC. Further study of the immune microenvironment and micropapillary features is warranted.
Zhang C, Wang H, Liu X, et al.Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP.
Oncogene. 2019; 38(11):1892-1904 [PubMed
] Related Publications
Lung cancer is one of the most common malignant diseases globally, composed of non-small cell lung cancer (NSCLC, 85%) and small cell lung cancer (SCLC, 15%). MicroRNAs (miRNAs) are single-stranded noncoding RNAs having important roles in lung cancer development. miR-411-5p/3p were reported to be increased significantly in human NSCLC tissues and cell lines. Moreover, miR-411-5p/3p overexpression could accelerate cell proliferation and migration, and impede cell apoptosis in NSCLC cell lines. Mechanically, SPRY4 is confirmed a direct target of miR-411-5p/3p. Furthermore, our findings showed that miR-411-5p/3p promoted lung tumor growth in vivo, decreased SPRY4 expression dramatically, and induced EGFR, AKT signaling activation, as well as epithelial-mesenchymal transition (EMT) simultaneously in tumor tissues. In addition, we showed that miR-411-5p also targeted tumor suppressor TXNIP, involved in regulating positively cell cycle progress in SPC-A1 cells rather than in H1299. Whether cell specificity of low TXNIP mRNA level in H1299 is responsible for the different response to cell cycle between H1299 and SPC-A1 would need further explorations. Collectively, these results suggest that miR-411-5p/3p are required for NSCLC development by suppressing SPRY4 and TXNIP; thus, the miR-411-SPRY4-AKT axis might act as a promising target for lung cancer therapy clinically.
Cho SY, Kim S, Son MJ, et al.Clinical Significance of the Thioredoxin System and Thioredoxin-Domain-Containing Protein Family in Hepatocellular Carcinoma.
Dig Dis Sci. 2019; 64(1):123-136 [PubMed
] Related Publications
BACKGROUND: Oxidative stress occurs due to the excessive generation of cellular reactive oxygen species and antioxidant system dysfunction. The thioredoxin (TXN) system and TXN-domain-containing protein (TXNDC) family form networks maintaining the cellular reducing environment. Recently, the importance of these genes in the tumor environment has been emphasized.
AIM: To investigate the clinical significance of TXNs and TXNDC family members in HCC.
METHODS: Genomic data from 367 hepatocellular carcinoma (HCC) patients who underwent hepatic resections were analyzed to determine genetic alterations in mRNA and protein levels between patients and healthy controls. In addition, functional enrichment and survival analyses were performed.
RESULTS: HCC patients were shown to have enhanced expression of TXN, TXNRD1, and TXNDC7/9/14 mRNA and protein compared with controls. In accordance with the survival analyses, strong associations were found that patients with TXN, TXNRD1, and TXNDC1/7/9 alterations were proven to have poor prognosis in overall survival. Moreover, gene set enrichment analysis and network analyses revealed that positive correlations were found in mRNA expression of TXN, TXNRD1, and TXNDC7/9 genes with upregulation of the tumor-promoting genes, specifically mTORC1, E2F targets, and Myc targets. On the other hand, elevated expressions of TXNIP and TXNDC11 genes were correlated with suppression of the above tumor-promoting genes.
CONCLUSIONS: TXN system and TXNDC family gene panel obtained from the resected tissue of the HCC patients could be used to predict survival prognosis of HCC, and these genes could be considered as potential therapeutic targets for improving HCC survival.
Qu X, Sun J, Zhang Y, et al.c-Myc-driven glycolysis via TXNIP suppression is dependent on glutaminase-MondoA axis in prostate cancer.
