LRP1

Gene Summary

Gene:LRP1; low density lipoprotein receptor-related protein 1
Aliases: APR, LRP, A2MR, CD91, APOER, LRP1A, TGFBR5, IGFBP3R
Location:12q13.3
Summary:The protein encoded by this gene is an endocytic receptor involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the A2M-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer patients. [provided by RefSeq, Jan 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:prolow-density lipoprotein receptor-related protein 1
HPRD
Source:NCBIAccessed: 27 August, 2015

Ontology:

What does this gene/protein do?
Show (36)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 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.

  • Genomics
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lung Cancer
  • Oligonucleotide Array Sequence Analysis
  • Tumor Markers
  • Neoplasm Proteins
  • Breast Cancer
  • CD Antigens
  • Cancer Gene Expression Regulation
  • Chromosome 12
  • Single Nucleotide Polymorphism
  • Pharmacogenetics
  • Multiple Drug Resistance
  • Survival Rate
  • alpha-Macroglobulins
  • Angiogenesis
  • Western Blotting
  • Oligonucleotides
  • Stromal Cells
  • Extracellular Signal-Regulated MAP Kinases
  • Neoplasm Invasiveness
  • Signal Transduction
  • Ligands
  • Multidrug Resistance-Associated Proteins
  • Ovarian Cancer
  • Cell Movement
  • Prostate Cancer
  • ATP-Binding Cassette Transporters
  • Vault Ribonucleoprotein Particles
  • Tumor Suppressor Proteins
  • DNA-Binding Proteins
  • p53 Protein
  • Carrier Proteins
  • Transcription Factors
  • P-Glycoprotein
  • Proteomics
  • Gene Expression Profiling
  • RTPCR
  • Tissue Array Analysis
  • Transfection
  • MMP9
  • Transforming Growth Factor beta
Tag cloud generated 27 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: LRP1 (cancer-related)

Rinaldi C, Bramanti P, Famà A, et al.
GLYOXALASE I A111E, PARAOXONASE 1 Q192R AND L55M POLYMORPHISMS IN ITALIAN PATIENTS WITH SPORADIC CEREBRAL CAVERNOUS MALFORMATIONS: A PILOT STUDY.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):493-500 [PubMed] Related Publications
It is already known that the conditions of increased oxidative stress are associated to a greater susceptibility to vascular malformations including cerebral cavernous malformations (CCMs). These are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1(Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Polymorphisms in the genes encoding for enzymes involved in the antioxidant systems such as glyoxalase I (GLO I) and paraoxonase I (PON I) could influence individual susceptibility to the vascular malformations. A single nucleotide polymorphism was identified in the exon 4 of GLO 1 gene that causes an amino acid substitution of Ala for Glu (Ala111Glu). Two common polymorphisms have been described in the coding region of PON1, which lead to glutamine → arginine substitution at 192 (Q192R) and a leucine → methionine substitution at 55 (L55M). The polymorphisms were characterized in 59 patients without mutations in the CCM genes versus 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that the frequency of patients carrying the GLO1 A/E genotype among the case group (56%) was four-fold higher than among the controls (14.1%). In the cohort of CCM patients, an increase in the frequency of PON192 Q/R genotype was observed (39% in the CCM group versus 3.7% in the healthy controls). Similarly, an increase was observed in the proportion of individuals with the genotype R/R in the disease group (5%) in respect to the normal healthy cohort (0.5%). Finally, the frequency of the PON55 heterozygotes L/M genotype was 29% in patients with CCMs and 4% in the healthy controls. The same trend was observed in PON55 homozygous M/M genotype frequency (CCMs 20% vs controls 10%). The present study aimed to investigate the possible association of GLO1 A111E, PON1 Q192R and L55M polymorphisms with the risk of CCMs. We found that individuals with the GLO1 A /E genotype, PON192/QR-RR genotypes and PON55/LM-MM genotypes had a significantly higher risk of CCMs compared with the other genotypes. However, because CCM is a heterogeneous disease, other additional factors might be involved in the initiation and progression of CCM disease.

