Gene Summary

Gene:NR0B1; nuclear receptor subfamily 0 group B member 1
Summary:This gene encodes a protein that contains a DNA-binding domain. The encoded protein acts as a dominant-negative regulator of transcription which is mediated by the retinoic acid receptor. This protein also functions as an anti-testis gene by acting antagonistically to Sry. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor subfamily 0 group B member 1
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (41)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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

  • X Chromosome
  • Infant
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Carcinogenesis
  • Steroidogenic Factor 1
  • Polymerase Chain Reaction
  • NR0B1
  • Gene Expression Profiling
  • Adrenocortical Cancer
  • Gene Expression
  • Transcription Factors
  • Up-Regulation
  • Transcriptional Activation
  • DNA-Binding Proteins
  • Cancer Stem Cells
  • Receptors, Retinoic Acid
  • Microsatellite Repeats
  • Immunohistochemistry
  • Homeodomain Proteins
  • DAX-1 Orphan Nuclear Receptor
  • Oncogene Fusion Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Bone Cancer
  • Childhood Cancer
  • Promoter Regions
  • Molecular Sequence Data
  • Neoplastic Cell Transformation
  • RNA-Binding Protein EWS
  • Ewing's Sarcoma
  • Lung Cancer
  • Wilms Tumour
  • Young Adult
  • Repressor Proteins
  • Cell Proliferation
  • Adenocarcinoma
  • Base Sequence
  • Transfection
  • FLI1
  • Fushi Tarazu Transcription Factors
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: NR0B1 (cancer-related)

Tripathy S, Tripathi M, Dattagupta S, et al.
In Vivo PSMA Expression in Head and Neck Paragangliomas on 68Ga PSMA 11 PET/CT.
Clin Nucl Med. 2019; 44(6):e398-e400 [PubMed] Related Publications
Head and neck paragangliomas are rare and often asymptomatic tumors and mostly present as painless masses. We describe Ga PSMA 11 PET/CT and Ga DOTANOC PET/CT findings of a 40 year old man with triple head and neck paragangliomas with emphasis on exploring the possible theranostic options.

Fu R, Yang P, Sajid A, Li Z
Avenanthramide A Induces Cellular Senescence via miR-129-3p/Pirh2/p53 Signaling Pathway To Suppress Colon Cancer Growth.
J Agric Food Chem. 2019; 67(17):4808-4816 [PubMed] Related Publications
Cellular senescence is the state of irreversible cell cycle arrest that provides a blockade during oncogenic transformation and tumor development. Avenanthramide A (AVN A) is an active ingredient exclusively extracted from oats, which possesses antioxidant, anti-inflammatory, and anticancer activities. However, the underlying mechanism(s) of AVN A in the prevention of cancer progression remains unclear. In the current study, we revealed that AVN A notably attenuated tumor formation in an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model. AVN A treatment triggered cellular senescence in human colon cancer cells, evidenced by enlarging cellular size, upregulating β-galactosidase activity, γ-H2AX positive staining, and G1 phase arrest. Moreover, AVN A treatment significantly increased the expression of miR-129-3p, which markedly repressed the E3 ubiquitin ligase Pirh2 and two other targets, IGF2BP3 and CDK6. The Pirh2 silencing by miR-129-3p led to a significant increase in protein levels of p53 and its downstream target p21, which subsequently induced cell senescence. Taken together, our data indicate that miR-129-3p/Pirh2/p53 is a critical signaling pathway in AVN A induced cellular senescence and AVN A could be a potential chemopreventive strategy for cancer treatment.

