SELENOP

Gene Summary

Gene:SELENOP; selenoprotein P
Aliases: SeP, SELP, SEPP, SEPP1
Location:5p12
Summary:This gene encodes a selenoprotein that is predominantly expressed in the liver and secreted into the plasma. This selenoprotein is unique in that it contains multiple selenocysteine (Sec) residues per polypeptide (10 in human), and accounts for most of the selenium in plasma. It has been implicated as an extracellular antioxidant, and in the transport of selenium to extra-hepatic tissues via apolipoprotein E receptor-2 (apoER2). Mice lacking this gene exhibit neurological dysfunction, suggesting its importance in normal brain function. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. The mRNA for this selenoprotein contains two SECIS elements. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2017]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:selenoprotein P
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Selenoproteins
  • Risk Factors
  • Breast Cancer
  • Sweden
  • Oxidative Stress
  • Apoptosis
  • Prostate Cancer
  • Superoxide Dismutase
  • Glutathione Peroxidase
  • Transfection
  • Transcription Factors
  • Biomarkers, Tumor
  • Logistic Models
  • Thioredoxin Reductase 1
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Thioredoxin Reductase 2
  • Thiobarbituric Acid Reactive Substances
  • Liver Cancer
  • Selenoprotein P
  • Colorectal Cancer
  • Proportional Hazards Models
  • Chromosome 5
  • Staging
  • Genetic Variation
  • Cohort Studies
  • Dihydrotestosterone
  • Odds Ratio
  • Alleles
  • Base Sequence
  • Single Nucleotide Polymorphism
  • Adenocarcinoma
  • Esophageal Cancer
  • Case-Control Studies
  • Signal Transduction
  • Genotype
  • Transcription
  • Genetic Predisposition
  • Cell Proliferation
  • Tumor Stem Cell Assay
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Selenium
Tag cloud generated 16 March, 2017 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: SEPP1 (cancer-related)

Gadkar K, Kirouac D, Parrott N, Ramanujan S
Quantitative systems pharmacology: a promising approach for translational pharmacology.
Drug Discov Today Technol. 2016 Sep - Dec; 21-22:57-65 [PubMed] Related Publications
Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody. In the second case study, a mitogen-activated protein kinase (MAPK) pathway signaling model is used to make translational predictions on clinical response and evaluate novel combination therapies. In the third case study, a physiologically based pharmacokinetic (PBPK) model it used to guide administration of oseltamivir in pediatric patients.

Dickmann LJ, Ware JA
Pharmacogenomics in the age of personalized medicine.
Drug Discov Today Technol. 2016 Sep - Dec; 21-22:11-16 [PubMed] Related Publications
The aim of personalized medicine is to offer the right treatment to the right person at the right dose, thus maximizing efficacy and minimizing toxicity for each individual patient. Pharmacogenomic approaches attempt to refine the aim of personalized medicine by utilizing an individual's germline and somatic DNA signatures to guide treatment. In this review, we highlight the current use of pharmacogenomic based biomarker information in drug labeling. We also present several case studies on the implementation of pharmacogenomic strategies in drug discovery and development. Lastly, we comment on current challenges to implementing pharmacogenomic based testing in the clinic.

Küçük Ü, Bayol Ü, Usturalı Keskin E, et al.
Investigating KRAS/BRAF mutation in oropharyngeal squamous cell carcinomas: a preliminary study.
Kulak Burun Bogaz Ihtis Derg. 2016 Sep-Oct; 26(5):265-7 [PubMed] Related Publications
OBJECTIVES: This study aims to investigate the role of KRAS/BRAF gene mutation in the pathogenesis of oropharyngeal squamous cell carcinoma (OSCC).
PATIENTS AND METHODS: A total of 26 OSCC patients (23 males, 3 females; mean age 60 years; range 41 to 77 years) diagnosed between January 2003 and November 2013 were included in the study. The methods used in our study were quantitative fluorescence polymerase chain reaction for KRAS/BRAF mutation analysis.
RESULTS: Ten of the tumors were located at the tongue base, 12 in the tonsil and four at the floor of mouth. The mean tumor size was 3.8 cm. Six of the tumors were well differentiated, 18 were moderately differentiated and two were poorly differentiated. All cases were analyzed for KRAS and BRAF gene mutations and none of them showed gene mutations.
CONCLUSION: We could not find any relation between OSCC and KRAS/BRAF gene mutations in our short case file. The role of mutations should be analyzed in larger series in OSCC to predict new targeted therapy modalities.

Hubacek M, Kripnerova T, Nemcikova M, et al.
Odontogenic keratocysts in the Basal Cell Nevus (Gorlin-Goltz) Syndrome associated with paresthesia of the lower jaw: Case report, retrospective analysis of a representative Czech cohort and recommendations for the early diagnosis.
Neuro Endocrinol Lett. 2016; 37(4):269-276 [PubMed] Related Publications
OBJECTIVES: Identification of early presenting signs of the Basal Cell Nevus (BCNS; synonyme Gorlin-Goltz) syndrome, which is associated with a principal triad of multiple basal cell nevi, jaw odontogenic keratocysts, and skeletal anomalies, in stomatological and neurological practices. Proposal of multidisciplinary diagnostic algorithm comprising other medical specialists, including pathology, imaging, laboratory and molecular analyses based on the study outcomes.
DESIGN: Case report of a male patient reporting paresthesia of their lower jaw, with right facial asymmetry (maxilla and mandible) and radiological detection of large osteolytic lesions in both jaws, including a retrospective analysis of a representative Czech cohort with BCNS from within the last decade.
SETTING: Clinical, imaging and laboratory analyses were carried out at a national tertiary centre.
RESULTS: A multidisciplinary clinical approach followed by surgical management lead to the identification of odontogenic cysts, which were substantiated by histological examination. DNA sequencing of the PTCH1 gene detected a c.2929dupT resulting in p. Tyr977Leufs*16 pathogenic variant. This finding confirmed the clinical and laboraoty diagnosis of BCNS. Parental DNA analysis showed that this causal genetic defect arose de novo. Surgical management and orthodontic therapy were successful.
CONCLUSIONS: Analysis of the reported case and retrospective data analysis provided evidence that paresthesia of the lower jaw should be considered as one of the early presenting signs of this rare disorder in stomatological and neurological practice. Obtained results allowed us to formulate recommendations for diagnostic practice in stomatology and neurology.

