NR0B1

Gene Summary

Gene:NR0B1; nuclear receptor subfamily 0, group B, member 1
Aliases: AHC, AHX, DSS, GTD, HHG, AHCH, DAX1, DAX-1, NROB1, SRXY2
Location:Xp21.3
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, GeneCard, Gene
Protein:nuclear receptor subfamily 0 group B member 1
HPRD
Source:NCBIAccessed: 21 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 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.

  • Molecular Sequence Data
  • DAX-1 Orphan Nuclear Receptor
  • Repressor Proteins
  • Binding Sites
  • Microsatellite Repeats
  • Messenger RNA
  • Transfection
  • Cancer Gene Expression Regulation
  • Receptors, Retinoic Acid
  • Wilms Tumour
  • Testis
  • X Chromosome
  • Polymerase Chain Reaction
  • Oncogene Fusion Proteins
  • FLI1
  • Up-Regulation
  • NR0B1
  • Transcriptional Activation
  • Base Sequence
  • Immunohistochemistry
  • Lung Cancer
  • Transcription
  • Fushi Tarazu Transcription Factors
  • Promoter Regions
  • DNA-Binding Proteins
  • Cell Line
  • Gene Expression Profiling
  • Adrenal Hyperplasia, Congenital
  • Ewing's Sarcoma
  • Tumor Markers
  • RTPCR
  • Steroidogenic Factor 1
  • Transcription Factors
  • RNA-Binding Protein EWS
  • Oligonucleotide Array Sequence Analysis
  • Adrenocortical Cancer
  • Young Adult
  • Bone Cancer
  • Homeodomain Proteins
  • Gene Expression
Tag cloud generated 21 August, 2015 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)

Jung G, Roh J, Lee H, et al.
Autophagic Markers BECLIN 1 and LC3 are Associated with Prognosis of Multiple Myeloma.
Acta Haematol. 2015; 134(1):17-24 [PubMed] Related Publications
BACKGROUND/AIMS: Autophagy is crucial for the survival and function of plasma cells including protection from toxic misfolded immunoglobulin and proper energy metabolism. Multiple myeloma (MM) is an indolent but eventually fatal neoplasm of plasma cells. Autophagy may play a critical role in the survival of MM cells and their response to chemotherapeutic agents. In this study, we correlated the expression of autophagy-related proteins with the prognosis of MM.
METHODS: In this retrospective cohort study, we examined the expression of the autophagic markers BECLIN 1 and microtubule-associated protein light chain 3 (LC3) in 89 cases of MM biopsied from 2001 to 2004 at the Asan Medical Center. The association of the expression scores of these markers with clinical outcomes was assessed.
RESULTS: Patients with strong immunoreactivity to BECLIN 1 or LC3 had a significantly better overall survival (OS) than patients with negative to moderate immunoreactivity (p = 0.036 and 0.018, respectively). This was also true for disease-specific survival (DSS; p = 0.051 and 0.043, respectively). In addition, LC3 immunostaining remained an independent factor impacting OS (p = 0.028) and DSS (p = 0.020) after multivariate analysis.
CONCLUSIONS: The results of this study suggest that higher immunoreactivity for autophagic markers in MM is associated with superior patient survival.

Oshima H, Nakayama M, Han TS, et al.
Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer.
Cancer Res. 2015; 75(4):766-76 [PubMed] Related Publications
Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined Apc(Δ716) Tgfbr2(ΔIEC) compound mutant mice that carry mutations in Apc and Tgfbr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple Tgfbr2(ΔIEC) mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these Tgfbr2(ΔIEC) mice developed invasive colon cancer associated with chronic inflammation. We also found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causing MMP2 activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFβ signaling-repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in Tgfbr2(ΔIEC) mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated Tgfbr2(ΔIEC) mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFβ signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans.

Xu MD, Qi P, Weng WW, et al.
Long non-coding RNA LSINCT5 predicts negative prognosis and exhibits oncogenic activity in gastric cancer.
Medicine (Baltimore). 2014; 93(28):e303 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) are recently discovered RNA transcripts that are aberrantly expressed in many tumor types. Numerous studies have suggested that lncRNAs can be utilized for cancer diagnosis and prognosis. LSINCT5 (long stress-induced non-coding transcript 5) is dramatically upregulated in breast and ovarian cancer and affects cellular proliferation. However, the expression pattern of LSINCT5 in gastrointestinal cancer and the association between aberrant expression of LSINCT5 in gastrointestinal cancer and malignancy, metastasis, or prognosis remain unknown. LSINCT5 expression was detected in gastrointestinal cancer and paired adjacent normal tissue samples or cell lines using reverse transcription quantitative PCR (RT-qPCR). We also investigated the potential relationship between tumor LSINCT5 levels and clinicopathological features of gastrointestinal cancer. Finally, we assessed whether LSINCT5 influences in vitro cell proliferation. The expression of LSINCT5 is significantly upregulated in gastrointestinal cancer tissues and cell lines relative to their normal counterparts. In addition, increased LSINCT5 expression was correlated with a larger tumor size, deeper tumor depth, and advanced clinical stage. Kaplan-Meier analysis indicated that gastric cancer (GC) and colorectal cancer (CRC) patients with higher LSINCT5 expression levels have worse disease-free survival (DFS) and disease-specific survival (DSS) rates. Moreover, multivariate analysis revealed that increased expression of LSINCT5 is an independent predictor of DFS and DSS rates in GC patients. The ectopic expression of LSINCT5 in gastrointestinal cancer cell lines resulted in an increase in cellular proliferation; conversely, knock down of LSINCT5 significantly inhibited proliferation. These results suggest that LSINCT5 may represent a novel prognostic indicator and a target for gene therapy in gastrointestinal cancer.