Penrose HM, Cable C, Heller S, et al.
Loss of Forkhead Box O3 Facilitates Inflammatory Colon Cancer: Transcriptome Profiling of the Immune Landscape and Novel Targets.
Cell Mol Gastroenterol Hepatol. 2019; 7(2):391-408 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: Diminished forkhead box O3 (FOXO3) function drives inflammation and cancer growth; however, mechanisms fostering these pathobiologies are unclear. Here, we aimed to identify in colon loss of FOXO3-dependent cellular and molecular changes that facilitate inflammation-mediated tumor growth.
METHODS: FOXO3 knockout (KO) and wild-type (WT) mice were used in the AOM/DSS model of inflammation-mediated colon cancer. Bioinformatics were used for profiling of mRNA sequencing data from human and mouse colon and tumors; specific targets were validated in human colon cancer cells (shFOXO3).
RESULTS: In mice, FOXO3 deficiency led to significantly elevated colonic tumor burden (incidence and size) compared with WT (P < .05). In FOXO3 KO colon, activated molecular pathways overlapped with those associated with mouse and human colonic inflammation and cancer, especially human colonic tumors with inflammatory microsatellite instability (false discovery rate < 0.05). FOXO3 KO colon, similar to tumors, had increased neutrophils, macrophages, B cells, T cells, and decreased natural killer cells (false discovery rate < 0.05). Moreover, in KO colon differentially expressed transcripts were linked to activation of inflammatory nuclear factor kappa B, tumorigenic cMyc, and bacterial Toll-like receptor signaling. Among differentially expressed transcripts, we validated altered expression of integrin subunit alpha 2 (ITGA2), ADAM metallopeptidase with thrombospondin type 1 motif 12, and ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 5 in mouse WT and FOXO3 KO colon and tumors (P < .05). Similarly, their altered expression was found in human inflammatory bowel disease and colon cancer tissues and linked to poor patient survival. Ultimately, in human colon cancer cells, FOXO3 knockdown (shFOXO3) led to significantly increased ITGA2, and silencing ITGA2 (siRNA) alone diminished cell growth.
CONCLUSIONS: We identified the loss of FOXO3-mediated immune landscape, pathways, and transcripts that could serve as biomarkers and new targets for inflammatory colon cancer treatment.

Li D, Xiao L, Ge Y, et al.
High expression of Tob1 indicates poor survival outcome and promotes tumour progression via a Wnt positive feedback loop in colon cancer.
Mol Cancer. 2018; 17(1):159 [PubMed] Free Access to Full Article Related Publications
Tob1, a Tob/BTG anti-proliferative protein family member, functions as a tumour suppressor in many cancers. Here, we reveal a unique oncogenic role of Tob1 in colon cancer. Tob1 expression was upregulated during colon cancer progression, was significantly correlated with tumour size and tumour differentiation, and was a prognostic indicator of colon cancer. Unlike in other cancers, where nuclear Tob1 performs anticancer activity, Tob1 is predominantly localized in the cytosol of colon cancer cells, where this protein binds and stabilizes β-catenin to activate Wnt/β-catenin signalling, which in turn enhances Tob1 expression, thus forming a positive feedback loop to promote cell proliferation. Moreover, Tob1 deficiency led to reduced tumourigenesis in AOM/DSS-treated and Apc

Hattori N, Niwa T, Ishida T, et al.
Antibiotics suppress colon tumorigenesis through inhibition of aberrant DNA methylation in an azoxymethane and dextran sulfate sodium colitis model.
Cancer Sci. 2019; 110(1):147-156 [PubMed] Free Access to Full Article Related Publications
Chronic inflammation is involved in the development of colon cancer by inducing mutations and aberrant DNA methylation in colon epithelial cells. Furthermore, there is growing evidence that colonic microbiota modulates the inflammation response in the host and influences colon tumorigenesis. However, the influence of colonic microbiota on aberrant DNA methylation remains unknown. Here, we show the effect of colonic microbes on DNA methylation and tumorigenicity using a mouse model of human ulcerative colitis. Mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS) showed an increase in degree of colitis, as estimated by body weight, occult blood, and stool consistency/diarrhea at 2 weeks after treatment, but treatment with antibiotics markedly reduced the severity of the colitis. Although mucosal hyperplasia and increased inflammation-related genes were observed in the colonic epithelial cells of the AOM/DSS-treated mice, treatment with antibiotics abrogated these changes. In addition, treatment with antibiotics significantly decreased the number of mucosal nodules from 5.9 ± 5.3 to 0.2 ± 0.6 (P < .01) and area of occupancy from 50.1 ± 57.4 to 0.5 ± 1.4 mm

Sand FL, Nielsen DMB, Frederiksen MH, et al.
The prognostic value of p16 and p53 expression for survival after vulvar cancer: A systematic review and meta-analysis.
Gynecol Oncol. 2019; 152(1):208-217 [PubMed] Related Publications
The tumor suppressor proteins p16 and p53 have been suggested to have prognostic value in some human papillomavirus (HPV)-associated cancers, however, this has been less well established for vulvar cancer. The aim of this review and meta-analysis was to examine the prognostic value of p16 and p53 expression status on survival after vulvar squamous cell carcinoma (VSCC). We conducted a thorough systematic literature search of multiple databases to identify studies examining survival after histolocally verified VSCC that were tested for p16 and/or p53. A total of 18 eligible studies were included. Using a fixed-effects model we calculated study-specific and pooled hazard ratios (HRs) of 5-year overall survival (OS). In the analyses of OS, we included 475 VSCC cases tested for p16 expression of which 38% were p16 positive. The pooled HR