Biochem Biophys Res Commun. 2018; 504(2):415-421 [PubMed
] Related Publications
Oncogenic c-Myc-induced metabolic reprogramming triggers cellular dependency on exogenous glucose and glutamine. Understanding how nutrients are used may provide new target for therapeutic intervention. We previously provided an alternate route to c-Myc-driven glucose metabolism via the repression of thioredoxin-interacting protein (TXNIP), which is a potent negative regulator of glucose uptake. Herein, we demonstrate that c-Myc suppression of TXNIP is predominantly through the activation of glutaminolysis via glutaminase (GLS1) in prostate cancer cells. Glutamine depletion blocked c-Myc-dependent reductions of TXNIP and its principal regulator MondoA transcriptional activity. Further, GLS1 inhibition by either siRNA or CB-839 resumed TXNIP expression that was repressed by c-Myc. The TXNIP promoter with mutant E-Box region, which was recognized by MondoA, failed to respond to c-Myc or GLS1, indicating c-Myc repression of TXNIP by GLS1 is predominantly through the blockage of MondoA activity. Especially, ectopic TXNIP expression decreased c-Myc-induce glucose uptake and lead to a broad range of glycolytic target gene suppressions. Thus TXNIP is a key adaptor for c-Myc-driven aerobic glycolysis. Supporting the biological significance of c-Myc and TXNIP, their reciprocal relationship are correlates with patient outcome and contributes to the aggressive phenotype in PCAs.
Vastrad C, Vastrad BBioinformatics analysis of gene expression profiles to diagnose crucial and novel genes in glioblastoma multiform.
Pathol Res Pract. 2018; 214(9):1395-1461 [PubMed
] Related Publications
Therefore, the current study aimed to diagnose the genes associated in the pathogenesis of GBM. The differentially expressed genes (DEGs) were diagnosed using the limma software package. The ToppFun was used to perform pathway and Gene Ontology (GO) enrichment analysis of the DEGs. Protein-protein interaction (PPI) networks, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network were used to obtain insight into the actions of DEGs. Survival analysis for DEGs carried out. A total of 701 DEGs, including 413 upregulated and 288 downregulated genes, were diagnosed between U1118MG cell line (PK 11195 treated with 1 h exposure) and U1118MG cell line (PK 11195 treated with 24 h exposure). The up-regulated genes were enriched in superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis, cell cycle, cell cycle process and chromosome. The down-regulated genes were enriched in folate transformations I, biosynthesis of amino acids, cellular amino acid metabolic process and vacuolar membrane. The current study screened the genes in PPI network, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network with higher degrees as hub genes, which included MYC, TERF2IP, CDK1, EEF1G, TXNIP, SLC1A5, RGS4 and IER5L Survival suggested that low expressed NR4A2, SLC7 A5, CYR61 and ID1 in patients with GBM was linked with a positive prognosis for overall survival. In conclusion, the current study could improve our understanding of the molecular mechanisms in the progression of GBM, and these crucial as well as new molecular markers might be used as therapeutic targets for GBM.
Zhu G, Zhou L, Liu H, et al.MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway.
Cell Physiol Biochem. 2018; 48(4):1735-1746 [PubMed
] Related Publications
BACKGROUND/AIMS: MicroRNAs (miRNAs) have been shown to participate in the development of pancreatic ductal adenocarcinoma (PDAC) by modulating multiple cellular processes. Increased miR-224 expression enhances proliferation and metastasis in human cancers. This study aimed to investigate the role of miR-224 and its underlying mechanism of action in PDAC.
METHODS: BrdU, MTT, and cell migration assays were performed to determine cell proliferation, viability, and migration, respectively. The binding sites of miR-224 were identified using a luciferase reporter system, whereas protein expression of target genes was determined by immunoblotting and immunofluorescence analyses. A BALB/c nude mouse xenograft model was used to evaluate the role of miR-224 in vivo.