Lee HY, Li CC, Huang CN, et al.
INHBA overexpression indicates poor prognosis in urothelial carcinoma of urinary bladder and upper tract.
J Surg Oncol. 2015; 111(4):414-22 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) originating from the bladder (UBUC) and upper urinary tract (UTUC) is the most common type of urinary tract tumor. While its pathogenesis remains obscured. Computerizing a published transcriptomic database of UBUC (GSE31684), we identified Inhibin, Beta A (INHBA) as the most significant upregulated gene associated with tumor progression among those associated with growth factor activity (GO:0008083). We therefore analyzed the clinicopathological significance of INHBA expression in UC.
DESIGN: QuantiGene assay was used to detect INHBA transcript level in 36 UTUCs and 30 UBUCs. Immunohistochemistry evaluated by H-score was used to determine INHBA protein expression in 340 UTUCs and 296 UBUCs. INHBA expression was correlated with clinicopathological features and disease-specific survival (DSS) and metastasis-free survival (MeFS).
RESULTS: Increments of INHBA transcript level was associated with higher pT status in both UTUC and UBUC. INHBA protein overexpression was significantly associated with advanced clinicopathological features in both groups of UC. INHBA overexpression significantly implied inferior DSS (UTUC, P = 0.002; UBUC, P = 0.005) and MeFS (UTUC and UBUC, both P < 0.001) in multivariate analysis.
CONCLUSION: INHBA overexpression implies adverse clinical outcomes for UC, justifying it is a potential prognostic biomarker and a novel therapeutic target in UC.

Roshan-Moniri M, Hsing M, Butler MS, et al.
Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers.
Cancer Treat Rev. 2014; 40(10):1137-52 [PubMed] Related Publications
Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and ‘‘dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1’’ (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers.

Tosso PN, Kong Y, Scher L, et al.
Synthesis and structure-activity relationship studies of small molecule disruptors of EWS-FLI1 interactions in Ewing's sarcoma.
J Med Chem. 2014; 57(24):10290-303 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing's sarcoma family tumors (ESFT). Using our previously reported lead compound 2 (YK-4-279), we designed and synthesized a focused library of analogues. The functional inhibition of the analogues was measured by an EWS-FLI1/NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and control PANC1 cell lines devoid of the oncoprotein. Our data revealed that substitution of electron donating groups at the para-position on the phenyl ring was the most favorable for inhibition of EWS-FLI1 by analogs of 2. Compound 9u (with a dimethylamino substitution) was the most active inhibitor with GI50 = 0.26 ± 0.1 μM. Further, a correlation of growth inhibition (EWS-FLI1 expressing TC32 cells) and the luciferase reporter activity was established (R(2) = 0.84). Finally, we designed and synthesized a biotinylated analogue and determined the binding affinity for recombinant EWS-FLI1 (Kd = 4.8 ± 2.6 μM).

Li CF, Fang FM, Lan J, et al.
AMACR amplification in myxofibrosarcomas: a mechanism of overexpression that promotes cell proliferation with therapeutic relevance.
Clin Cancer Res. 2014; 20(23):6141-52 [PubMed] Related Publications
PURPOSE: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the α-methylacyl coenzyme A racemase (AMACR) at 5p13.3.
EXPERIMENTAL DESIGN: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed florescence in situ hybridization (FISH) and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpressing myxofibrosarcoma cells and xenografts, we elucidated the biologic function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide.
RESULTS: AMACR protein overexpression and gene amplification were significantly associated with each other (P < 0.001), with higher tumor grades (both P ≤ 0.002), and univariately with worse metastasis-free survival (MFS; both P < 0.0001) and disease-specific survival (DSS; P = 0.0002 for overexpression; P = 0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, P = 0.007; MFS, P = 0.001). However, 39% of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared with fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to ebselen oxide, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro, but also dose-dependently suppressed xenografted tumor growth in vivo.
CONCLUSIONS: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and may be relevant as a druggable target.

King TF, Conway GS
Swyer syndrome.
Curr Opin Endocrinol Diabetes Obes. 2014; 21(6):504-10 [PubMed] Related Publications
PURPOSE OF REVIEW: This review focuses on the pathogenesis, diagnosis, management and long-term outcomes of disorders of sex development, specifically women with Swyer syndrome (46,XY complete gonadal dysgenesis).
RECENT FINDINGS: Recent discoveries have broadened our understanding of the complex pathways involved in normal and abnormal sex development. In 46,XY gonadal dysgenesis, lack of testis development may be triggered by sex determining region Y, NR5A1, DHH or testis-determining gene loss-of-function mutations, DAX1 or WNT4 duplication or MAP3K1 gain-of-function mutations. The diagnosis and management of patients with Swyer syndrome is complex, and optimal care requires an experienced multidisciplinary team. Early diagnosis is vital because of the significant risk of germ cell tumour, and bilateral gonadectomy should be performed. Furthermore, early sex hormone treatment is necessary to induce and maintain typical pubertal development and to achieve optimal bone mineral accumulation. Pregnancy is possible via ova donation, and outcomes are similar to women with 46,XX ovarian failure.
SUMMARY: Further pathogenic gene mutations are likely to be identified, and the function, interaction and phenotypic effects of new and existing mutations will be further defined. Patients require long-term follow-up in specialist centres.