Zhou WP, Liu X, Yang Y, Liu YF
THE INFLUENCE AND REGULATORY MECHANISM OF Y-BOX BINDING PROTEIN 1 IN OSTEOSARCOMA AND ITS SIGNIFICANCE.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):485-91 [PubMed] Related Publications
This study quantified the expression of Y-box binding protein 1 (YB-1) by the immunohistochemical method based on pathological paraffin block specimens of aspiration biopsy from patients with osteosarcoma to explore the influence and regulatory mechanism of YB-1 in osteosarcoma and its significance. Patients were divided into two groups with high and low expressed YB-1, and results showed that 7 cases (13.7%) and 18 cases (26.1%) were in level III, and 44 cases (86.3%) and 51 cases (76.9%) were in level IV respectively, and patients with high YB-1 expression quantity had higher malignant tumor degree (p=0.03). Moreover, the tumor necrosis rate induced by chemotherapy in the two groups were 21 cases (41.2%) and 38 cases (51.8%), respectively. By survival analysis, it was found that a 5-year overall survival rate of patients with high YB-1 expression and low YB-1 expression were 61.2% and 76.6%, respectively (p = 0.054), and 5-year event free survival rates were 52.5% and 72.4%, respectively (p = 0.033). Furthermore, metastasis rate of high YB-1 expression and low YB-1 expression were 41.8% and 22.7%, respectively (p = 0.036), indicating that patients with high YB-1 expression had higher pulmonary metastasis rate. Through further study, we discovered that possibly miR-382 plays a regulatory role in YB-1 gene in osteosarcoma.

Song B, Yu J, Wu TS
CORRELATION BETWEEN C-erbB-2 WITH GASTRIC MUCOSAL ATYPICAL HYPERPLASIA AND GASTRIC CARCINOMA.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):471-7 [PubMed] Related Publications
C-erbB-2 is a cancer gene originating from cells. The high-expression and amplification of C-erbB-2 and its protein products (P185) are found in a wide variety of tumors. The abnormal expression of C-erbB-2 has great influence on the occurrence and development of gastric carcinoma. This paper aimed to analyze the expression of C-erbB-2 in the tissues of gastric carcinoma, gastric mucosal atypical hyperplasia and gastritis, and discuss its role in the occurrence and development of gastric carcinoma. The morphological differences and connections among simple intestinal metaplasia (SIM), atypical intestinal metaplasia (AIM) and dysplasia in intestinal metaplasia through hematoxylin and eosin (HE) staining were studied. Three groups were set to detect the expression condition of C-erbB-2 by immunohistochemical method (IHC). The result showed that C-erbB-2 had no significant difference in AIM and gastric carcinoma, that is, AIM was closely related to gastric carcinoma. The positive expression was demonstrated of C-erbB-2 products (P185) in medium and gastric mucosa dysplasia tissues and was 29.41% and 66.67%, respectively, while it was 25%, 50% and 77.78% in high, medium and low differentiation of gastric carcinoma. It can be seen that there was a significant difference between them (P<0.05), and the expression degree was significantly enhanced (P<0.05); the expression degree in high differentiation gastric cancer tissue was significantly higher than the middle and low differentiation gastric cancer tissue. It was concluded that C-erbB-2 played an important role in the pathogenic mechanism of gastric carcinoma, and it might act on the later period of the gastric carcinoma, which provides objective reference index for the diagnosis and prognosis of gastric carcinoma and meanwhile provides instructional theoretical reference for the application of targeted drugs in the clinical treatment of gastric carcinoma.