RESULTS: We demonstrated that miR-224 expression was enhanced in PDAC cells and tissues, and was related to migration and proliferation. Noticeably, miR-224 overexpression promoted the proliferation, migration, and metastasis of Panc1 cells, while miR-224 inhibition had the reverse effect on PDAC cells. Moreover, we found that thioredoxin-interacting protein (TXNIP) is a target of miR-224. The results also indicated that miR-224 inversely regulated TXNIP by binding directly to its 3'-untranslated region, which resulted in the activation of hypoxia-inducible factor 1α (HIF1α). Further, either TXNIP re-expression or HIF1α depletion abolished the effects of miR-224 on the proliferation and migration of PDAC cells in vitro and in vivo. Regarding the relationship of TXNIP and HIF1α, we found that TXNIP mediated the nuclear export of HIF1α and its degradation by forming a complex with HIF1α.
CONCLUSION: The miR-224-TXNIP-HIF1α axis may be useful in developing novel therapies for PDAC.
Zhang B, Lyu J, Liu Y, et al.BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition.
Oncogene. 2018; 37(49):6341-6356 [PubMed
] Related Publications
BRCA1 is a tumor suppressor frequently mutated in breast and ovarian cancer, serving it as a target for therapeutic exploitation. Here, we show that BRCA1 has a synthetic lethality interaction with an epigenetics regulator, bromodomain and extra-terminal domain (BET). BET inhibition led to gene expression changes reversing MYC-dependent transcription repression of a redox regulator, thioredoxin-interacting protein (TXNIP), via switching the promoter occupant from MYC to MondoA:MLX complex. Reversing the MYC-TXNIP axis inhibited thioredoxin activity and elevated cellular oxidative stress, causing DNA damages that are detrimental to BRCA1-deficient breast cancer cells. Tumor xenograft models and breast cancer clinical data analyses further demonstrated an in vivo synthetic lethality interaction and clinical association between BET/TXNIP and BRCA1 deficiency in the survival of breast cancer patients.
BACKGROUND: Targeted therapy has always been the focus in developing therapeutic approaches in cancer, especially in the treatment of acute myeloid leukemia (AML). A new small molecular inhibitor, JQ1, targeting BRD4, which recognizes the acetylated lysine residues, has been shown to induce cell cycle arrest in different cancers by inhibiting MYC oncogene. However, the downstream signaling of MYC inhibition induced by BET inhibitor is not well understood.
METHODS: In this study, we explored the more mechanisms of JQ1-induced cell death in acute myeloid lukemia and downstream signaling of JQ1.
RESULTS: We found that JQ1 is able to reactivate the tumor suppressor gene, TXNIP, and induces apoptosis through the ASK1-MAPK pathway. Further studies confirmed that MYC could repress the expression of TXNIP through the miR-17-92 cluster.
CONCLUSIONS: These findings provide novel insight on how BET inhibitor can induce apoptosis in AML, and further support the development of BET inhibitors as a promising therapeutic strategy against AML.
Zhang GM, Goyal H, Song LLBioinformatics analysis of differentially expressed miRNA-related mRNAs and their prognostic value in breast carcinoma.
Oncol Rep. 2018; 39(6):2865-2872 [PubMed
] Related Publications
Breast carcinoma is one of the most common types of malignant neoplasms, and is associated with high rates of morbidity and mortality. Altered gene expression is critical in the development of breast cancer. To identify the important differentially expressed genes and microRNAs in breast carcinoma, mRNA (GSE26910, GSE42568, and GSE89116) and microRNA (GSE35412) microarray datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed microRNA expression data were extracted with GEO2R online software. The DAVID online database was used to perform a function and pathway enrichment analysis of the key identified differentially expressed genes. A protein-protein interaction (PPI) network was constructed using the STRING online database, and visualized in Cytoscape software. The effect of the expression level of the key identified genes on overall survival (OS) time was analyzed by using the Kaplan-Meier Plotter online database. Furthermore, the online miRNA databases TargetScan, microT-CDS, and TarBase were used to identify the target genes of the differentially expressed miRNAs. A total of 254 differentially expressed genes were identified, which were enriched in cell adhesion, polysaccharide binding, extracellular region part and ECM-receptor interactions. The PPI network contained 250 nodes and 375 edges. Five differentially expressed genes were found to be significantly negatively correlated with the differentially expressed miRNAs, which were potentially also target genes for miRNAs. Four of the five genes, including AKAP12, SOPB, TCF7L2, COL12A1 and TXNIP were downregulated, and were associated with the OS of patients with breast carcinoma. In addition, a total of 130 differentially expressed miRNAs were identified. In conclusion, these results constitute a novel model for miRNA-mRNA differential expression patterns, and further studies may provide potential targets for diagnosing and understanding the mechanisms of breast carcinoma.