Zhou D, Jin J, Liu Q, et al.
PPARδ agonist enhances colitis-associated colorectal cancer.
Eur J Pharmacol. 2019; 842:248-254 [PubMed] Related Publications
As a nuclear receptor, peroxisome proliferator-activated receptor-δ (PPARδ) plays a critical role in regulating inflammation and cancer, while it is still unclear the mechanism of PPARδ agonist GW501516 on colitis-associated colorectal cancer. Here we found that GW501516 significantly enhanced colitis-associated colorectal cancer in AOM/DSS-induced mice. In addition, PPARδ agonist GW501516 enhanced pro-inflammatory gene expressions (COX-2, IL-6, IL-8 and MCP-1) in inflamed colon. Further analysis showed that GW501516 increased the expressions of Glut1 and SLC1A5 in colon cancer cells as well as AOM/DSS-induced colorectal tumors. These findings revealed a new mechanism of PPARδ agonist GW501516-mediated colitis-associated colorectal cancer.

Eckstein M, Wirtz RM, Gross-Weege M, et al.
mRNA-Expression of
Int J Mol Sci. 2018; 19(11) [PubMed] Free Access to Full Article Related Publications
Recently, muscle-invasive bladder cancer (MIBC) has been subclassified by gene expression profiling, with a substantial impact on therapy response and patient outcome. We tested whether these complex molecular subtypes of MIBC can be determined by mRNA detection of keratin 5 (

Moreira-Barbosa C, Barros-Silva D, Costa-Pinheiro P, et al.
Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients.
Clin Epigenetics. 2018; 10(1):132 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prostate cancer (PCa) is one of the most common cancers among men worldwide. Current screening methods for PCa display limited sensitivity and specificity, not stratifying for disease aggressiveness. Hence, development and validation of new molecular markers is needed. Aberrant gene promoter methylation is common in PCa and has shown promise as clinical biomarker. Herein, we assessed and compared the diagnostic and prognostic performance of two-gene panel promoter methylation in the same sample sets.
METHODS: Promoter methylation of panel #1 (singleplex-miR-34b/c and miR-193b) and panel #2 (multiplex-APC, GSTP1, and RARβ2) was evaluated using MethyLight methodology in two different cohorts [prostate biopsy (#1) and urine sediment (#2)]. Biomarkers' diagnostic (validity estimates) and prognostic (disease-specific survival, disease-free survival, and progression-free survival) performance was assessed.
RESULTS: Promoter methylation levels of both panels showed the highest levels in PCa samples in both cohorts. In tissue samples, methylation panel #1 and panel #2 detected PCa with AUC of 0.9775 and 1.0, respectively, whereas in urine samples, panel #2 demonstrated superior performance although a combination of miR-34b/c, miR-193b, APC, and RARβ2 disclosed the best results (AUC = 0.9817). Furthermore, higher mir-34b/c and panel #2 methylation independently predicted for shorter DSS. Furthermore, time-dependent ROC curves showed that both miR-34b/c and GSTP1 methylation levels identify with impressive performance patients that relapse up to 15 years after diagnosis (AUC = 0.751 and AUC = 0.765, respectively).
CONCLUSIONS: We concluded that quantitative gene panel promoter methylation might be a clinically useful tool for PCa non-invasive detection and risk stratification for disease aggressiveness in both tissue biopsies and urines.

Ries M, Khreish F, Veith C, et al.
Large Paraesophageal Schwannoma With Intense Prostate-Specific Membrane Antigen Expression on 68Ga-PSMA-PET/CT Mimicking Lymph Node Metastasis in a Patient With Prostate Cancer.
Clin Nucl Med. 2019; 44(2):153-154 [PubMed] Related Publications
Prostate-specific membrane antigen (PSMA)-PET/CT as an emerging modality in molecular imaging will lead to earlier detection and localization of relapse in prostate cancer but will undoubtedly also lead to false-positive findings, as it becomes clear that this new tracer is not as specific as its name would suggest. In this context, we present a case of a large PSMA-expressing schwannoma, a rare nerve sheath tumor mimicking paraesophageal lymph node metastasis in a patient with a history of prostate cancer and biochemical recurrence.