Zhao H, Wang QT, Geng SQ, et al.
PROTEIN EXPRESSION OF METADHERIN AND SENSIBILITY OF BREAST CANCER MDA-MB-231 CELLS TO TREATMENT BEFORE AND AFTER TRANSFECTION.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):459-64 [PubMed] Related Publications
Breast cancer tends to have an increasing mortality, severely threatening the health of females. The invasion and metastasis of breast cancer are the leading causes of death. It has been reported that breast cancer is caused by the activation of a series of proto-oncogenes and inactivation of anti-oncogenes. In the present study, Real-time PCR and Western blot were used to detect the protein expression level of metadherin before and after transfecting MDA-MB-231 cells to identify the effect, while the sensitivity of MDA-MB-231 cells to 1 mg/L doxorubicin and 8mg/L taxol was measured by methylthiazolyldiphenyl-tetrazolium bromide (MTT). The results demonstrated that mRNA and protein expression level of metadherin both improved after transfection. The inhibition effect of 1 mg/L doxorubicin and 8 mg/L taxol on breast cancer cells decreased after transfection. Detected by flow cytometry, the apoptosis rate of breast cancer cells was 39.68±0.42%, 20.64±0.55%, respectively, under the effect of 1 mg/L doxorubicin; while under the effect of 8 mg/L taxol, the rate was 24.89±0.41% and 13.8±0.63%, respectively. Thus the inhibition effects of 1 mg/L doxorubicin and 8mg/L taxol to breast cancer cells and their effects on apoptosis were different, and the differences were statistically significant (P<0.05). Based on the statistics on the expression level of metadherin after transfecting breast cancer cells MDA-MB-231 and the exploration of the sensitivity of the cells to treatment, the effect of metadherin on breast cancer MDA-MB-232 cells was proved.

Wan YC, Li T, Han YD, et al.
EFFECT OF PREGNANE XENOBIOTIC RECEPTOR ACTIVATION ON INFLAMMATORY BOWEL DISEASE TREATED WITH RIFAXIMIN.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):401-10 [PubMed] Related Publications
The causes and pathogenesis of Inflammatory Bowel Disease (IBD) are still not clearly understood. This study aims to prove the important role of rifaximin played in inflammatory reaction caused by abnormity of the intestinal mucosal immune system. Intestinal microflora can greatly promote and maintain the inflammatory reaction of IBD, therefore, antibiotics can be used to treat IBD. Rifaximin is a medicine usually used for local intestinal infection. Many clinical and basic studies have shown that both a single application of rifaximin and the joint application with other medicines could achieve a good efficacy. This paper studied the activation of Pregnane Xenobiotic Receptor (PXR) in treating IBD with rifaximin and analyzed its efficacy in IBD when PXR was involved in the transport of medicine and metabolism. The results prove that rifaximin can not only serve as an anti-microbial drug, but can activate PXR and actually weaken the reaction of IBD. Thus it is safe to say that rifaximin has great potential in treating IBD.

Wang JG, Zhang LK, Chen YB, et al.
INFLUENCE OF miR-373 ON THE INVASION AND MIGRATION OF BREAST CANCER AND THE EXPRESSION LEVEL OF TARGET GENES TXNIP.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):367-72 [PubMed] Related Publications
An increasing number of people die from breast cancer every year. Consequently, more research has been concentrated on the study of this type of tumour, and miR-373 resulted as an important gene for treating breast cancer. To explore the influence of miR-373 on the invasion and migration of breast cancer and the expression level of target gene TXNIP, a set of therapeutic methods were designed based on miR-373. The transfection was performed using miR-373 inhibitor; the concentration of miR-373 was controlled by inhibitor, and it was transfected into MCF-7 cell by lipofectin. Fluorescent quantitative polymerase chain reaction was used to detect the expression level of miR-373 in cells after transfection as well as that of Caspase-3 and Caspase-8. MTT assay was used to detect the influence of miR-373 inhibitor on MCF-7 cells. The expression quantity of miR-373 in cell and tissue of breast cancer with high-low invasion and migration ability was detected by qRT-PCR (quantitative real-time polymerase chain reaction), thus the influence of the expression quantity of miR-373 on the invasion and migration of cell was determined. The expression of miR-373, EMT and TXNIP was determined by Western blot. Through the identification of proteomics and bioinformatics, it was finally found that TXNIP was regulated by miR-373. The protein expression level of TXNIP was negatively correlated with the level of miR-373. Thus it was concluded that miR-373 could promote the invasion and migration of breast cancer. In addition, in the tissue and cell of breast cancer with different invasion and migration abilities, the expression level of TXNIP was negatively correlated with the level of miR-373.