Li CF, He HL, Wang JY, et al.
Fibroblast growth factor receptor 2 overexpression is predictive of poor prognosis in rectal cancer patients receiving neoadjuvant chemoradiotherapy.
J Clin Pathol. 2014; 67(12):1056-61 [PubMed] Related Publications
AIMS: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is an increasingly used therapeutic strategy for advanced rectal cancer, but risk stratification and final outcomes remain suboptimal. Recently, the oncogenic role of the fibroblast growth factor/fibroblast growth factor receptor (FGFR) signalling pathway has been recognised; however, its clinical significance in rectal cancer has not been elucidated. In this study, we identify and validate targetable drivers associated with the FGFR signalling pathway in rectal cancer patients treated with CCRT.
METHODS: Using a published transcriptome of rectal cancers, we found FGFR2 gene significantly predicted response to CCRT. The expression levels of FGFR2, using immunohistochemistry assays, were further evaluated in 172 rectal cancer specimens that had not received any treatment. Expression levels of FGFR2 were statistically correlated with major clinicopathological features and clinical survival in this valid cohort.
RESULTS: High expression of FGFR2 was significantly related to advanced pretreatment tumour (p=0.022) and nodal status (p=0.026), post-treatment tumour (p<0.001) and nodal status (p=0.004), and inferior tumour regression grade (p<0.001). In survival analyses, high expression of FGFR2 was significantly associated with shorter local recurrence-free survival (p=0.0001), metastasis-free survival (MeFS; p=0.0003) and disease-specific survival (DSS; p<0.0001). Notably, high expression of FGFR2 was independently predictive of worse outcomes for MeFS (p=0.002, HR=5.387) and DSS (p=0.004, HR=4.997).
CONCLUSIONS: High expression of FGFR2 is correlated with advanced tumour stage, poor therapeutic response and worse survival in rectal cancer patients receiving neoadjuvant CCRT. These findings indicate that FGFR2 is a prognostic factor for treating rectal cancer.

Jiang HL, Xu D, Yu H, et al.
DAX-1 inhibits hepatocellular carcinoma proliferation by inhibiting β-catenin transcriptional activity.
Cell Physiol Biochem. 2014; 34(3):734-42 [PubMed] Related Publications
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1), an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored.
METHODS: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP) assay was used to show the interaction between DAX-1 and β-Catenin. Small interfering RNA (siRNA) was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells.
RESULTS: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with β-Catenin and attenuate its transcriptional activity.
CONCLUSION: Therefore, our results suggest a previously unknown DAX-1/β-Catenin molecular network controlling HCC development.

He HL, Lee YE, Shiue YL, et al.
Overexpression of REG4 confers an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy.
J Surg Oncol. 2014; 110(8):1002-10 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is the standard treatment for locally advanced rectal cancer. Through data mining from published transcriptomic database, we identified Regenerating Gene Type IV (REG4) as the most significantly associated gene with resistance to CCRT. This study examined the prognostic impact of REG4 expression in patients with rectal cancer receiving neoadjuvant CCRT.
METHODS: REG4 immunohistochemistry was retrospectively assessed for pre-treatment biopsy specimens from 172 rectal cancer patients who received neoadjuvant CCRT followed by surgery without initial distant metastasis. The results were correlated with the clinicopathological variables, disease-specific survival (DSS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS), as well as γ-H2AX expression in post-treatment tumor samples.
RESULTS: High expression of REG4 was associated with advanced pre-treatment nodal status (P = 0.026), advanced post-treatment tumor status (P = 0.006), advanced post-treatment nodal status (P = 0.001), advanced post-treatment tumor stage (P < 0.001), and inferior tumor regression grade (P = 0.001). Of note, high expression of REG4 emerged as an adverse prognosticator for DSS (P = 0.0004), LRFS (P = 0.0009), and MeFS (P = 0.0254). After multivariate comparisons, it remained independently prognostic for worse DSS (hazard ratio [HR] = 2.731; P = 0.025) and LRFS (HR = 2.676; P = 0.029). High expression of REG4 was also negatively associated with γ-H2AX expression (P < 0.0001, r = -0.708).
CONCLUSIONS: High expression of REG4 is associated with poor therapeutic response, adverse outcome and an aggressive phenotype in rectal cancer patients treated with neoadjuvant CCRT, justifying REG4 is a surrogate marker to predict CCRT resistance.