Mo JS, Han SH, Yun KJ, Chae SC
MicroRNA 429 regulates the expression of CHMP5 in the inflammatory colitis and colorectal cancer cells.
Inflamm Res. 2018; 67(11-12):985-996 [PubMed] Related Publications
OBJECTIVE AND DESIGN: MicroRNAs (miRNAs) play an important role in the pathogenesis of human diseases by regulating the expression of target genes in specific cells or tissues. In this study, we analyzed the association between the MIR429 and its target gene, charged multivesicular body protein 5 (CHMP5), in human colon cancer cells and in a DSS-induced colitis mouse model.
MATERIALS AND METHODS: A luciferase reporter system was used to confirm the effect of MIR429 on CHMP5 expression. Protein or mRNA expression of the target gene and associated molecules were measured by Western blot or quantitative RT-PCR (qRT-PCR), respectively. Flow cytometry was used to compare cell viability or cell cycle progression.
RESULTS: CHMP5 mRNA and protein expression was directly down-regulated by MIR429. We found that MIR429 inhibited colon cancer cell growth and cell cycle progression, and CHMP5 was overexpressed in the DSS-induced colitis mouse model and human ulcerative colitis (UC) tissues.
CONCLUSIONS: Our findings show that CHMP5 is a direct target of MIR429 in human colon cancer cell lines and suggest that CHMP5 up-regulation as a result of reduced MIR429 expression in DSS-induced mice colitis tissues and human UC tissues may restrict apoptosis and promote cell proliferation.

Pires KSN, Sun SY, Gonçalves CM, et al.
Versican silencing in BeWo cells and its implication in gestational trophoblastic diseases.
Histochem Cell Biol. 2019; 151(4):305-313 [PubMed] Related Publications
Versican is a proteoglycan known to interact with cells to influence their ability to proliferate, differentiate, migrate, invade and assemble extracellular matrix, with all of these cell functions present during placentation. In the placenta, cytotrophoblast cells have the ability to differentiate into the syncytiotrophoblast, a mechanism that is greatly increased in gestational trophoblastic diseases (GTD). Nevertheless, the molecular signaling underlying the increased syncytiotrophoblast differentiation are still being unveiled and may result in novel therapeutic targets for GTD. Versican expression was investigated to establish its differential expression among GTD (partial moles, complete moles, invasive moles and choriocarcinoma) and the possible functional outcomes from versican gene silencing. Tissue samples had their versican expression evaluated using immunohistochemistry and RT-PCR. BeWo cells were employed for versican silencing with siRNA and the efficiency was confirmed by RT-PCR, immunofluorescence and flow cytometry. Cell death and forskolin-induced syncytialization were analyzed by a morphological analysis and human chorionic gonadotropin (hCG) production using immunofluorescence. Versican V0 and V1 isoforms were mainly expressed in the syncytiotrophoblast and they were the most expressed in benign rather than in malignant tumors. BeWo cells also expressed V0 and V1 isoforms, but only in cells undergoing syncytial fusion. After versican silencing, cell death was greatly increased, whereas spontaneous and forskolin-induced syncytialization decreased as well as hCG production. Versican is differentially expressed in GTD and is important for hydatidiform moles pathophysiology, protecting trophoblast cells from death and playing a role in their differentiation and functionality.

Wang T, Fan C, Yao A, et al.
The Adaptor Protein CARD9 Protects against Colon Cancer by Restricting Mycobiota-Mediated Expansion of Myeloid-Derived Suppressor Cells.
Immunity. 2018; 49(3):504-514.e4 [PubMed] Related Publications
The adaptor protein CARD9 links detection of fungi by surface receptors to the activation of the NF-κB pathway. Mice deficient in CARD9 exhibit dysbiosis and are more susceptible to colitis. Here we examined the impact of Card9 deficiency in the development of colitis-associated colon cancer (CAC). Treatment of Card9