Tyulkina DV, Pleshkan VV, Alekseenko IV, et al.
Expression of the FAP gene in non-fibroblast human cell lines. Development of cancer-associated fibroblast models.
Dokl Biochem Biophys. 2016; 470(1):319-321 [PubMed] Related Publications
The fibroblast activation protein (FAP) is selectively expressed in cancer-associated fibroblasts (CAFs) and facilitates tumor progression, which makes this protein an attractive therapeutic target. There are difficulties in obtaining CAFs for studying the function and suppression of FAP. In this work, the expression level of FAP was determined by PCR assay in 25 human cell lines and 8 surgical samples of tumor stroma. The expression of FAP was observed in all tumor stroma samples and in four cell lines: NGP-127, SJCRH30, SJSA-1, and A375. The level of FAP expression in NGP-127, SJCRH30, and SJSA-1 lines as well as in CAFs of patients was comparable, which makes these cell lines a possible model for studying FAP.

Adam J, Sourisseau T, Olaussen KA, et al.
MMS19 as a potential predictive marker of adjuvant chemotherapy benefit in resected non-small cell lung cancer.
Cancer Biomark. 2016; 17(3):323-333 [PubMed] Related Publications
BACKGROUND: Resectable non-small cell lung cancer (NSCLC) treatment options most often consist of surgical resection along with adjuvant chemotherapy (ACT). The benefit of ACT however is modest and is accompanied by important side effects.
OBJECTIVE: One central quest in the field is therefore the identification of a predictive marker of the response to ACT.
METHODS: We applied an unbiased approach based on high content analysis of expression data generated from a discovery patient cohort.
RESULTS: We identified MMS19, a component of the cytoplasmic Iron-Sulfur Assembly (CIA) machinery important for the Nucleotide Excision Repair (NER) pathway as a pivotal gene for cisplatin toxicity. We then confirmed the association between MMS19 expression and the response to Cisplatin treatment in a panel of NSCLC cell lines. Finally we validated these pre-clinical data in a subgroup of JBR.10 trial patients through a hypothesis-driven analysis, and showed that MMS19 levels associated with ACT benefit.
CONCLUSIONS: We therefore propose the expression level of MMS19 as a candidate predictive marker of ACT benefit in resected NSCLC patients.

Wen X, Lu R, Xie S, et al.
APE1 overexpression promotes the progression of ovarian cancer and serves as a potential therapeutic target.
Cancer Biomark. 2016; 17(3):313-322 [PubMed] Related Publications
BACKGROUND: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that is involved in DNA repair and the redox regulation of transcription factors. Blocking these functions leads to cell-growth inhibition, apoptosis and other effects. Previous studies have demonstrated that high expression levels of the APE1 protein are associated with the progression and chemoresistance of cancers. We hypothesized that APE1 silencing in ovarian cancer cells might have anticancer effects mediated by cell-growth inhibition and an increase in drug-sensitivity.
OBJECTIVE: In this study, we explored the consequences of APE1 silencing in ovarian cancer cells.
METHODS: Immunohistochemistry (IHC) was used to detect the APE1 protein levels in tissue samples from twelve ovarian cancer (OC) patients and eleven non-OC patients. APE1 knockdown was achieved via the stable transfection of SKOV3 and A2780 cells with a construct encoding a short hairpin DNA directed against the APE1 gene. Then, cell proliferation, colony formation, cell cycle and apoptosis assays were performed to reveal the consequences of APE1 silencing in ovarian cancer cells. Additionally, the SKOV3 and A2780 cells were subjected to the treatment with camptothecin (CPT) and ultraviolet rays (UV) to assess the possible link between the APE1 protein and drug-resistance.
RESULTS: Our results revealed that the APE1 protein was overexpressed in OC tissues. APE1 knockdown in A2780 and SKOV3 cells reduced cell proliferation, arrested cell cycle progression, repressed colony formation and weakly promoted cell apoptosis through the BAX and BCL-2 apoptotic pathways. Additionally, the down-regulation of APE1 significantly enhanced the sensitivity of ovarian cancer cells to the CPT/UV treatment.
CONCLUSION: Our study suggested that the APE1 protein is important for the proliferation and growth of ovarian cancer cells. APE1 silencing might enhance drug-sensitivity, and thus APE1 might serve as a novel anti-OC therapeutic target.