Sieuwerts AM, Willis S, Burns MB, et al.
Elevated APOBEC3B correlates with poor outcomes for estrogen-receptor-positive breast cancers.
Horm Cancer. 2014; 5(6):405-13 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Recent observations connected DNA cytosine deaminase APOBEC3B to the genetic evolution of breast cancer. We addressed whether APOBEC3B is associated with breast cancer clinical outcomes. APOBEC3B messenger RNA (mRNA) levels were related in 1,491 primary breast cancers to disease-free (DFS), metastasis-free (MFS), and overall survival (OS). For independent validation, APOBEC3B mRNA expression was associated with patient outcome data in five additional cohorts (over 3,500 breast cancer cases). In univariate Cox regression analysis, increasing APOBEC3B expression as a continuous variable was associated with worse DFS, MFS, and OS (hazard ratio [HR] = 1.20, 1.21, and 1.24, respectively; all P < .001). Also, in untreated ER-positive (ER+), but not in ER-, lymph-node-negative patients, high APOBEC3B levels were associated with a poor DFS (continuous variable: HR = 1.29, P = .001; dichotomized at the median level, HR = 1.66, P = .0002). This implies that APOBEC3B is a marker of pure prognosis in ER + disease. These findings were confirmed in the analyses of five independent patient sets. In these analyses, APOBEC3B expression dichotomized at the median level was associated with adverse outcomes (METABRIC discovery and validation, 788 and 706 ER + cases, disease-specific survival (DSS), HR = 1.77 and HR = 1.77, respectively, both P < .001; Affymetrix dataset, 754 ER + cases, DFS, HR = 1.57, P = 2.46E-04; NKI295, 181 ER + cases, DFS, HR = 1.72, P = .054; and BIG 1-98, 1,219 ER + cases, breast-cancer-free interval (BCFI), HR = 1.42, P = 0.0079). APOBEC3B is a marker of pure prognosis and poor outcomes for ER + breast cancer, which strongly suggests that genetic aberrations induced by APOBEC3B contribute to breast cancer progression.

Lee YY, Li CF, Lin CY, et al.
Overexpression of CPS1 is an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy.
Tumour Biol. 2014; 35(11):11097-105 [PubMed] Related Publications
Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but stratification of risk and final outcomes remain suboptimal. In view of the fact that glutamine metabolism is usually altered in cancer, we profiled and validated the significance of genes involved in this pathway in rectal cancers treated with CCRT. From a published transcriptome of rectal cancers (GSE35452), we focused on glutamine metabolic process-related genes (GO:0006541) and found upregulation of carbamoyl phosphate synthetase 1 (CPS1) gene most significantly predicted poor response to CCRT. We evaluated the expression levels of CPS1 using immunohistochemistry to analyze tumor specimens obtained during colonoscopy from 172 rectal cancer patients. Expression levels of CPS1 were further correlated with major clinicopathological features and survivals in this validation cohort. To further confirm CPS1 expression levels, Western blotting was performed for human colon epithelial primary cell (HCoEpiC) and four human colon cancer cells, including HT29, SW480, LoVo, and SW620. CPS1 overexpression was significantly related to advanced posttreatment tumor (T3, T4; P = 0.006) and nodal status (N1, N2; P < 0.001), and inferior tumor regression grade (P = 0.004). In survival analyses, CPS1 overexpression was significantly associated with shorter disease-specific survival (DSS) and metastasis-free survival (MeFS). Furthermore, using multivariate analysis, it was also independently predictive of worse DSS (P = 0.021, hazard ratio = 2.762) and MeFS (P = 0.004, hazard ratio = 3.897). CPS1 protein expression, as detected by Western blotting, is more abundant in colon cancer cells than nonneoplastic HCoEpiC. Overexpression of CPS1 is associated with poor therapeutic response and adverse outcomes among rectal cancer patients receiving CCRT, justifying the potential theranostic value of CPS1 for such patients.

Kennedy AE, Kamdar KY, Lupo PJ, et al.
Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes.
Leuk Res. 2014; 38(9):1055-60 [PubMed] Related Publications
Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83-2.35), which increased to 2.96 (95% CI=1.29-6.80) in the presence of a particular TFRC genotype for rs3817672 (P interaction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05-6.12; P interaction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52-2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29-3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.

Shibuya R, Matsuyama A, Nakamoto M, et al.
The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma.
Virchows Arch. 2014; 465(5):599-605 [PubMed] Related Publications
Ewing sarcoma (ES) is a high-grade malignant neoplasm primarily affecting children and young adults. The diagnosis of ES is often difficult because of its broad differential diagnosis comprising a diverse group of small round cell tumors (SRCTs). Although the identification of tumor type-specific fusion genes by molecular testing is the gold standard for the diagnosis of ES, such approaches are not always available in a routine pathology practice. Thus, a reliable immunohistochemical marker is required. A recent study using a limited number of tumor samples has shown that NKX2.2, a putative transcriptional target of EWSR1-FLI1, is a useful marker for the diagnosis of ES. In the present study, the immunohistochemical expression of NKX2.2 was evaluated on 46 genetically confirmed ES and 85 non-ES SRCTs, together with comparative assessment of CD99 and other molecular targets of EWSR1-FLI1, including NR0B1, E2F3, and EZH2. NKX2.2 was expressed in 37 (80 %) of the ES samples with a mostly diffuse and strong staining pattern, and 14 (16 %) of the non-ES SRCTs, including olfactory neuroblastomas, extraskeletal myxoid chondrosarcoma, mesenchymal chondrosarcoma, small cell carcinomas, and Merkel cell carcinoma, also expressed this marker. The sensitivity and specificity of the NKX2.2 expression in this cohort were 80 and 84 %, respectively. The specificity when combined with CD99 was 98 %, with exceptional expression of both markers in only two non-ES SRCTs, including one case each of mesenchymal chondrosarcoma and small cell carcinoma. NR0B1, E2F3, and EZH2 were less sensitive for specific markers for ES when applied singly or in any combination. In conclusion, the study reinforces that NKX2.2 is a useful immunohistochemical marker for ES, and that the combination of CD99 and NKX2.2 is a powerful diagnostic tool that can differentiate ES from other SRCTs.