Pleiman JK, Irving AA, Wang Z, et al.
The conserved protective cyclic AMP-phosphodiesterase function PDE4B is expressed in the adenoma and adjacent normal colonic epithelium of mammals and silenced in colorectal cancer.
PLoS Genet. 2018; 14(9):e1007611 [PubMed] Free Access to Full Article Related Publications
Conservation over three mammalian genera-the mouse, rat, and human-has been found for a subset of the transcripts whose level differs between the adenoma and normal epithelium of the colon. Pde4b is one of the triply conserved transcripts whose level is enhanced both in the colonic adenoma and in the normal colonic epithelium, especially adjacent to adenomas. It encodes the phosphodiesterase PDE4B, specific for cAMP. Loss of PDE4B function in the ApcMin/+ mouse leads to a significant increase in the number of colonic adenomas. Similarly, Pde4b-deficient ApcMin/+ mice are hypersensitive to treatment by the inflammatory agent DSS, becoming moribund soon after treatment. These observations imply that the PDE4B function protects against ApcMin-induced adenomagenesis and inflammatory lethality. The paradoxical enhancement of the Pde4b transcript in the adenoma versus this inferred protective function of PDE4B can be rationalized by a feedback model in which PDE4B is first activated by early oncogenic stress involving cAMP and then, as reported for frank human colon cancer, inactivated by epigenetic silencing.

Sinha P, Haughey BH, Kallogjeri D, Jackson RS
Long-term analysis of transorally resected p16 + Oropharynx cancer: Outcomes and prognostic factors.
Laryngoscope. 2019; 129(5):1141-1149 [PubMed] Related Publications
OBJECTIVE: We observed high survival in a previous report of a p16-positive, oropharyngeal carcinoma (OPC) cohort treated primarily with transoral laser microsurgery (TLM) ± adjuvant therapy and followed for ≥ 12 months. To address long-term outcomes of primary transoral surgery for this unique disease, we present an updated analysis of our cohort with extended follow-up.
METHODS: A prospectively assembled TLM cohort of 171 OPC patients was analyzed for disease-free, disease-specific, and overall survival (disease-free survival [DFS], disease-specific survival [DSS], overall survival [OS]) and functional outcomes, with a minimum follow-up of 60 months or to death.
RESULTS: Median follow-up was 103 (60-201) months. Five-year DFS, DSS, and OS estimates were 85% (95% confidence interval [CI]: 80%-91%), 93% (95% CI: 89%-97%), and 90% (95% CI: 86%-95%). Recurrence occurred in 20 (12%; 7 locoregional, 13 distant); median time to recurrence was 18.8 months; and 90% occurred within 48 months. Age, smoking, American Joint Committee on Cancer 8th edition clinical tumor-category, pathologic tumor (pT)-category, pathologic tumor-node-metastasis (pTNM), and any adjuvant were significantly associated with disease-free survival in multivariable analyses, whereas pT-category, pN-category, TNM grouping, and angioinvasion were associated with DSS. A second primary developed in six (3.5%) patients. Indications for gastrostomy were recurrence/second primary (11), postadjuvant esophageal stenosis (6), comorbidities (3), and osteo/chondroradionecrosis (3); only seven (4%) had a gastrostomy tube in the absence of these factors, all of whom received adjuvant therapy. Two had a tracheostomy tube [chondoradionecrosis (1), recurrence (1)].
CONCLUSION: High 5-year survival and locoregional control were observed, with recurrence occurring more commonly as distant metastasis. The observed time to recurrence suggests posttreatment oncologic surveillance for at least 48 months. Identified prognosticators will inform adjuvant treatment considerations, trial planning, and patient counseling for long-term outcomes. Laryngoscope, 2018 LEVEL OF EVIDENCE: 2b Laryngoscope, 129:1141-1149, 2019.

Zhang HX, Xu ZS, Lin H, et al.
TRIM27 mediates STAT3 activation at retromer-positive structures to promote colitis and colitis-associated carcinogenesis.
Nat Commun. 2018; 9(1):3441 [PubMed] Free Access to Full Article Related Publications
STAT3 is a transcription factor that plays central roles in various physiological processes and its deregulation results in serious diseases including cancer. The mechanisms on how STAT3 activity is regulated remains enigmatic. Here we identify TRIM27 as a positive regulator of II-6-induced STAT3 activation and downstream gene expression. TRIM27 localizes to retromer-positive punctate structures and serves as a critical link for recruiting gp130, JAK1, and STAT3 to and subsequent phosphorylation of STAT3 at the retromer-positive structures. Overexpression of TRIM27 promotes cancer cell growth in vitro and tumor growth in nude mice, whereas knockdown of TRIM27 has opposite effects. Deficiency of TRIM27 significantly impairs dextran sulfate sodium (DSS)-induced STAT3 activation, inflammatory cytokine expression and colitis as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. These findings reveal a retromer-dependent mechanism for regulation of STAT3 activation, inflammation, and inflammation-associated cancer development.