Zhang K, Yu M, Hao F, et al.
Knockdown of S100A4 blocks growth and metastasis of anaplastic thyroid cancer cells in vitro and in vivo.
Cancer Biomark. 2016; 17(3):281-291 [PubMed] Related Publications
Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. It is often incurable because it does not respond to radioiodine, radiotherapy, or chemotherapy. With conventional treatment, the median survival is about 6 months; therefore, new treatment options are needed. S100A4 is a calcium-binding protein related to the metastatic potential of carcinoma. Previous study has found S100A4 was overexpressed in human papillary thyroid carcinomas (PTC) tissues, and overexpression of S100A4 is associated with thyroid tumour invasion and metastasis. In the present study, we first examined S100A4 protein expression in 14 ATC tissues, 20 PTC tissues and 14 normal thyroid tissue by immunohistochemistry analysis. We then knocked down of S100A4 expression by RNA interference (S100A4 siRNA) and investigated its effects on growth and metastasis in two human ATC cell lines 8505C (BRAFV600E) and Cal-62 (BRAFwt) in vitro and in vivo. S100A4 and BRAFV600E protein expression was evaluated by western blot assay and immunohistochemistry analysis. Using immunohistochemistry, we found that high levels of S100A4 were detected in ATC specimens and PTC specimens. No S100A4 staining was observed in normal thyroid tissues. S100A4 siRNA significantly decreased proliferation and increased apoptosis, and inhibited the invasive potential of the two cells in vitro. In addition, S100A4 siRNA could effectively inhibit BRAFV600E expression in the 8505C cells, and treatment with 100 ng/ml human recombinant BRAF V600E in S100A4 siRNA/8505C cells could partly restore its proliferative and invasive ability. Results of implantation in vivo showed S100A4 shRNA could significantly inhibit abdominal cavity metastasis and tumor growth in vivo. Furthermore, knockdown of S100A4 has significant role on invasion, metastasis and growth inhibition in the 8505C cells than that of in the Cal-62 cells. These results support the hypothesis that S100A4 contributes significantly to growth and metastasis, and that down-regulation of S100A4 expression decreases the metastatic potential of ATC cells. Furthermore, down-regulation of S100A4 expression is more marked in BRAFV600E cells than that of in the BRAFwt cells.

Shahbazi S, Khorasani M, Mahdian R
Gene expression profile of FVII and AR in primary prostate cancer.
Cancer Biomark. 2016; 17(3):353-358 [PubMed] Related Publications
OBJECTIVES: The ectopic expression of coagulation Factor VII has been shown in various cancers. Recently, F7 gene has been identified as a direct target of the androgen receptor in breast cancer. In this study, we examined the mRNA expression of F7 and AR in clinical sample series of prostate cancer and BPH.
MATERIAL AND METHODS: All the prostate cancer patients were new cases with no medical history of surgery or chemotherapy. The tissue samples were assigned as either prostate cancer tumor (n= 45) harboring at least 80% tumor cell content, or BPH (n= 36). Relative AR and F7 mRNA expression in each tissue sample was normalized to the mean of the Ct values determined for GAPDH and PSA genes.
RESULTS: Mean plasma level of prostate specific antigen (PSA) was 17.82 ± 3.71 ng/ml and 7.71 ± 1.28 ng/ml (Mean ± SEM) in PCa and BPH group, respectively. AR mean expression was up-regulated 22.468 fold in clinical tumor sample cohort (S.E., 0.175-2,916, 95% CI: 0.001-126,764, P= 0.001). The mean expression of F7 gene in tumor tissues relative to PBH samples was 6.981 (S.E., 0.099-413.001, 95% CI: 0.002-34,183, P= 0.012). ANOVA analysis of the gene expression results showed significant correlation between F7 and AR mRNA expression in tumor samples (p< 0.001).
CONCLUSIONS: Our study findings suggest a link between FVII and AR in prostate cancer pathogenesis. F7 gene expression could be up-regulated via various AR mediators affecting the promoter region of the F7 gene. Should this be confirmed by further studies, it may be suggested as a potential contributing factor in prostate cancer.

Wang SH, Zhang MD, Wu XC, et al.
Overexpression of LncRNA-ROR predicts a poor outcome in gallbladder cancer patients and promotes the tumor cells proliferation, migration, and invasion.
Tumour Biol. 2016; 37(9):12867-12875 [PubMed] Related Publications
LncRNA-ROR has been reported to be involved in many kinds of human cancers. However, whether LncRNA-ROR is involved in gallbladder cancer progression remains largely unknown. The objective of this study is to investigate the role of LncRNA-ROR in gallbladder cancer. We found that LncRNA-ROR expression level was upregulated in gallbladder cancer tissues (P < 0.05) and was significantly associated with tumor sizes (P < 0.05) and lymph node metastasis (P < 0.05). High expression of LncRNA-ROR was significantly associated with poor prognosis in gallbladder cancer patients (P < 0.05). Moreover, knockdown of LncRNA-ROR inhibited cell proliferation, migration, and invasion. The epithelial-mesenchymal transition (EMT) phenotype induced by TGF-β1 was reversed after LncRNA-ROR knocking down in SGC-996 and Noz cells. LncRNA-ROR plays an important role in the development of gallbladder cancer and mediates the EMT in gallbladder cancer. LncRNA-ROR might act as a marker of prognosis and therapeutic target for gallbladder cancer.

Liu K, Wang S, Liu Y, et al.
Overexpression of MYCN promotes proliferation of non-small cell lung cancer.
Tumour Biol. 2016; 37(9):12855-12866 [PubMed] Related Publications
V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) is an oncogene that is known amplified and overexpressed in different human malignancies including small cell lung cancer. However, the role of MYCN in non-small cell lung cancer (NSCLC) development remains elusive. In the present study, Western blot and immunohistochemistry assays demonstrated that MYCN was overexpressed in NSCLC tumor tissues and cell lines. In addition, immunohistochemistry analysis revealed that upregulation of MYCN expression was positively correlated with a more invasive tumor phenotype and poor prognosis. In vitro studies using serum starvation-refeeding experiment and MYCN-siRNA transfection assay demonstrated that MYCN expression promoted proliferation of NSCLC cells, while MYCN knockdown led to decreased cell growth resulted from growth arrest of cell cycle at G0/G1 phase. Furthermore, upregulation and knockdown of sex-determining region Y-box 2 (SRY) (SOX2), which was a well-known oncogene, confirmed that MYCN might be a downstream gene of the transcription factor SOX2. Collectively, our finding suggested that MYCN might contribute to the progression of NSCLC by enhancing cell proliferation, and that targeting MYCN might provide beneficial effects for the clinical therapy of NSCLC.