Kim DH, Sung B, Kang YJ, et al.
Anti-inflammatory effects of betaine on AOM/DSS‑induced colon tumorigenesis in ICR male mice.
Int J Oncol. 2014; 45(3):1250-6 [PubMed] Related Publications
Betaine is an important human nutrient obtained from various foods and studies in animals and humans have provided results suggesting their pathogenesis of various chronic diseases and points to a role in risk assessment and disease prevention. However, the molecular mechanisms of its activity remain poorly understood and warrant further investigation. This study was performed to investigate the anti-inflammation and tumor preventing capacity of betaine on colitis-associated cancer in mice. In in vivo experiments, we induced colon tumors in mice by azoxymethane (AOM) and dextran sulfate sodium (DSS) and evaluated the effects of betaine on tumor growth. Administration with betaine significantly decreased the incidence of tumor formation with downregulation of inflammation. Treatment with betaine inhibited ROS generation and GSSG concentration in colonic mucosa. Based on the qPCR data, administration of betaine inhibited inflammatory cytokines such TNF-α, IL-6, iNOS and COX-2. In in vitro experiments, LPS-induced NF-κB and inflammatory-related cytokines were inhibited by betaine treatment in RAW 264.7 murine macrophage cells. Our findings suggest that betaine is one of the candidates for the prevention of inflammation-associated colon carcinogenesis.

Parris TZ, Aziz L, Kovács A, et al.
Clinical relevance of breast cancer-related genes as potential biomarkers for oral squamous cell carcinoma.
BMC Cancer. 2014; 14:324 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
BACKGROUND: Squamous cell carcinoma of the oral cavity (OSCC) is a common cancer form with relatively low 5-year survival rates, due partially to late detection and lack of complementary molecular markers as targets for treatment. Molecular profiling of head and neck cancer has revealed biological similarities with basal-like breast and lung carcinoma. Recently, we showed that 16 genes were consistently altered in invasive breast tumors displaying varying degrees of aggressiveness.
METHODS: To extend our findings from breast cancer to another cancer type with similar characteristics, we performed an integrative analysis of transcriptomic and proteomic data to evaluate the prognostic significance of the 16 putative breast cancer-related biomarkers in OSCC using independent microarray datasets and immunohistochemistry. Predictive models for disease-specific (DSS) and/or overall survival (OS) were calculated for each marker using Cox proportional hazards models.
RESULTS: We found that CBX2, SCUBE2, and STK32B protein expression were associated with important clinicopathological features for OSCC (peritumoral inflammatory infiltration, metastatic spread to the cervical lymph nodes, and tumor size). Consequently, SCUBE2 and STK32B are involved in the hedgehog signaling pathway which plays a pivotal role in metastasis and angiogenesis in cancer. In addition, CNTNAP2 and S100A8 protein expression were correlated with DSS and OS, respectively.
CONCLUSIONS: Taken together, these candidates and the hedgehog signaling pathway may be putative targets for drug development and clinical management of OSCC patients.

Lee YE, He HL, Lee SW, et al.
AMACR overexpression as a poor prognostic factor in patients with nasopharyngeal carcinoma.
Tumour Biol. 2014; 35(8):7983-91 [PubMed] Related Publications
The molecular prognostic adjunct in patients with nasopharyngeal carcinomas (NPCs) still remains obscured. Through data mining from published transcriptomic database, alpha-methylacyl-CoA racemase (AMACR) was first identified as a differentially upregulated gene in NPC tissues, which is a key enzyme for isometric conversion of fatty acids entering the β-oxidation. Given the roles of AMACR in prognostication and frontline therapeutic regimen of common carcinomas, such as prostate cancer, we explored AMACR immunoexpression status and its clinical significance in NPC patients. AMACR immunohistochemistry was retrospectively performed and analyzed using H-score for biopsy specimens from 124 NPC patients who received standard treatment without distant metastasis at initial diagnosis. Those cases with H-score larger than the median value were construed as featuring AMACR overexpression. The findings were correlated with the clinicopathological variables, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Endogenous AMACR protein expressions were assessed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting in NPC cells and non-neoplastic mucosal cells. AMACR overexpression was significantly associated with increment of primary tumor status (P = 0.009) and univariately predictive of adverse outcomes for DSS, DMFS, and LRFS. In the multivariate comparison, AMACR overexpression still remained prognostically independent to portend worse DSS (P = 0.006, hazard ratio = 2.129), DMFS (P = 0.001, hazard ratio = 2.795), and LRFS (P = 0.041, hazard ratio = 2.009), together with advanced American Joint of Cancer Committee (AJCC) stages III-IV. Compared with non-neoplastic cells, both HONE1 and TW01 NPC cells demonstrated markedly increased AMACR expression. AMACR overexpression was identified as an important prognosticator and a potential therapeutic target in the future.