Chen TJ, He HL, Shiue YL, et al.
High chloride channel accessory 1 expression predicts poor prognoses in patients with rectal cancer receiving chemoradiotherapy.
Int J Med Sci. 2018; 15(11):1171-1178 [PubMed] Free Access to Full Article Related Publications

Means AL, Freeman TJ, Zhu J, et al.
Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer.
Cell Mol Gastroenterol Hepatol. 2018; 6(3):257-276 [PubMed] Free Access to Full Article Related Publications
Background & Aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells.
Methods: The
Results: Dextran sodium sulfate treatment was sufficient to drive carcinogenesis in mice lacking colonic
Conclusions: TGFβ suppresses the expression of proinflammatory genes in the colon epithelium, and loss of its downstream mediator, SMAD4, is sufficient to initiate inflammation-driven colon cancer. Transcript profiling: GSE100082.

Ren J, Ding L, Zhang D, et al.
Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19.
Theranostics. 2018; 8(14):3932-3948 [PubMed] Free Access to Full Article Related Publications
Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors, including colorectal cancer (CRC). The crosstalk between carcinoma- associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment promotes tumor development and confers chemoresistance. In this study, we further investigated the underlying tumor-promoting roles of CAFs and the molecular mediators involved in these processes.

Liang H, Xiong Z, Li Y, et al.
Prognostic and Clinicopathological Value of
Biomed Res Int. 2018; 2018:4621015 [PubMed] Free Access to Full Article Related Publications

Han S, Huang T, Li W, et al.
Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis.
Cell Physiol Biochem. 2018; 48(2):516-527 [PubMed] Related Publications
BACKGROUND/AIMS: Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC.
METHODS: Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Trial sequential analysis (TSA) was used to estimate the required sample information.
RESULTS: HIF-2α protein expression was more frequent in CRC than in normal colonic tissues (OR = 150.49, P < 0.001), higher in male than female CRC patients (OR = 1.47, P = 0.008), and lower in high-grade than low-grade CRC (OR = 0.49, P = 0.029). TSA verified the reliability of the above results. HIF-2α expression was not linked to the prognosis of CRC in overall survival (OS), disease-specific survival (DSS), metastasis-free survival, and relapse-free survival, and no significant correlation was found between HIF-2α alteration and OS or disease-free survival (DFS) of CRC. Expression of both HIF-2α and vascular endothelial growth factor (VEGFA, VEGFB, or VEGFC) was associated with a poor metastasis-free survival of CRC (HR = 6.95, HR = 113.51, and HR = 8.11, respectively). No association was observed between HIF-2α expression and DFS in other cancers, but HIF-2α expression was correlated with a worse DFS of CRC (HR = 1.23, P = 0.037). Moreover, HIF-2α expression was linked to a good survival benefit in some cancers (B-cell lymphoma and lung adenocarcinoma: OS, multiple myeloma: DSS, breast cancer: distant metastasis-free survival, liposarcoma: distant recurrence-free survival) (all HRs < 1, Ps < 0.05).
CONCLUSIONS: HIF-2α expression may be associated with the carcinogenesis of CRC, which is higher in males than in females, negatively linked to tumor differentiation, and correlated with a worse DFS of CRC. Additional prospective studies are needed.