Liu W, Wang DW, Yu SY, et al.
THE EFFECT OF DIHYDROARTEMISININ ON THE PROLIFERATION, METASTASIS AND APOPTOSIS OF HUMAN OSTEOSARCOMA CELLS AND ITS MECHANISM.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):335-42 [PubMed] Related Publications
This study aims to research the effect of dihydroartemisinin on the proliferation, metastasis and apoptosis in human osteosarcoma cells 143B and the underlying mechanism. This study designed five groups for experiment and control, using dimethylsulfoxide (DMSO), and docosahexaenoic acid (DHA) at concentrations of 15, 25, 35 μmol.L-1 respectively. Experiments including methyl thiazolyl tetrazolium (MTT) assay, clone formation assay, Hoechst 33258 staining assay, luciferase reporter plasmid assay, Western blot and scratch test were carried out. In addition, SPSS 18.0 software from IBM was used for statistical analysis and all the data obtained from the experiments were expressed as mean ± SD, and variance was used to compare the difference between the groups. DHA is proved to be able to inhibit the proliferation and metastasis of osteosarcoma cells, as well as leaving a positive effect on apoptosis in the cytomorphosis. It achieves regulation over the human osteosarcoma cells by keeping the expression of related protein under control.

Ye LC, Jiang C, Bai J, et al.
KNOCKDOWN OF CASEIN KINASE 1e INHIBITS CELL PROLIFERATION AND INVASION OF COLORECTAL CANCER CELLS VIA INHIBITION OF THE Wnt/β-CATENIN SIGNALING.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):307-15 [PubMed] Related Publications
Deregulation of casein kinase 1 epsilon (CK1ε) is involved in the development of multiple pathological disorders such as cancer, however the function and molecular mechanism of CK1εin cancer are still unclear. In the present study, we aimed to investigate the role of CK1ε in human colorectal cancer (CRC). The expression of CK1ε was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was performed to observe the effects of lentivirus-mediated CK1ε shRNA (Lv-shCK1ε) on cell proliferation and invasive potential by MTT and Transwell assays in CRC cell line (SW480). As a result, we found that the expression of CK1ε protein was significantly increased in CRC tissues compared with that in adjacent non-cancerous tissues (ANCT) (68.9% vs 42.2%, P=0.017) and was correlated with the Duke’s staging and depth of invasion in CRC patients (P=0.012; P=0.015). Knockdown of CK1ε reduced cell proliferation and invasion of CRC cells followed by the downregulation of wnt3α, β-catenin, PCNA and MMP-9. In conclusion, our findings show that high expression of CK1ε is positively associated with the Duke’s staging and depth of invasion in CRC patients, and knockdown of CK1ε suppresses the growth and invasion of CRC cells through inhibition of the wnt/β-catenin signaling, suggesting that CK1ε may serve as a promising therapeutic target for the treatment of CRC.

Sumantran VN, Mishra P, Sudhakar N
Microarray analysis of differentially expressed genes regulating lipid metabolism during melanoma progression.
Indian J Biochem Biophys. 2015; 52(2):125-31 [PubMed] Related Publications
A new hallmark of cancer involves acquisition of a lipogenic phenotype which promotes tumorigenesis. Little is known about lipid metabolism in melanomas. Therefore, we used BRB (Biometrics Research Branch) class comparison tool with multivariate analysis to identify differentially expressed genes in human cutaneous melanomas, compared with benign nevi and normal skin derived from the microarray dataset (GDS1375). The methods were validated by identifying known melanoma biomarkers (CITED1, FGFR2, PTPRF, LICAM, SPP1 and PHACTR1) in our results. Eighteen genes regulating metabolism of fatty acids, lipid second messengers and gangliosides were 2-9 fold upregulated in melanomas of GDS-1375. Out of the 18 genes, 13 were confirmed by KEGG pathway analysis and 10 were also significantly upregulated in human melanoma cell lines of NCI-60 Cell Miner database. Results showed that melanomas upregulated PPARGC1A transcription factor and its target genes regulating synthesis of fatty acids (SCD) and complex lipids (FABP3 and ACSL3). Melanoma also upregulated genes which prevented lipotoxicity (CPT2 and ACOT7) and regulated lipid second messengers, such as phosphatidic acid (AGPAT-4, PLD3) and inositol triphosphate (ITPKB, ITPR3). Genes for synthesis of pro-tumorigenic GM3 and GD3 gangliosides (UGCG, HEXA, ST3GAL5 and ST8SIA1) were also upregulated in melanoma. Overall, the microarray analysis of GDS-1375 dataset indicated that melanomas can become lipogenic by upregulating genes, leading to increase in fatty acid metabolism, metabolism of specific lipid second messengers, and ganglioside synthesis.

van Gisbergen MW, Voets AM, Starmans MH, et al.
How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models.
Mutat Res Rev Mutat Res. 2015 Apr-Jun; 764:16-30 [PubMed] Related Publications
Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.