Park JW, Lee SH, Woo GH, et al.Downregulation of TXNIP leads to high proliferative activity and estrogen-dependent cell growth in breast cancer.
Biochem Biophys Res Commun. 2018; 498(3):566-572 [PubMed
] Related Publications
TXNIP is a potent tumor suppressor with reduced expression in various types of human cancer. The prognostic and predictive power of TXNIP has been recognized in human breast cancer. The aim of this study is to investigate the clinical relevance and functional roles of TXNIP downregulation in breast cancer. We examined TXNIP expression at the protein level in tissue microarray (TMA)-based human breast cancers and its correlation with clinical parameters and molecular markers on immunohistochemistry (IHC). Compared with normal tissues, TXNIP expression was significantly decreased in human breast cancer tissues and animal mammary tumors, along with tumor progression. TXNIP was restored immediately after histone deacetylase inhibitor treatment in breast cancer cells, implying transcriptional regulation of TXNIP by histone modification. Decreased TXNIP protein levels were more common in tumors showing high proliferative activity, such as high Ki-67 labeling indexes and low p27 expression. TXNIP knockdown led to increased in vitro and in vivo breast cancer cell growth accompanied by p27 reduction and GLUT1 induction. Interestingly, estrogen receptor (ER)-positive breast cancer samples showed higher TXNIP expression compared to ER-negative samples. TXNIP expression decreased when ER signaling was activated by estradiol, while its expression increased under ER blockage by anti-estrogen fulvestrant. In addition, TXNIP knockdown in breast cancer cells caused significant reduction in the cell-growth inhibitory effect of anti-estrogen fulvestrant. In conclusion, our data demonstrated that TXNIP functions to suppress high proliferative activity and estrogen-dependent cell growth in breast cancer.
Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulin-like growth factor 1 (IGF1) deficiencies. Life-long exposure to minute endogenous IGF1 levels is linked to low stature as well as a number of endocrine and metabolic abnormalities. While elevated IGF1 is correlated with increased cancer incidence, epidemiological studies revealed that patients with LS do not develop tumors. The mechanisms associated with cancer protection in LS are yet to be discovered. Recent genomic analyses identified a series of metabolic genes that are overrepresented in patients with LS. Given the augmented expression of these genes in a low IGF1 milieu, we hypothesized that they may constitute targets for IGF1 action. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular redox control by thioredoxin. TXNIP serves as a glucose and oxidative stress sensor, being commonly silenced by genetic or epigenetic events in cancer cells. Consistent with its enhanced expression in LS, we provide evidence that
Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induces nuclear factor-like 2 (Nrf2) antioxidant response, endoplasmic reticulum (ER) stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes such as thioredoxin-interacting protein 1 (TXNIP) and early growth response 1 (EGR1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer.
DHHC-type protein acyltransferases may regulate the localization, stability, and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types.
Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide, and its incidence is increasing rapidly in the United States, tripling over the past 3 decades. The current chemotherapeutic strategies against localized and metastatic HCC are ineffective. Here we report that 6-methoxyethylamino-numonafide (MEAN) is a potent growth inhibitor of murine xenografts of 2 human HCC cell lines. At the same dose and with the same treatment strategies, MEAN was more efficacious in inhibiting tumor growth in mice than sorafenib, the only approved drug for HCC. Treatment by MEAN at an effective dose for 6 wk was well tolerated by animals. Combined therapy using both sorafenib and MEAN enhanced tumor growth inhibition over monotherapy with either agent. Additional experiments revealed that MEAN inhibited tumor growth through mechanisms distinct from those of either its parent compound, amonafide, or sorafenib. MEAN suppressed C-MYC expression and increased expression of several tumor suppressor genes, including Src homology region 2 domain-containing phosphatase-1 (
Abu El Maaty MA, Alborzinia H, Khan SJ, et al.1,25(OH)
Biochim Biophys Acta Mol Cell Res. 2017; 1864(10):1618-1630 [PubMed
] Related Publications
Prostate cell metabolism exhibits distinct profiles pre- and post-malignancy. The malignant metabolic shift converts prostate cells from "citrate-producing" to "citrate-oxidizing" cells, thereby enhancing glucose metabolism, a phenotype that contrasts classical tumoral Warburg metabolism. An on-line biosensor chip system (BIONAS 2500) was used to monitor metabolic changes (glycolysis and respiration) in response to the putative anti-cancer nutraceutical 1,25-dihydroxyvitamin D
Lin F, Zhang P, Zuo Z, et al.Thioredoxin-1 promotes colorectal cancer invasion and metastasis through crosstalk with S100P.
Cancer Lett. 2017; 401:1-10 [PubMed
] Related Publications
Thioredoxin-1 (Trx-1) is a small redox-regulating protein, which plays an important role in several cellular functions. Despite recent advances in understanding the biology of Trx-1, the role of Trx-1 and its underlying signaling mechanism in colorectal cancer (CRC) metastasis have not been extensively studied. In this study, we observed that Trx-1 expression is increased in CRC tissues compared to the paired non-cancerous tissues and is significantly correlated with clinical staging, lymph node metastasis and poor survival. Overexpression of Trx-1 enhanced CRC cell invasion and metastasis in vitro and in vivo. Conversely, suppression of Trx-1 expression decreased cell invasion and metastasis in vitro and in vivo. Moreover, Trx-1 activates S100P gene transcription. S100P, in turn, promotes Trx-1 expression and nuclear localization by upregulating p-ERK1/2 and downregulating TXNIP expression. Our finding provides new insight into the mechanism of Trx-1/S100P axis in the promotion of CRC metastasis, and suggests that the Trx-1/S100P axis and their related signaling pathways could be novel targets for the treatment of metastatic CRC.
Li J, Yue Z, Xiong W, et al.TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation.
Oncol Rep. 2017; 37(6):3369-3376 [PubMed
] Related Publications
Thioredoxin binding protein (thioredoxin-interacting protein, TXNIP), known as vitamin D3 increase protein 1, has been identified as a tumor suppressor in various cancers such as pancreatic, breast, lung and thyroid cancer. However, the role of TXNIP in hepatocellular carcinoma cell proliferation and apoptosis remains unknown. In this study, we first used qRT-PCR, western blotting and immunohistochemistry to compare the expression of TXNIP between hepatocellular carcinoma tissues and tumor-adjacent normal liver tissues. In vitro, we explored the role of TXNIP in hepatocellular carcinoma progression via transfection of the pcDNA-3.1-TXNIP plasmid into SMMC7221 cells. Our results showed that the expression of TXNIP was significantly decreased in hepatocellular carcinoma tissues. Moreover, TXNIP over-expression inhibited hepatocellular carcinoma cell proliferation and induced apoptosis by triggering mitochondrial-mediated ROS generation and activating MAPK pathways. This study provides insight into the molecular mechanisms of TXNIP overexpression in liver cancer cell survival and apoptosis and indicated that TXNIP may be a novel promising agent for liver cancer treatment.