Feng Y, Dong YW, Song YN, et al.
MicroRNA‑449a is a potential predictor of colitis‑associated colorectal cancer progression.
Oncol Rep. 2018; 40(3):1684-1694 [PubMed] Related Publications
An early diagnosis of colitis‑associated colorectal cancer (CAC) is important for its clinical management. However, it is currently difficult to distinguish the different stages of CAC development. MicroRNA dysregulation is common in human colorectal disorders, however little is known regarding whether miRNA affects tumor progression by regulating inflammation. In the present study, we identified a novel miRNA (miR‑449a), the expression of which was significantly reduced in CAC tissues than in paired adjacent non‑cancerous tissues (ANTs). Notably, the level of miR‑449a was in a markedly decreased pattern during the neoplastic transformation of ulcerative colitis (UC)‑to‑CAC, as demonstrated by both clinical investigations and the experimental mouse model induced by AOM/DSS treatment. In addition, we observed that decreased miR‑449a expression was associated with advanced T or N status, later clinical stage and poor histological differentiation of CAC. Mechanistic studies revealed that miR‑449a inhibited the growth and metastasis of human colon cancer cells by directly binding to the 3'‑UTR of Notch‑1 and thereby, suppressed the activation of the Notch signaling pathway. Therefore, these findings provide strong evidence for the translational potential of miR‑449a in the discrimination of patients with UC that is likely to progress into CAC, from those unlikely to progress, as well as in the prognosis and diagnosis of CAC.

Chang SL, Chen TJ, Lee YE, et al.
CDKN3 expression is an independent prognostic factor and associated with advanced tumor stage in nasopharyngeal carcinoma.
Int J Med Sci. 2018; 15(10):992-998 [PubMed] Free Access to Full Article Related Publications

Yuan Y, Qi G, Shen H, et al.
Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer.
Int J Cancer. 2019; 144(7):1584-1595 [PubMed] Related Publications
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In our study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target.

Kim YE, Lee M, Gu H, et al.
HIF-1α activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice.
Dis Model Mech. 2018; 11(7) [PubMed] Free Access to Full Article Related Publications
Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (

Song J, Chen Z, Geng T, et al.
Deleting MyD88 signaling in myeloid cells promotes development of adenocarcinomas of the colon.
Cancer Lett. 2018; 433:65-75 [PubMed] Related Publications
Intestinal myeloid cells are not only essential for keeping local homeostasis, but also play an important role in regulating the occurrence of colitis and colitis-associated cancer (CAC). In these diseases, the manner in which the myeloid cells work and which molecular pathways influence them are still not fully understood. In our study, we discovered that MyD88 signaling in colonic myeloid cells participates in the development of CAC. Myeloid MyD88-deficient mice showed greater susceptibility to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC, as evidenced by the increase in the number and sizes of tumors. Myeloid MyD88 deletion markedly increased production of pro-inflammatory and pro-tumor cytokines; recruitment of more IL-1β producing-neutrophils in colon from bone marrow; increased in epithelial cell apoptosis and decreased in epithelial cell proliferation; enhancement of colon mucosal expression of COX-2, p-STAT3, β-catenin, and cyclinD1; induction of further DNA damage and β-catenin mutation. To sum up, these results suggest that myeloid MyD88 signaling protects the intestine from tumorigenesis during the development of CAC.

Deng S, Wang H, Fan H, et al.
Over-expressed miRNA-200b ameliorates ulcerative colitis-related colorectal cancer in mice through orchestrating epithelial-mesenchymal transition and inflammatory responses by channel of AKT2.
Int Immunopharmacol. 2018; 61:346-354 [PubMed] Related Publications
Our study was to explore the potential role of miRNA-200b in modulating tumorigenesis in the model of ulcerative colitis-related colorectal cancer (UCRCC) and, further, to decipher the underlying mechanisms associated with this effect. In this study, we examined a greater number of polyps or adenomas, a higher grade of epithelial dysplasia accompanied with a decrease in survival ratio in azoxymethane (AOM)/dextran sulfate sodium (DSS) model mice compared to mice treated with over-expressed miRNA-200b. Surprisingly, enforced miRNA-200b expression significantly suppressed AOM/DSS-induced up-regulation of oncologic markers including β-catenin and CD133. Independent of this, treatment with miRNA-200b obviously attenuated inflammatory responses, as indicated by down-regulating tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and blockade of AKT2-mediated NF-κB/IL-6/STAT3 signaling pathway. Furthermore, a simultaneous shift in epithelial-mesenchymal transition (EMT) markers such as E-cadherin and N-cadherin were observed to be increased and decreased, respectively. Coupled with the associated influence of over-expressed miRNA-200b were change in colorectal cell morphology shown by Transmission electron microscope (TEM) and a decrease in expression of rho-kinase2 (ROCK2) together with AKT2 phosphorylation (p-AKT2). Moreover, mice which were transfected with negative control of miRNA-200b possessed results that were in line with that obtained from AOM/DSS model mice. Additionally, we demonstrated that the 3'untranslated region (UTR) of AKT2 was a direct target of miRNA-200b through bioinformatics analysis and dual-luciferase assay. Collectively, these findings suggest that miRNA-200b's contribution to tumor-suppressing program was correlated with EMT and inflammatory responses in a AKT2-dependent manner.