Gao XJ, Liu JW, Zhang QG, et al.
Nobiletin inhibited hypoxia-induced epithelial-mesenchymal transition of lung cancer cells by inactivating of Notch-1 signaling and switching on miR-200b.
Pharmazie. 2015; 70(4):256-62 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) is an early step in the process of tumor metastasis. It is well known that tumor microenvironment affects malignancy in various carcinomas; in particular, that hypoxia induces EMT. Deregulated notch signaling also contributes a lot to the development of EMT in lung cancer. In this study, we investigated the use of Notch-1-inhibiting compound as novel therapeutic candidates to regulate hypoxia-induced EMT in lung cancer cells. According to previous screening, nobiletin was selected as a Notch-1 inhibitor. Hypoxia-induced EMT was characteristic of increased N-cadherin & vimentin expressions and decreased E-cadherin expressions. Treatment with nobiletin notably attenuated hypoxia-induced EMT, invasion and migration in H1299 cells, accompanied with reduced Notch-1, Jagged1/2 expressions and its downstream genes Hey-1 and Hes-1. Nobiletin treatment also promoted tumorsuppressive miR-200b level. Moreover, notch-1 siRNA prevented hypoxia-mediated cell migration and decreased Twist1, Snail1, and ZEB1/2 expressions, which are key EMT markers. Re-expression of miR-200b blocked hypoxia-induced EMT and cell invasion. Our findings suggest that downregulation of Notch-1 and reexpression of miR-200b by nobiletin might be a novel remedy for the therapy of lung cancer.

Zhao DC, Lu HW, Huang ZH
Association between the receptor for advanced glycation end products gene polymorphisms and cancer risk: a systematic review and meta-analysis.
J BUON. 2015 Mar-Apr; 20(2):614-24 [PubMed] Related Publications
PURPOSE: Polymorphisms in the receptor for advanced glycation end products (RAGE) gene may influence the risk of cancer, but the results are inconsistent. Therefore, we performed a systematic review to identify statistical evidence of the association between the 3 polymorphisms rs2070600 G/S (82G>S), rs1800624 T/A ( -374 T>A) and rs1800625C/T (-429 C>T) and the risk of cancer.
METHODS: We searched PubMed database (http://www.ncbi. nlm.nih.gov/pubmed/), EMBASE database (http://www.elsevier.com/online-tools/embase ) and China National Knowledge Infrastructure (CNKI) database (http://www.cnki.net/) until Aug 30, 2014 to identify eligible studies.
RESULTS: The pooled analysis revealed positive association between RAGE rs2070600 polymorphism and cancer risk in all genetic models (homozygous: OR=1.831, 95%CI: 1.548-2.166, p<0.001, allele: OR=1.321, 95%CI: 1.164-1.499, p<0.001, heterozygous: OR=1.42, 95%CI:1.126-1.792, p=0.003, dominant: OR=1.499, 95%CI: 1.200-1.874 ; p<0.001, recessive: OR=1.376, 95%CI: 1.197-1.583, p<0.001). We failed to get an effective conclusion about the association between the rs1800624 and rs1800625 polymorphisms and cancer risk in overall comparison. But in subgroup analysis, the rs1800624 polymorphism significantly increased lung cancer susceptibility in the homozygous model (OR=1.486, 95%CI:1.147-1.924, p=0.003) and the allele model (OR=1.15, 95%CI:1.029-1.285, p=0.014), but most likely contributed to decreased susceptibility to breast cancer in the allele model (OR=0.791 95%CI: 0.648-0.965, p=0.021), the heterozygous model (OR=0.733, 95%CI:0.577-0.931, p=0.011) and the dominant model (OR=0.741, 95%CI:0.588-0.934, p=0.011). No significant association was found between RAGE rs1088625 polymorphism and cancer risk in Caucasians, but these results should be interpreted with caution.
CONCLUSION: The polymorphism of rs2070600 in the RAGE gene may increase the susceptibility to several human cancers, especially to lung cancer and to Asians. The rs1800264 most likely contributes to decreased susceptibility to breast cancer but increased susceptibility to lung cancer. However, large-scale studies involving various cancer types and different populations are needed for a precise conclusion.