Serup-Hansen E, Linnemann D, Skovrider-Ruminski W, et al.
Human papillomavirus genotyping and p16 expression as prognostic factors for patients with American Joint Committee on Cancer stages I to III carcinoma of the anal canal.
J Clin Oncol. 2014; 32(17):1812-7 [PubMed] Related Publications
PURPOSE: Carcinomas of the anal canal are strongly associated with the human papillomavirus (HPV). Expression of p16 is used as a surrogate marker of HPV infection. In a retrospective study, we evaluated HPV genotyping and p16 expression as prognostic markers of overall survival (OS) and disease-specific survival (DSS) in patients diagnosed with American Joint Committee on Cancer (AJCC) stages I to III carcinoma of the anal canal.
PATIENTS AND METHODS: HPV genotyping polymerase chain reaction (high-risk subtypes 16, 18, 31, 33, 45, 52, and 58) and immunohistochemical expression of p16 were analyzed by using paraffin-embedded tumor biopsies from 143 anal carcinomas. The patients were treated with combined chemoradiotherapy or radiotherapy alone.
RESULTS: HPV16 was detected in 81.0% of the tumors, followed by HPV33 (5.1%), HPV18 (2.2%), and HPV58 (0.7%). p16 positivity was found in 92.9% of the tumors. In univariable survival analysis, HPV positivity was significantly correlated with improved OS (74% v 52%; P=.036) and DSS (84% v 52%; P=.002), and p16 positivity was significantly correlated with improved OS (76% v 30%; P<.001) and DSS (85% v 30%; P<.001). In multivariable COX analysis that included HPV status, p16 status, sex, T stage, N stage, and treatment, p16 positivity remained an independent prognostic factor for OS (hazard ratio [HR], 0.07; 95% CI, 0.01 to 0.61; P=.016) and DSS (HR, 0.07; 95% CI, 0.01 to 0.53; P=.011).
CONCLUSION: p16 positivity is an independent prognostic factor for OS and DSS in patients with AJCC stages I to III carcinoma of the anal canal.

Chen TJ, Lee SW, Lin LC, et al.
Cyclin-dependent kinase 4 overexpression is mostly independent of gene amplification and constitutes an independent prognosticator for nasopharyngeal carcinoma.
Tumour Biol. 2014; 35(7):7209-16 [PubMed] Related Publications
Data mining in the public domain demonstrates that cyclin-dependent kinase 4 (CDK4) is highly expressed in nasopharyngeal carcinomas (NPC). Associated with cyclin-D, CDK4 phosphorylates and inactivates retinoblastoma (Rb) protein family members and mediates progression through the G1- to the S-phase of the cell cycle. Amplification and overexpression of CDK4 has been identified in various human malignancies. However, its expression and amplification has never been systemically evaluated in NPC. This study aimed to evaluate the amplification and expression status, correlation with clinicopathological features, and prognostic implications of CDK4 based on public domain dataset and in our well-defined cohort of NPC patients. The association between CDK4 transcript level and gene dosage was explored by analysis of an independent public domain dataset. We retrospectively assessed CDK4 immunoexpression in biopsies of 124 consecutive NPC patients devoid of initial distant metastasis and treated according to consistent guidelines. The results were correlated with clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific survival (DSS). High levels of CDK4 protein were positively correlated with the T 3, 4 status (p = 0.024); N 2, 3 status (p < 0.001); and the American Joint Committee on Cancer stage 3, 4 (p < 0.001). Multivariate analysis suggested high CDK4 expression was an independent prognostic indicator of worse DMeFS (p = 0.001, hazard ratio (HR) = 3.226) and DSS (p = 0.037, HR = 1.838). Although CDK4 is frequently upregulated, its gene locus is very uncommonly amplified in NPC. CDK4 overexpression is mostly independent with gene amplification and represents a potential prognostic biomarker in NPC and may indicate tumor aggressiveness through cell cycle dysregulation.

Chen T, Yang M, Yu Z, et al.
Small GTPase RBJ mediates nuclear entrapment of MEK1/MEK2 in tumor progression.
Cancer Cell. 2014; 25(5):682-96 [PubMed] Related Publications
Ras-related small GTPases play important roles in cancer. However, the roles of RBJ, a representative of the sixth subfamily of Ras-related small GTPases, in tumorigenesis and tumor progression remain unknown. Here, we report that RBJ is dysregulated in human gastrointestinal cancers and can promote carcinogenesis and tumor progression via nuclear entrapment of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)1/MEK2 and activation of ERK1/ERK2. Nucleus-localized RBJ interacts with MEK/ERK and prolongs the duration of MEK/ERK activation. Rbj deficiency abrogates nuclear accumulation of MEK1/MEK2, attenuates ERK1/ERK2 activation, and impairs AOM/DSS-induced colonic carcinogenesis. Moreover, Rbj knockdown inhibits growth of established tumors. Our data suggest that RBJ may be an oncogenic Ras-related small GTPase mediating nuclear accumulation of active MEK1/MEK2 in tumor progression.