Accumulating evidence suggests that natural bioactive compounds, alone or in combination with traditional chemotherapeutic agents, could be used as potential therapies to fight cancer. In this study, we employed four natural bioactive compounds (curcumin, resveratrol, melatonin, and silibinin) and studied their role in redox control and ability to promote apoptosis in androgen sensitive and insensitive prostate cancer cells. Here is shown that curcumin and resveratrol promote ROS production and induce apoptosis in LNCaP and PC-3. An increase in reactive species is a trigger event in curcumin-induced apoptosis and a consequence of resveratrol effects on other pathways within these cells. Moreover, here we demonstrated that these four compounds affect differently one of the main intracellular redox regulator, the thioredoxin system. Exposure to curcumin and resveratrol promoted TRX1 oxidation and altered its subcellular location. Furthermore, resveratrol diminished TRX1 levels in PC-3 cells and increased the expression of its inhibitor TXNIP. Conversly, melatonin and silibinin only worked as cytostatic agents, reducing ROS levels and showing preventive effects against TRX oxidation. All together, this work explores the effect of compounds currently tested as chemo-preventive agents in prostate cancer therapy, on the TRX1 redox state and function. Our work shows the importance that the TRX system might have within the differences found in their mechanisms of action. These bioactive compounds trigger different responses and affect ROS production and redox systems in prostate cancer cells, suggesting the key role that redox-related pathways might play in processes like differentiation or survival in prostate cancer.
Cai Z, Zhang C, Zou Y, et al.Tissue thioredoxin-interacting protein expression predicted recurrence in patients with meningiomas.
Int J Clin Oncol. 2017; 22(4):660-666 [PubMed
] Related Publications
BACKGROUND: The redox regulatory protein, thioredoxin-interacting protein (TXNIP), has been confirmed as an important tumor suppressor gene in various types of human cancers. In previous studies, we found that overexpression of tumor suppressor gene RIZ1 in meningiomas can significantly improve the expression of TXNIP by microarray data analysis. Therefore, we hypothesized that TXNIP was associated with the initiation and progression of meningiomas.
METHODS: First, we evaluated the expression of TXNIP and Ki-67 in meningioma tissues from 65 patients using immunohistochemistry. We also analyzed the correlation between TXNIP immunoreactivity and clinicopathological features, as well as patient prognostic factors.
RESULTS: According to immunohistochemistry results, high-grade meningioma tissues had significantly lower expression of TXNIP than benign meningioma tissues (29.31 ± 18.70 vs 74.61 ± 7.51, P < 0.0001). TXNIP and Ki67 were negatively correlated (P < 0.0001). Moreover, the expression of TXNIP was higher in nonrecurrent high-grade meningiomas (P < 0.05). In addition, Kaplan-Meier analysis indicated that expression of TXNIP and Ki-67 was related to recurrence-free time. Multivariate Cox analysis showed that TXNIP expression level was the only independent predictor for meningioma prognosis.
CONCLUSION: Our results demonstrated that high expression of TXNIP indicates a lower pathological grade of meningnioma, and is also associated with longer recurrence-free time. Therefore, TXNIP could be regarded as a potential molecular marker to predict recurrence in patients with meningiomas.
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
Sodium butyrate (NaBu) and sodium 4-phenylbutyrate (4PBA) have promising futures in cancer treatment; however, their underlying molecular mechanisms are not clearly understood. Here, we show A549 cell death induced by NaBu and 4PBA are not the same. NaBu treatment induces a significantly higher level of A549 cell death than 4PBA. A gene expression microarray identified more than 5000 transcripts that were altered (>1.5-fold) in NaBu-treated A549 cells, but fewer than 2000 transcripts that were altered in 4PBA. Moreover, more than 100 cell cycle-associated genes were greatly repressed by NaBu, but slightly repressed by 4PBA; few genes were significantly upregulated only in 4PBA-treated cells. Gene expression was further validated by other experiments. Additionally, A549 cells that were treated with these showed changes in glucose consumption, caspase 3/7 activation and histone modifications, as well as enhanced mitochondrial superoxide production. TXNIP was strongly induced by NaBu (30- to 40-fold mRNA) but was only slightly induced by 4PBA (two to fivefold) in A549 cells. TXNIP knockdown by shRNA in A549 cells significantly attenuated caspase 3/7 activation and restored cell viability, while TXNIP overexpression significantly increased caspase 3/7 activation and cell death only in NaBu-treated cells. Moreover, TXNIP also regulated NaBu- but not 4PBA-induced H4K5 acetylation and H3K4 trimethylation, possibly by increasing WDR5 expression. Finally, we demonstrated that 4PBA induced a mitochondrial superoxide-associated cell death, while NaBu did so mainly through a TXNIP-mediated pathway. The above data might benefit the future clinic application.