Mutlu P, Mutlu M, Yalcin S, et al.
Detection of XRCC1 gene polymorphisms in Turkish head and neck squamous cell carcinoma patients: a comparative analysis with different populations.
J BUON. 2015 Mar-Apr; 20(2):540-7 [PubMed] Related Publications
PURPOSE: X-ray repair cross-complementing (XRCC1) is one of the most important genes for the maintenance of genomic integrity and protection of cells from DNA damage. Although tobacco and alcohol consumption are the major risk factors for the development of head and neck squamous cell carcinoma (HNSCC), sequence variation in XRCC1 gene may alter HNSCC susceptibility. Reports on the relationship between HNSCC and polymorphisms in XRCC1 gene have been inconsistent so far. The aim of this study was to investigate the association of XRCC1 Arg194Trp and Arg399Gln single nucleotide polymorphisms (SNP), smoking and alcohol consumption with the risk of HNSCC in Turkish population and also to compare to these results with the ones from both Turkish and different populations in the literature. The frequencies of Arg194Trp and Arg399Gln SNPs were studied in 55 HNSCC and 69 healthy individuals.
METHODS: Genomic DNA was isolated from peripheral blood and SNP was genotyped by PCR-RFLP method.
RESULTS: The genotype and allele frequencies of both polymorphisms were not statistically different between the HNSCC and control groups. On the other hand, smoking and chronic alcohol consumption were associated with risk of HNSCC, but there was no association between Arg194Trp, Arg399Gln polymorphisms, smoking and alcohol consumption in HNSCC cases.
CONCLUSION: These results indicate that both Arg194Trp and Arg399Gln polymorphisms were not associated with the development of HNSCC in Turkish population. In addition, the allele frequencies of polymorphisms were in line with other Turkish population results that were studied previously. However, compared to different populations, there were marked differences in allele frequencies.

Tsvetkova A, Todorova A, Todorov T, et al.
Molecular and clinico-histological data in aggressive prostate cancer patients from Bulgaria.
J BUON. 2015 Mar-Apr; 20(2):498-504 [PubMed] Related Publications
PURPOSE: Metastatic prostate cancer (PCa) is one of the leading causes of death in men worldwide. We report Bulgarian patients with strongly aggressive, castration-resistant PCa.
METHODS: PCA3 overexpression, GSTP1 promoter hyper-methylation, TMPRSS2-ERG gene fusions, IVS1-27G>A in the KLF6 gene and mutations in androgen receptor (AR) gene, for diagnostic purposes were assessed. PCR, real-time PCR (RT-PCR), sequencing, and bisulfite conversion of DNA were applied. We correlated the molecular data to the histological and clinical findings.
RESULTS: The obtained molecular profile in 11 PCa Bulgarian patients coincided with the clinico-histological data of strongly aggressive PCa. Association was detected between the tumor stage (assessed by TNM as T3 and T4) and the detected molecular profile of aggressive cancer behavior with one exception, assessed as T2. None of our patients had positive family history of prostate cancer and no somatic mutations were detected in the AR gene. All patients showed normal genotype with respect to the KLF6 IVS1- 27G>A polymorphism. The rest of the markers were positive in fresh prostatic tissues and biopsies from all patients, whereas only one blood sample showed triple positive result.
CONCLUSIONS: The appearance of PCa-specific markers in blood was considered as a predictor for a PCa (micro) dissemination into the circulation. The GSTP1 promoter hypermethylation is the earliest epigenetic alteration, which indicates cancerous changes and the first and long-lasting marker that is detectable in blood circulation. The molecular profile needs to be strictly monitored during treatment, which is of great help in determining the patient's individual response to therapy.