Lin CY, Sheu MJ, Li CF, et al.
Deficiency in asparagine synthetase expression in rectal cancers receiving concurrent chemoradiotherapy: negative prognostic impact and therapeutic relevance.
Tumour Biol. 2014; 35(7):6823-30 [PubMed] Related Publications
Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but risk stratification and final outcomes remain suboptimal. In this study, we identify and validate targetable metabolic drivers relevant to the prognosis of patients with rectal cancer treated with CCRT. Using a published transcriptome of rectal cancers, we found that asparagine synthetase (ASNS) gene significantly predicted the response to CCRT. From 172 patients with rectal cancer, the expression levels of ASNS, using immunohistochemistry assays, were further evaluated in tumor specimens initially obtained by using colonoscopy. Expression levels of ASNS were further correlated with major clinicopathological features and clinical survivals in this valid cohort. ASNS deficiency was significantly related to advanced posttreatment tumor (T3, T4; P = .015) and nodal status (N1, N2; P = .004) and inferior tumor regression grade (P < .001). In survival analyses, ASNS deficiency was significantly associated with shorter local recurrence-free survival (LRFS; P = .0039), metastasis-free survival (MeFS; P = .0001), and disease-specific survival (DSS; P = .0006). Furthermore, ASNS deficiency was independently predictive of worse outcomes for MeFS (P = .012, hazard ratio = 3.691) and DSS (P = .022, hazard ratio = 2.845), using multivariate analysis. ASNS deficiency is correlated with poor therapeutic response and worse survivals in patients with rectal cancer receiving neoadjuvant CCRT. These findings indicate that ASNS is a prognostic factor with therapeutic potential for treating rectal cancer.

Färkkilä A, Andersson N, Bützow R, et al.
HER2 and GATA4 are new prognostic factors for early-stage ovarian granulosa cell tumor-a long-term follow-up study.
Cancer Med. 2014; 3(3):526-36 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Granulosa cell tumors (GCTs) carry a risk of recurrence also at an early stage, but reliable prognostic factors are lacking. We assessed clinicopathological prognostic factors and the prognostic roles of the human epidermal growth factor receptors (HER 2-4) and the transcription factor GATA4 in GCTs. We conducted a long-term follow-up study of 80 GCT patients with a mean follow-up time of 16.8 years. A tumor-tissue microarray was immunohistochemically stained for HER2-4 and GATA4. Expression of HER2-4 mRNA was studied by means of real time polymerase chain reaction and HER2 gene amplification was analyzed by means of silver in situ hybridization. The results were correlated to clinical data on recurrences and survival. We found that GCTs have an indolent prognosis, with 5-year disease-specific survival (DSS) being 97.5%. Tumor recurrence was detected in 24% of the patients at a median of 7.0 years (range 2.6-18 years) after diagnosis. Tumor stage was not prognostic of disease-free survival (DFS). Of the molecular prognostic factors, high-level expression of HER2, and GATA4, and high nuclear atypia were prognostic of shorter DFS. In multivariate analyses, high-level coexpression of HER2 and GATA4 independently predicted DFS (hazard ratio [HR] 8.75, 95% CI 2.20-39.48, P = 0.002). High-level expression of GATA4 also predicted shorter DSS (HR 3.96, 95% CI 1.45-12.57, P = 0.006). In multivariate analyses, however, tumor stage (II-III) and nuclear atypia were independent prognostic factors of DSS. In conclusion HER2 and GATA4 are new molecular prognostic markers of GCT recurrence, which could be utilized to optimize the management and follow-up of patients with early-stage GCTs.

Cougnoux A, Dalmasso G, Martinez R, et al.
Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype.
Gut. 2014; 63(12):1932-42 [PubMed] Related Publications
BACKGROUND: Escherichia coli strains harbouring the pks island (pks+ E. coli) are often seen in human colorectal tumours and have a carcinogenic effect independent of inflammation in an AOM/IL-10(-/-) (azoxymethane/interleukin) mouse model.
OBJECTIVE: To investigate the mechanism sustaining pks+ E. coli-induced carcinogenesis.
METHOD: Underlying cell processes were investigated in vitro and in vivo (xenograft model) using intestinal epithelial cells infected by pks+ E. coli or by an isogenic mutant defective for pks (pks- E. coli). The results were supported by data obtained from an AOM/DSS (azoxymethane/dextran sodium sulphate) colon cancer mouse model and from human colon cancer biopsy specimens colonised by pks+ E. coli or pks- E. coli.
RESULTS: Colibactin-producing E. coli enhanced tumour growth in both xenograft and AOM/DSS models. Growth was sustained by cellular senescence (a direct consequence of small ubiquitin-like modifier (SUMO)-conjugated p53 accumulation), which was accompanied by the production of hepatocyte growth factor (HGF). The underlying mechanisms involve microRNA-20a-5p, which targets SENP1, a key protein regulating p53 deSUMOylation. These results are consistent with the expression of SENP1, microRNA-20a-5p, HGF and phosphorylation of HGF receptor found in human and mouse colon cancers colonised by pks+ E. coli.
CONCLUSION: These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role.

Rogler A, Hoja S, Giedl J, et al.
Loss of MTUS1/ATIP expression is associated with adverse outcome in advanced bladder carcinomas: data from a retrospective study.
BMC Cancer. 2014; 14:214 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
BACKGROUND: Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer.
METHODS: MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured.
RESULTS: MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability.
CONCLUSIONS: MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort.