RNF2, also known as RING1b or RING2, is identified as the catalytic subunit of polycomb repressive complex 1 (PRC1), which mediates the mono-ubiquitination of histone H2A. RNF2 has been proved to have oncogenic function in many kinds of cancers, but the function of RNF2 in prostate cancer (PCa) has not been evaluated. Here we show that PCa tissues showed higher RNF2 expression than the benign prostatic hyperplasia (BPH) tissues. Knockdown of RNF2 in PCa cells resulted in cell cycle arrest, increased apoptosis and inhibited cell proliferation, and the growth of RNF2 knockdown PCa xenografts were obviously inhibited in nude mice. Gene microarray analysis was performed and tumor suppressor gene TXNIP was found to be significantly increased in RNF2 knockdown cells. Simultaneously knockdown of RNF2 and TXNIP can partially rescue the arrested cell cycle, increased apoptosis and inhibited cell proliferation in RNF2 single knockdown cells. Furthermore, ChIP assay result showed that RNF2 enriched at the TXNIP promoter, and the enrichment of RNF2 and ubiquitination of H2A in TXNIP promoter was obviously inhibited in RNF2 knockdown cells. In conclusion, our results demonstrate that RNF2 functions as an oncogene in PCa and RNF2 may regulate the progression of PCa through the inhibition of TXNIP.
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment.
Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.
PURPOSE: Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.
MATERIALS AND METHODS: The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation.
RESULTS: The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (
CONCLUSION: The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.
MiR-204 and miR-211 (miR-204/211) share the same seed site sequence, targeting many of the same genes. Their role in cancer development remains controversial, as both cell proliferative and suppressive effects have been identified. This study aimed to address the relationship between the two structurally similar microRNAs (miRs) by examining their target genes in depth as well as to reveal their contribution in breast cancer cells. Genome-wide pathway analysis with the dysregulated genes after overexpression of either of the two miRs in MCF-7 breast cancer cell identified the "Cancer"- and "Cell signaling"-related pathway as the top pathway for miR-204 and miR-211, respectively. The majority of the target genes for both miRs notably comprised ones that have been characterized to drive cells anti-tumorigenic. Accordingly, the miRs induced the proliferation of MCF-7 and MDA-MB-231 cells, judged by cell proliferation as well as colony forming assay. Tumor suppressors, MX1 and TXNIP, were proven to be direct targets of the miRs. In addition, a high association was observed between miR-204 and miR-211 expression in breast cancer tissue. Our results indicate that miR-204/211 serve to increase cell proliferation at least in MCF-7 and MDA-MB-231 breast cancer cells by downregulating tumor suppressor genes.
Ji S, Qin Y, Liang C, et al.FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer.
Clin Cancer Res. 2016; 22(15):3950-60 [PubMed
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PURPOSE: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy.
EXPERIMENTAL DESIGN: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo Finally, gene expression profiling was performed to identify core signaling pathways.
RESULTS: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose ((18)F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner.
CONCLUSIONS: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950-60. ©2016 AACR.
PURPOSE: To investigate the difference of expression of autophagy and reactive oxygen species (ROS) related proteins in adenoid cystic carcinoma (ACC) of lacrimal gland in comparison with ACC of salivary gland.
MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissue samples from patients pathologically diagnosed as lacrimal gland ACC (n=11) and salivary gland ACC (n=64) were used. Immunochemistry was used to measure expression of autophagy related proteins [beclin-1, light chain (LC) 3A, LC3B, p62, and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] and ROS related proteins [catalase, thioredoxinreductase, glutathione S-transferasepi (GSTpi), thioredoxin interacting protein, and manganese superoxide dismutase (MnSOD)]. The prognostic factors related to disease-free and overall survival (OS) in lacrimal gland ACC by log-rank tests, were determined.