Guo K, Zheng S, Xu Y, et al.
Loss of miR-26a-5p promotes proliferation, migration, and invasion in prostate cancer through negatively regulating SERBP1.
Tumour Biol. 2016; 37(9):12843-12854 [PubMed] Related Publications
The biological role of miR-26a involved in the carcinogenesis of prostate cancer (PC) has been controversial. Besides, the underlying mechanism by which miR-26a plays a role in PC has been unclear. To investigate the role of miR-26a-5p in the PC, miR-26a-5p was detected and statistically analyzed in clinical PC tissues and a panel of PC cell lines. Using bioinformatics analysis, we found that serpine1 messenger RNA (mRNA) binding protein 1 (SERBP1) was a potential downstream target of miR-26a-5p. Using luciferase reporter and western blot, we identified that miR-26a-5p negatively regulated SERBP1 on the PC cell line level. It was confirmed that miR-26a-5p was markedly downregulated in PC tissues compared with normal controls whose reduced expression was significantly associated with metastasis and poor overall prognosis and found that miR-26a-5p was able to prevent proliferation and motility of PC cells in vitro. Additionally, SERBP1 was identified as a downstream target of miR-26a-5p. Moreover, it was observed that SERBP1 was markedly upregulated in prostate cancer tissues and was significantly associated with tissue metastasis and Gleason score. Taken together, our results for the first time demonstrate that the loss of miR-26a-5p promotes proliferation, migration, and invasion through targeting SERBP1 in PC, supporting the tumor-suppressing role of miR-26a-5p in PC.

Koshkin S, Danilova A, Raskin G, et al.
Primary cultures of human colon cancer as a model to study cancer stem cells.
Tumour Biol. 2016; 37(9):12833-12842 [PubMed] Related Publications
The principal cause of death in cancer involves tumor progression and metastasis. Since only a small proportion of the primary tumor cells, cancer stem cells (CSCs), which are the most aggressive, have the capacity to metastasize and display properties of stem cells, it is imperative to characterize the gene expression of diagnostic markers and to evaluate the drug sensitivity in the CSCs themselves. Here, we have examined the key genes that are involved in the progression of colorectal cancer and are expressed in cancer stem cells. Primary cultures of colorectal cancer cells from a patient's tumors were studied using the flow cytometry and cytological methods. We have evaluated the clinical and stem cell marker expression in these cells, their resistance to 5-fluorouracil and irinotecan, and the ability of cells to form tumors in mice. The data shows the role of stem cell marker Oct4 in the resistance of primary colorectal cancer tumor cells to 5-fluorouracil.

Wei S, Wang L, Zhang L, et al.
ZNF143 enhances metastasis of gastric cancer by promoting the process of EMT through PI3K/AKT signaling pathway.
Tumour Biol. 2016; 37(9):12813-12821 [PubMed] Related Publications
The zinc finger protein 143 (ZNF143) is a transcription factor, which regulates many cell cycle-associated genes. ZNF143 expressed strongly in multiple solid tumors. However, the influence of ZNF143 on gastric cancer (GC) remains largely unknown. In this study, we investigated the ZNF143 mRNA level in GC tissues and cells by quantitative real-time PCR (qRT-PCR). The protein expression of ZNF143 in GC cells, and the signaling pathway proteins were detected by Western blotting. Transwell assay and wound healing assay were performed to explore the effects of ZNF143 for the migration ability of GC cells in vitro. We also performed the tail vein injection in nude mice with GC cells to explore the impact of ZNF143 on GC metastasis in vivo. ZNF143 was overexpressed in specimens of GC compared with adjacent normal tissues and increased more significantly in GC tissues of patients who had lymph node metastasis. Ectopic overexpression of ZNF143 enhanced GC migration, whereas ZNF143 knockdown suppressed this effect in vitro. In vivo, ZNF143 knockdown reduced distant metastasis of GC cells in nude mice. In addition, overexpression of ZNF143 reduced the expression of epithelial cell marker (E-cadherin) and induced the expression of mesenchymal cell marker (N-cadherin,Vimentin), Snail and Slug. We also found that ZNF143 enhanced GC cell migration by promoting the process of EMT through PI3K/AKT signaling pathway. In general, our findings show that ZNF143 expressed strongly in GC and enhanced migration of GC cells in vitro and in vivo. It is conceivable that ZNF143 could be a therapeutic genetic target for GC treatment.

Cao WJ, Du WQ, Mao LL, et al.
Overexpression of p42.3 promotes cell proliferation, migration, and invasion in human gastric cancer cells.
Tumour Biol. 2016; 37(9):12805-12812 [PubMed] Related Publications
As a newly discovered tumor-specific gene, p42.3 is overexpressed in most of human gastric cancers (GC). However, the role of p42.3 in GC progression remains unclear. To assess the role of p42.3 in gastric cancers, immunohistochemistry and western blot were performed to detect the p42.3 expression in human GC tissues and cells. We also investigated the role of p42.3 in GC cell proliferation, migration, and invasion. Our results showed that the p42.3 expression was increased dramatically in human GC tissue and cells. In addition, we found that overexpression of p42.3 promotes GC cell proliferation, migration, and invasion abilities. Furthermore, p42.3 expression suppressed the E-cadherin protein level and promoted the β-catenin and p-ERK protein level. Taken together, overexpressed p42.3 is correlated with gastric cancer cell proliferation, migration, and invasion, suggesting its use as a biological marker in gastric cancer.