Williams JS, Xiao Y, Brownell I
Low pH reprograms somatic murine cells into pluripotent stem cells: a novel technique with therapeutic implications.
Cancer Biol Ther. 2014; 15(6):675-7 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Induced pluripotent stem cells (iPSCs) are somatic cells that are reprogrammed into a state resembling embryonic stem cells (ESCs). iPSCs represent a promising technology with applications in cancer research, yet current methods used to generate iPSCs limit their translation to clinical use. In a recent Nature article, Obokata et al. detail a novel technique to generate pluripotent murine cells called stimulus-triggered acquisition of pluripotency (STAP). STAP eliminates the need for exogenous expression of reprogramming factors used in previous iPSC technologies, instead transforming somatic cells to pluripotency using physical and chemical stimuli. The authors found that STAP cells are generated at a 10-fold higher efficiency than prior iPSC technologies. STAP cells display several features of pluripotency, namely the expression of pluripotency-related genes (Oct4, Nanog, Sox2, Ecat1, Esg1, and Dax1), the ability to form teratomas in vivo, and the ability to produce viable, fertile mice in blastocyst complementation assays. Here, we review these findings on STAP and contrast it to previous iPSC technologies, while noting the potential of this method to generate autologous anti-tumor immune cells for cancer therapy.

Li M, Ma X, Li M, et al.
Prognostic role of microRNA-210 in various carcinomas: a systematic review and meta-analysis.
Dis Markers. 2014; 2014:106197 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
OBJECTIVE: Many studies have shown that microRNAs (miRNAs) could play a potential role as prognostic biomarkers of tumors. The aim of this study is to summarize the global predicting role of microRNA-210 (miR-210) for survival in patients with a variety of carcinomas.
METHODS: Relevant literature was identified using PubMed and the information in eligible studies has been extracted. Then meta-analysis of hazard ratio (HR) was performed to evaluate the prognostic role of the miR-210 in different tumors.
RESULTS: This meta-analysis included 9 published studies dealing with various carcinomas. For recurrence free survival or disease free survival (RFS/DFS), the combined hazard ratio (HR) and 95% confidence interval (95% CI) of higher miR-210 expression were 2.47 [1.36, 4.46], which could significantly predict poor survival in general carcinomas. MicroRNA-210 was also a significant predictor for overall survival (OS), metastasis free survival or distant relapse free survival (MFS/DRFS), and disease specific survival (DSS). Importantly, subgroup analysis suggested that higher expression of miR-210 correlated with worse RFS/DFS, OS, and MFS/DRFS, especially in breast cancer, which were 3.36 [2.30, 4.93], 3.29 [1.65, 6.58], and 2.85 [1.76, 4.62] separately.
CONCLUSION: Our studies suggested that microRNA-210 could predict the outcome of patients with varieties of tumors, especially in breast cancers.

Wang Y, Ning H, Ren F, et al.
GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis.
Mol Cell. 2014; 53(5):752-65 [PubMed] Related Publications
Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of TC-PTP) and STAT3 specifically. GdX stabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficient dephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX converts TC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.

Sivendran S, Chang R, Pham L, et al.
Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.
J Invest Dermatol. 2014; 134(8):2202-11 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.

Li Y, Sun Y, Fan L, et al.
Paris saponin VII inhibits growth of colorectal cancer cells through Ras signaling pathway.
Biochem Pharmacol. 2014; 88(2):150-7 [PubMed] Related Publications
Dysregulation of the Ras signaling pathway plays a key role in the progression of colorectal cancer. When bound to GTP, Ras is activated and stimulates several downstream effectors' pathways, including the Raf/MEK/ERK kinase cascade, the PI3-kinase/AKT/mTor pathway, and the Ral GTPase pathway. Saponins extracted from Liliaceae family herbs have strong antitumor activities with low toxicity. In this study, Paris saponin VII (PSVII), isolated from Trillium tschonoskii Maxim., was evaluated on human colorectal cancer cells (HT-29 and SW-620), a mouse model of colitis associated colorectal cancer (CACC) and a murine model of xenograft tumor. It was found that PSVII inhibited colorectal cancer cell growth in a concentration-dependent manner. The IC50 values of PSVII for growth inhibition of HT-29 and SW-620 cells were 1.02 ± 0.05 μM and 4.90 ± 0.23 μM. It could induce cell apoptosis, together with cell cycle arrest in G1 phase, and trigger apoptosis in a caspase-3-dependent manner. PSVII-induced growth inhibitory effect was associated with disturbance of MAPK pathway by down-regulating MEK1/2, ERK1/2 phosphorylation, and suppression of AKT pathway by reducing AKT and GSK-3β phosphorylation. In the CACC mouse model, PSVII protected mice from intestinal toxicities and carcinogenesis induced by 1,2-dimethylhydrazine (DMH) and dextran sodium sulfate (DSS). In the model of xenograft tumor, PSVII remarkably decreased the xenograft tumor size and triggered the apoptosis of tumor cells. Both in vitro and in vivo study showed that PSVII inhibited Ras activity. Taken together, PSVII might be a potential therapeutic reagent for colorectal cancer through targeting Ras signaling pathway.

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