Kim JY, Lim JE, Jung HH, et al.
Validation of the new AJCC eighth edition of the TNM classification for breast cancer with a single-center breast cancer cohort.
Breast Cancer Res Treat. 2018; 171(3):737-745 [PubMed] Related Publications
PURPOSE: The new eighth edition TNM classification by the AJCC for breast cancer (BC) incorporates biologic factors and gene expression prognostic panels, in addition to traditional anatomic factors. In this study, we evaluated the prognostic value of this new staging system compared to the previous AJCC 7th edition staging system.
METHODS: We conducted a retrospective analysis of women with stage I, II, or III BC who underwent curative surgery with/without adjuvant systemic therapy at Samsung Medical Center between July 2004 and December 2008.
RESULTS: Of 3,208 BCs, this study was analyzed using the information of 2,790 BC patients. Hormone receptor-positive (HR+) and human epidermal growth factor 2 (HER2)- BCs were observed in 62.9% of BCs, HR+/ HER2+ in 9.3%, HR-/HER2- in 17.0%, and HR-/HER2+ in 10.8%. In survival analysis, we observed 245 distant recurrences and 198 deaths caused by BC progression. The median follow-up duration was 116.2 months. 10-year disease-specific survival (DSS) rates according to the AJCC 7th edition criteria were 97.2% of stage IA, 100% of IB, 94.9% of IIA, 87.9% of IIB, 86.4% of IIIA, 95.7% of IIIB, and 65.7% of IIIC (p < 0.001). After applying 8th edition criteria, the 10-year DSS rates were 98.1% of stage IA, 97.7% of IB, 93.8% of IIA, 92.7% of IIB, 88.2% of IIIA, 80.8% of IIIB, and 70.3% of IIIC (p < 0.001).
CONCLUSIONS: The AJCC 8th edition clinical staging system provides a good prognostic value and addresses the weakness of the AJCC 7th edition, which uses only anatomical pathologic staging.

Ma J, Yang Y, Fu Y, et al.
PIAS3-mediated feedback loops promote chronic colitis-associated malignant transformation.
Theranostics. 2018; 8(11):3022-3037 [PubMed] Free Access to Full Article Related Publications

Niu W, Wu Z, Wang J, et al.
Tumor Necrosis Factor Ligand-Related Molecule 1A Regulates the Occurrence of Colitis-Associated Colorectal Cancer.
Dig Dis Sci. 2018; 63(9):2341-2350 [PubMed] Related Publications
BACKGROUND: Tumor necrosis factor ligand-related molecule 1 A (TLlA) is closely related to the occurrence and development of inflammatory bowel disease.
AIMS: We aimed to explore whether TLlA was involved in the occurrence of colitis-associated colorectal cancer (CAC).
METHODS: Firstly, azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to construct the CAC mice model in wild-type (WT) and TL1A transgenic (Tg) mice with TL1A high expression. The histopathological analysis was used for the evaluation of inflammation level, and the immunohistochemistry staining analysis was used to test the expression and location of proliferating cell nuclear antigen (PCNA) and β-catenin. Secondly, the HCT116 and HT29 cell lines were used for knockdown of TL1A gene for further assay including cell viability, cell clone, cell apoptosis and matrigel invasion. Western blot were used for quantitative protein expression of β-catenin and downstream oncogenes including c-myc and Cyclin D1 after knockdown of TL1A gene.
RESULTS: The evaluation of inflammation level showed that the disease activity index score and tumor formation rate were significantly higher in AOM + DSS/Tg group than that in AOM + DSS/WT group. The expression of PCNA, β-catenin, c-myc, and Cyclin D1 in AOM + DSS/Tg group was significantly higher than that in AOM + DSS/WT group. The cell experiment showed that TL1A knockdown inhibited the cell proliferation, invasion, and migration. Moreover, the expression of c-myc and Cyclin D1 was significantly decreased after TL1A knockdown.
CONCLUSIONS: TL1A can induce tumor cell proliferation and promote the occurrence of CAC by activating Wnt/β-catenin pathway.

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