Cheng G, He J, Zhang L, et al.
HIC1 modulates uveal melanoma progression by activating lncRNA-numb.
Tumour Biol. 2016; 37(9):12779-12789 [PubMed] Related Publications
Uveal melanoma (UM) is the most common primary intraocular cancer in adults. Although the diagnosis modality of primary UM was improved significantly, there are currently no effective therapies for metastatic UM. Hypermethylated in cancer 1 (HIC1) is frequently deleted or epigenetically silenced in various human cancers. However, the role and mechanism of HIC1 in UM is still unclear. In this study, we found that HIC1 acted as a tumor suppressor and that its expression was downregulated in UM. Functional studies demonstrated that ectopic expression of HIC1 in UM cells inhibited cell proliferation and invasion. Moreover, through long non-coding RNA (lncRNA) microarray and real-time PCR, we found that expression of lncRNA-numb was activated by HIC1 in UM. The results provide evidence that lncRNA-numb is a newly proposed tumor suppressor that is involved in HIC1-induced phenotypes. Taken together, our studies of UM reveal a critical role of HIC1 in the regulation of tumorigenesis, at least partly through its downstream target, lncRNA-numb, and provide a potential therapeutic target for UM.

Likhitrattanapisal S, Tipanee J, Janvilisri T
Meta-analysis of gene expression profiles identifies differential biomarkers for hepatocellular carcinoma and cholangiocarcinoma.
Tumour Biol. 2016; 37(9):12755-12766 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the members of hepatobiliary diseases. Both types of cancer often exert high levels of similarity in terms of phenotypic characteristics, thus leading to difficulties in HCC and CCA differential diagnoses. In this study, a transcriptome meta-analysis was performed on HCC and CCA microarray data to identify differential transcriptome networks and potential biomarkers for HCC and CCA. Raw data from nine gene expression profiling datasets, consisting of 1,185 samples in total, were methodologically compiled and analyzed. To evaluate differentially expressed (DE) genes in HCC and CCA, the levels of gene expression were compared between cancer and its normal counterparts (i.e., HCC versus normal liver and CCA versus normal bile duct) using t test (P < 0.05) and k-fold validation. A total of 226 DE genes were specific to HCC, 249 DE genes specific to CCA, and 41 DE genes in both HCC and CCA. Gene ontology and pathway enrichment analyses revealed different patterns between functional transcriptome networks of HCC and CCA. Cell cycle and glycolysis/gluconeogenesis pathways were exclusively dysregulated in HCC whereas complement and coagulation cascades as well as glycine, serine, and threonine metabolism were prodominantly differentially expressed in CCA. Our meta-analysis revealed distinct dysregulation in transcriptome networks between HCC and CCA. Certain genes in these networks were discussed in the context of HCC and CCA transition, unique characteristics of HCC and CCA, and their potentials as HCC and CCA differential biomarkers.

Yin L, Liu S, Li C, et al.
CYLD downregulates Livin and synergistically improves gemcitabine chemosensitivity and decreases migratory/invasive potential in bladder cancer: the effect is autophagy-associated.
Tumour Biol. 2016; 37(9):12731-12742 [PubMed] Related Publications
Although GC (gemcitabine and cisplatin) chemotherapy remains an effective method for treating bladder cancer (BCa), chemoresistance is a major obstacle in chemotherapy. In this study, we determined whether gemcitabine resistance correlates with migratory/invasive potential in BCa and whether this relationship is regulated by the cylindromatosis (CYLD)-Livin module. First, we independently investigated the correlation of CYLD/Livin and gemcitabine resistance with the potential for tumor migration and invasiveness. Second, we found that co-transfected CYLD and Livin dramatically improved sensitivity to gemcitabine chemotherapy and decreased migration/invasion potential. Next, we determined that CYLD may regulate Livin by the NF-κB-dependent pathway. We also found that CYLD overexpression and Livin knockdown might improve gemcitabine chemosensitivity by decreasing autophagy and increasing apoptosis in BCa cells. Finally, the effects of CYLD-Livin on tumor growth in vivo were evaluated. Our study demonstrates that CYLD-Livin might represent a potential therapeutic for chemoresistant BCa.

Yang Q, Zhu M, Wang Z, et al.
4.1N is involved in a flotillin-1/β-catenin/Wnt pathway and suppresses cell proliferation and migration in non-small cell lung cancer cell lines.
Tumour Biol. 2016; 37(9):12713-12723 [PubMed] Related Publications
The membrane-cytoskeletal protein 4.1N has recently been proposed as a tumor suppressor in a number of cancers of epithelial origin, including non-small-cell lung cancer (NSCLC). However, the molecular mechanism associated with 4.1N tumor suppression remains has not been thoroughly characterized. In this study, 4.1N was shown to directly interact with the lipid raft marker flotillin-1 through its FERM and U2 domains in several different NSCLC cell lines using immunoprecipitation, co-immunoprecipitation and pull-down assays. Moreover, 4.1N silencing/overexpression experiments in paired 95C/95D cells that are of homologous origin but varying endogenous 4.1N expression (high expression in 95C cells, low expression in 95D cells) indicated that 4.1N is involved in the suppression of cell proliferation and migration through a flotillin-1/β-catenin/Wnt pathway. Taken together, the findings of this study help to elucidate the novel tumor suppressor role of 4.1N in NSCLC.