RESULTS: GSTpi in stromal cells was more highly expressed in lacrimal gland ACC (p=0.006), however, MnSOD in epithelial cells was expressed more in salivary gland ACC (p=0.046). LC3B positivity and BNIP3 positivity in epithelial component were associated with shorter disease-free survival (both p=0.002), and LC3A positivity in stromal component was the factor related to shorter OS (p=0.005).
CONCLUSION: This is the first study to demonstrate the expression of autophagy and ROS related proteins in lacrimal gland ACC in comparison with the salivary gland ACC, which would provide a basis for further study of autophagy and ROS mechanism as novel therapeutic targets in lacrimal gland ACC.
Noguchi C, Kamitori K, Hossain A, et al.D-Allose Inhibits Cancer Cell Growth by Reducing GLUT1 Expression.
Tohoku J Exp Med. 2016; 238(2):131-41 [PubMed
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Glucose is a major energy source for mammalian cells and is transported into cells via cell-specific expression of various glucose transporters (GLUTs). Especially, cancer cells require massive amounts of glucose as an energy source for their dysregulated growth and thus over-express GLUTs. d-allose, a C-3 epimer of d-glucose, is one of rare sugars that exist in small quantities in nature. We have shown that d-allose induces the tumor suppressor gene coding for thioredoxin interacting protein (TXNIP) and inhibits cancer cell growth by G1 cell cycle arrest. It has also been reported that GLUTs including GLUT1 are over-expressed in many cancer cell lines, which may contribute to larger glucose utilization. Since d-allose suppresses the growth of cancer cells through the upregulation of TXNIP expression, our present study focused on whether d-allose down-regulates GLUT1 expression via TXNIP expression and thus suppresses cancer cell growth. Western blot and real-time PCR analyses revealed that d-allose significantly induced TXNIP expression and inhibited GLUT1 expression in a dose-dependent manner in three human cancer cell lines: hepatocellular carcinoma (HuH-7), Caucasian breast adenocarcinoma (MDA-MB-231), and neuroblastoma (SH-SY5Y). In these cell lines, d-allose treatment inhibited cell growth. Importantly, d-allose treatment decreased glucose uptake, as measured by the uptake of 2-deoxy d-glucose. Moreover, the reporter assays showed that d-allose decreased the expression of luciferase through the hypoxia response element present in the tested promoter region. These results suggest that d-allose may cause the inhibition of cancer growth by reducing both GLUT1 expression and glucose uptake.
Metabolic reprogramming towards aerobic glycolysis is a common feature of transformed cells and can be driven by a network of transcription factors. It is well established that c-Myc and hypoxia-inducible factor-1α (HIF-1α) contribute to metabolic reprogramming by driving the expression of glycolytic target genes. More recently, the c-Myc-related transcription factor MondoA has been shown to restrict glucose uptake and aerobic glycolysis via its induction of thioredoxin-interacting protein (TXNIP). Three recent studies demonstrate that complex and cancer type-specific interactions between c-Myc, MondoA and HIF-1α underlie metabolism, tumourigenesis and drug response. In triple-negative breast cancer, c-Myc blocks MondoA-dependent activation of TXNIP to stimulate aerobic glycolysis. In contrast, in neuroblastoma, N-Myc requires MondoA for metabolic reprogramming and tumourigenesis. Finally, the therapeutic response of BRAF(V600E) melanoma cells to vemurafenib requires downregulation of c-Myc and HIF-1α and upregulation of MondoA-TXNIP, and the subsequent reprogramming away from aerobic glycolysis. In this minireview we highlight the findings in these three studies and present a working model to explain why c-Myc and MondoA function cooperatively in some cancers and antagonistically in others.