Lu YJ, Liu RY, Hu K, Wang Y
MiR-541-3p reverses cancer progression by directly targeting TGIF2 in non-small cell lung cancer.
Tumour Biol. 2016; 37(9):12685-12695 [PubMed] Related Publications
Lung cancer remains a leading cause of cancer-associated mortality worldwide, and non-small lung cancer (NSCLC) is responsible for over 80 % of lung cancer-related deaths. Identifying novel molecular biomarker that can inhibit the progression of lung cancer will facilitate the development of new treatment strategies. Herein, we demonstrated that miR-541-3p is a tumor-suppressor microRNA (miRNA) in NSCLC progression. We found that expression of miR-541-3p was decreased obviously in NSCLC tissues and plasma. Down-regulation of miR-541-3p was associated with TNM stage and postoperative survival. Overexpression of miR-541-3p inhibited the growth and metastasis of NSCLC cells. The TGIF2 was a direct target of miR-541-3p and promoted the growth and metastasis of NSCLC cells. Further study showed that TGIF2 could reverse the inhibitory effect of miR-541-3p on growth and metastasis of NSCLC cells. Taken together, our data highlight the pivotal role of miR-541-3p in the progression of NSCLC. Thus, miR-541-3p may be a potential prognostic marker and of treatment relevance for NSCLC progression intervention.

Shang D, Zheng T, Zhang J, et al.
Profiling of mRNA and long non-coding RNA of urothelial cancer in recipients after renal transplantation.
Tumour Biol. 2016; 37(9):12673-12684 [PubMed] Related Publications
The molecular mechanism and signal transduction pathways involved in urothelial cancer (UC) after renal transplantation (RTx) remain unknown. In this study, we investigated the profiling of messenger RNA (mRNA) and long non-coding RNA (lncRNA) in RTx recipients with UC. The mRNA and lncRNA of six pairs of UC and corresponding normal urothelial tissues in RTx recipients were profiled using Arraystar Human lncRNA Microarray V3.0, which is designed for the global profiling of 26,109 coding transcripts and 30,586 lncRNAs. Quantitative real-time PCR (qRT-PCR) was used to validate the differentially expressed mRNAs and lncRNAs. Molecular function classification and biological process classification for the differentially expressed mRNAs were analyzed with Gene Ontology. The key pathways that were associated with UC after RTx were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Compared to normal urothelial tissues, 1597 mRNAs were upregulated and 1032 mRNAs were downregulated in UC; 2107 lncRNAs were upregulated and 1794 lncRNAs were downregulated (greater than twofold). Further qRT-PCR analysis of mRNA and lncRNA expression showed well consistency with the data of microarray analysis. The expression of matrix metalloprotease (MMP)-3, MMP-10, MMP-12, and MMP-13 was significantly increased, while the expression of CD36 was decreased in UC after RTx. Co-expression analysis of lncRNAs and their nearby coding genes showed that lncRNAs may play critical roles in regulating nearby genes in the carcinogenesis of UC. Our results also suggest that peroxisome proliferator-activated receptor (PPAR) signaling may be involved in UC after RTx. Moreover, several cytokines and their receptors were also significantly upregulated in UC after RTx, suggesting that cytokines might be modulated and participated in the carcinogenesis of UC after RTx. We analyzed the potential molecular mechanism and pathways involved in the UC of RTx recipients. Our results revealed that several key regulatory pathways and lncRNAs play critical roles in the carcinogenesis of UC, and suggest that UC in RTx recipients may be more likely to invade and metastasis. However, the detailed functional analysis of these mechanisms should be further performed in the future.

Qiu W, Yang Z, Fan Y, Zheng Q
ZNRF3 is downregulated in papillary thyroid carcinoma and suppresses the proliferation and invasion of papillary thyroid cancer cells.
Tumour Biol. 2016; 37(9):12665-12672 [PubMed] Related Publications
Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that has emerged as an important regulator of cancer development; however, its cancer-related function remains controversial. Here, we investigated the possible role of ZNRF3 in thyroid carcinoma (TC). We found that ZNRF3 is downregulated in papillary thyroid carcinoma (PTC) compared to normal thyroid tissues and inversely correlated with the degree of cell differentiation. Overexpression of ZNRF3 significantly suppressed cell malignant behaviors, including cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Consistent with recent studies showing that ZNRF3 is involved in the Wnt/β-catenin pathway, ZNRF3 overexpression negatively regulated β-catenin activation, modulating PTC cell behaviors. Clinical specimens revealed a significant inverse correlation between ZNRF3 and β-catenin mRNA levels. Taken together, these results provide insight into a potential tumor suppressor role of ZNRF3 in PTC progression, and may have potential clinical relevance for the prognosis and treatment of PTC.

Burdelski C, Dieckmann T, Heumann A, et al.
p16 upregulation is linked to poor prognosis in ERG negative prostate cancer.
Tumour Biol. 2016; 37(9):12655-12663 [PubMed] Related Publications
Altered expression of the p16 tumor suppressor is frequently found in prostate cancer, but its role for tumor development and patient prognosis is disputed. In order to clarify the prognostic role of p16 and to draw conclusions on interactions with key molecular features of prostate cancer, we studied p16 expression in a tissue microarray (TMA) with more than 12,400 prostate cancers and attached clinical, pathological, and molecular data such as ERG status and deletions of 3p13, 5q21, 6q15, and PTEN. p16 immunostaining was absent in non-neoplastic prostate cells but was found in 37 % of 9627 interpretable prostate cancers. Finding p16 expression in 58 % of ERG positive but in only 22 % of ERG negative cancers (p < 0.0001), highlights the known androgen-dependence of both genes. Significant associations between p16 upregulation and tumor phenotype or patient prognosis were strictly limited to the subset of ERG negative cancers. For example, p16 positivity increased from 15 % in Gleason ≤3 + 3 to 38 % in Gleason ≥4 + 4 cancers (p < 0.0001) and was associated with early PSA recurrence (p < 0.0001). p16 upregulation was strongly linked to deletions of PTEN (p < 0.0001), highlighting the interaction of both genes in growth control. In conclusion, p16 upregulation is a strong prognostic factor in ERG negative cancers. The strict limitation of its prognostic impact to a molecularly defined subgroup challenges the concept of molecular prognosis testing without considering molecular subtypes.

Dirican E, Akkiprik M
Functional and clinical significance of SALL4 in breast cancer.
Tumour Biol. 2016; 37(9):11701-11709 [PubMed] Related Publications
The gene encoding Sal-like 4 (Drosophila) (SALL4) is a zinc-finger transcriptional factor and a vertebrate orthologous of the Drosophila gene spalt (sal), which is upregulated in some cancers. SALL4 is expressed in the early developmental stages of Drosophila. Moreover, murine SALL4 plays a vital role in protecting the properties of embryonic stem (ES) cells and guiding the outcome of the primal inner cell mass by interacting with OCT4 and NANOG. SALL4 in ES cells and tumor cells is known as a regulator for controlling cell growth, proliferation, and apoptosis. However, the downstream goals of SALL4 remain largely uncharted. SALL4 expression has been detected in various cancers, including a subset (30 %) of solid tumors, such as breast cancer (BCa), ovarian cancer, gastric cancer, Wilms tumor, and germ cell tumors. A study has reported that SALL4 expression is commonly upregulated in human breast tumors (~86 %) and that overregulation of this gene is often linked to tumor progression. In this review, we provide an overview concerning the role of SALL4 in BCa development and progression. Furthermore, this review may identify some drugs/inhibitors for the development of BCa-specific therapies by targeting SALL4. In the future, SALL4 may be a new biomarker as a diagnostic/therapeutic target of BCa, which would be a new direction in targeted BCa therapy. To our knowledge, this is the first review of the role of SALL4 in BCa development and progression.

Hudcova K, Raudenska M, Gumulec J, et al.
Expression profiles of miR-29c, miR-200b and miR-375 in tumour and tumour-adjacent tissues of head and neck cancers.
Tumour Biol. 2016; 37(9):12627-12633 [PubMed] Related Publications
Altered expression of microRNAs (miRNAs) has been shown in many types of malignancies including the head and neck squamous cell carcinoma (HNSCC). Although there are many new and innovative approaches in the treatment of HNSCC, a clear marker of this disease is still missing. Three candidate miRNAs (miR-29c-3p, miR-200b-5p and miR-375-3p) were studied in connection with HNSCC using quantitative real-time PCR expression levels in 42 tissue samples of HNSCC patients and histologically normal tumour-adjacent tissue samples of these patients. Primary HNSCC carcinoma tissues can be distinguished from histologically normal-matched noncancerous tumour-adjacent tissues based on hsa-miR-375-3p expression (sensitivity 87.5 %, specificity 65 %). Additionally, a significant decrease of hsa-miR-200b-5p expression was revealed in tumour-adjacent tissue samples of patients with node positivity. Lower expression of hsa-miR-200b-5p and hsa-miR-29c-3p in HNSCC tumour tissue was associated with higher tumour grade. Consequently, survival analysis was performed. Lower expression of hsa-miR-29c-3p in tumour-adjacent tissue was associated with worse overall and disease-specific survivals. Lower expression of miR-29c-3p in tumourous tissue was associated with worse relapse-free survival. hsa-miR-375-3p seems to be a relatively promising diagnostic marker in HNSCC but is not suitable for prognosis of patients. Furthermore, this study highlighted the importance of histologically normal tumour-adjacent tissue in HNSCC progress (significant decrease of hsa-miR-200b-5p expression in tumour-adjacent tissue of patients with node positivity and low expression of hsa-miR-29c-3p in HNSCC tumour-adjacent tissue associated with worse prognosis).

Li T, Pan H, Li R
The dual regulatory role of miR-204 in cancer.
Tumour Biol. 2016; 37(9):11667-11677 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are a group of endogenous, small (about 22 nucleotides) non-coding RNAs which negatively regulate gene expressions. As one of them, miR-204 originates from the sixth intron of the transient receptor potential melastatin 3 (TRPM3) gene. Therefore, expression of miR-204 is under the control of the TRPM3 promoter and regulated by genetic and epigenetic mechanisms. miR-204 has been found to play the important roles in development of eyes and adipogenesis. Its pathological functions have been observed in a few diseases including pulmonary arterial hypertension, diabetes, and various types of cancers. It is believed that miR-204 acts as a tumor-suppressor via promoting apoptosis, conferring the resistance of cancer cells to chemotherapy, and suppressing the self-renewal of cancer stem cells (CSCs) and the epithelial to mesenchymal transition (EMT). Expression of miR-204 is repressed by its targets XRN1 and TRKB in prostate cancer and endometrial carcinoma, respectively; therefore, they establish an oncogenic feedback loops that play an important role promoting development of cancer. In this review, we summarize our current knowledge regarding miR-204, including its expression, regulation and biological functions, especially focusing our discussion on its role in tumor development and tumor progression.

Yang F, Gong Q, Shi W, et al.
Aberrant DNA methylation of acute myeloid leukemia and colorectal cancer in a Chinese pedigree with a MLL3 germline mutation.
Tumour Biol. 2016; 37(9):12609-12618 [PubMed] Related Publications
Unlike genetic aberrations, epigenetic alterations do not modify the deoxyribonucleic acid (DNA) coding sequence and can be reversed pharmacologically. Identifying a particular epigenetic alteration such as abnormal DNA methylation may provide better understanding of cancers and improve current therapy. In a Chinese pedigree with colorectal carcinoma and acute myeloid leukemia, we examined the genome-wide DNA methylation level of cases and explored the role of methylation in pathogenesis and progression. DNA methylation status in the four cases, which all harbor a MLL3 germline mutation, differed from that of the normal control, and hypermethylation was more prevalent. Also, more CpG sites were hypermethylated in the acute-phase AML patient than in the AML patient in remission. Fifty-nine hyper- or hypomethylated genes were identified as common to all four cases. Genome-wide DNA methylation analysis demonstrated that differentially methylated sites among acute myeloid leukemia and colorectal carcinoma cases and the control were in both promoters (CpG island) and gene body regions (shelf/shore areas). Hypermethylation was more prevalent in cancer cases. The study supports the suggestion that the level of DNA methylation changes in AML progression.

Wang G, Wang H, Zhang C, et al.
Rac3 regulates cell proliferation through cell cycle pathway and predicts prognosis in lung adenocarcinoma.
Tumour Biol. 2016; 37(9):12597-12607 [PubMed] Related Publications
Lung cancer is still the leading cause of malignant deaths in the world. It is of great importance to find novel functional genes for the tumorigenesis of lung cancer. We demonstrated that Rac3 could promote cell proliferation and inhibit apoptosis in lung adenocarcinoma cell line A549 previously. The aim of this study was to investigate the function and mechanism of Rac3 in lung adenocarcinoma cell lines. Immunohistochemistry staining was performed in 107 lung adenocarcinoma tissues and matched non-tumor tissues. Multivariate analysis and Kaplan-Meier analysis were used to investigate the correlation between Rac3 expression and the clinical outcomes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and flow cytometry analysis were employed to determine the proliferative ability, cell cycle distribution, and apoptosis in H1299 and H1975 cell lines. Gene expression microarray and pathway analysis between the Rac3-siRNA group and the control group in A549 cells were performed to investigate the pathways and mechanism of Rac3 regulation. Rac3 was shown to be positively expressed in lung adenocarcinoma tissues, and the expression of Rac3 associates with longer survival in lung adenocarcinoma patients. Silencing of Rac3 significantly induced cell growth inhibition, colony formation decrease, cell cycle arrest, and apoptosis of lung adenocarcinoma cell lines, which accompanied by obvious downregulation of CCND1, MYC, and TFDP1 of cell cycle pathway involving in the tumorigenesis of lung adenocarcinoma based on the gene expression microarray. In conclusion, these findings suggest that Rac3 has the potential of being a therapeutic target for lung adenocarcinoma.

Salimi S, Hajizadeh A, Yaghmaei M, et al.
The effects of p21 gene C98A polymorphism on development of uterine leiomyoma in southeast Iranian women.
Tumour Biol. 2016; 37(9):12497-12502 [PubMed] Related Publications
Uterine leiomyoma (UL) is a monoclonal tumor which arises from uninhibited proliferation of a single myometrial cell; therefore, the imbalance in cell cycle regulation could be a key event in its development. In the present study, we aimed to assess the association of p21 gene polymorphisms and UL. Genomic DNA was extracted from blood samples of 154 women with UL and 197 age-, BMI-, and ethnically matched controls. p21 C98A (rs1801270) and C70T (rs1059234) polymorphism genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The CA genotype of p21 C98A polymorphism was significantly higher in UL women (28 %) compared to the controls (18 %), and the UL risk was 1.8-fold greater in women with CA genotype compared to CC genotype before and after adjusting for age, BMI, and ethnicity (OR, 1.8 [95 % CI, 1.1 to 3]; P = 0.02). There was no association between the AA genotype of p21 C98A polymorphism and UL. Moreover, the frequency of p21 98A allele was significantly higher in the UL women compared to controls (17 vs. 12 %, p = 0.04). The p21 C70T polymorphism did not correlate with UL before and after adjusting for age, BMI, and ethnicity. There was no difference in haplotype frequency of p21 C70T and C98A polymorphisms between UL patients and the controls. CA genotype of p21 C98A polymorphism may be a risk factor for UL susceptibility; however, p21 C70T polymorphism did not associate with UL.

Rogers MA, Kalter V, Strowitzki M, et al.
IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes.
Tumour Biol. 2016; 37(9):12485-12495 [PubMed] Related Publications
Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T. The cells were analyzed for changes in proliferation, cell cycle, apoptosis, adhesion, and invasion. Expression profiling analysis was performed, and, for a subset of the identified genes, expression was validated by qRT-PCR and Western blot. IGF2 knockdown inhibited cell proliferation in both cell lines induced G1 cell cycle blockade and decreased adhesion to several extracellular matrix proteins. Knockdown of IGF2 did not alter invasiveness in SW480 cells, while a slight increase in apoptosis was seen only in the LS174T cell line. Knockdown of IGF2 in SW480 deregulated 58 genes, several of which were associated with proliferation and cell-cell/cell-ECM contacts. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. This study supports the concept of direct autocrine/paracrine tumor cell activation through IGF2 and a shows role of IGF2 in CRC proliferation, adhesion and, to a limited extent, apoptosis.

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