Chen H, Wu Q
Expression of GW112 and GRIM-19 in colorectal cancer tissues.
J BUON. 2015 Mar-Apr; 20(2):438-42 [PubMed] Related Publications
PURPOSE: To investigate the expression of GW112 and GRIM-19 in colorectal cancer tissues.
METHODS: Immunohistochemistry and semi-quantitative PCR were used to simultaneously detect the levels of expression of GW112 and GRIM-19 in colorectal cancer tissues and normal colorectal tissues in 39 cases.
RESULTS: Expression of GW112 protein and mRNA were significantly higher in colorectal cancer tissues than in normal tissues (p<0.05). Expression of GRIM-19 protein and mRNA were significantly lower in colorectal cancer tissues than in normal tissues (p<0.05). GW112 gene mRNA copy number(GAPDH gene mRNA copy number were 0.53 ± 0.21 and 1.81 ± 0.65 in normal colorectal tissues and colorectal cancer tissues respectively, and GRIM-19 gene mRNA copy number/GAPDH gene mRNA copy number were 1.15 ± 0.29 and 1.74 ± 0.0.44 in colorectal cancer tissues and normal colorectal tissues, respectively. Expression of GW112 gene mRNA was significantly higher in colorectal cancer tissues than in normal tissues (p<0.05), and expression of GRIM- 19 gene mRNA was significantly lower in colorectal cancer tissues than in normal tissues (p<0.05).
CONCLUSION: High expression of GW112 in colorectal cancer tissues and reduced expression of GRIM-19 in colorectal cancer tissues may be associated with abnormal proliferation of cancer cells and are possibly one of the reasons for development of colorectal cancer, which can provide effective targets for clinical treatment of this disease.

Muresan M, Zaharie F, Bojan A, et al.
MicroRNAs in liver malignancies. Basic science applied in surgery.
J BUON. 2015 Mar-Apr; 20(2):361-75 [PubMed] Related Publications
Liver malignancies represent one of the major public health problems worldwide because of late diagnosis and failure of current treatments to offer a curative option for many of the patients. MicroRNAs (miRs) are small non-coding RNA molecules that are known to regulate the gene expression at a post-transcriptional level through complementary base pairing with thousands of messenger (m)RNAs. Recent data has shown the involvement of miRs in the pathogenesis of many human cancers, including those of the liver, with huge possible impact in the clinic, mainly due to the identification of non-coding RNAs as biomarkers that can often be detected in the systemic circulation. In the current review, we present the importance of miRs in liver cancers by discussing their role in the pathobiology of these diseases, apart from their role as diagnostic and prognostic markers for liver malignancies.

Iobagiu C, Lambert C, Raica M, et al.
Loss of heterozygosity in tumor tissue in hormonal receptor genes is associated with poor prognostic criteria in breast cancer.
Cancer Genet. 2015; 208(4):135-42 [PubMed] Related Publications
The estrogen receptors (ESRα and β) and the androgen receptor (AR) mediate genomic and non-genomic effects on breast tumor growth and proliferation. We analyzed 101 breast cancer patients for allelic loss in microsatellites located in regulatory regions of the ESRs and AR genes in breast cancer tumors. The loss of heterozygosity (LOH) at these loci was found in 36.2% of tumor tissues (ductal carcinoma cases), for 19% of cases at the ESRα locus, for 16% at the ESRβ locus, and for 10% at the AR locus. The LOH in at least one of the two ESR loci was correlated to poor prognosis criteria: ESR-negative status (P = 0.007), PR-negative status (P = 0.003), high Scarff-Bloom-Richardson (SBR) grade (P = 0.0007), high MIB-1 proliferation index (P = 0.02), and diminished apoptosis potential (TP53-positive status, P = 0.018). When AR was also considered, the LOH in at least one of the three loci was associated with ESR-negative status (P = 0.036), PR-negative status (P = 0.027), high SBR grade (P = 0.005), high mitotic index (P = 0.0002), TP53-positive status (P = 0.029), and proliferating index (high MIB-1, P = 0.03). Allelic loss was observed in 26% of normal tissue adjacent to tumor with LOH at the ESRα locus and in 7.1% of tumors with LOH at the ESRβ locus. The LOH in tumor tissue in the regulatory regions of ESRα, ESRβ, and AR genes has potentially synergistic effects on tumor proliferation, histological aggressiveness, down-regulation of ESRα and progesterone receptor (PR) genes, and is an early genetic alteration in cancer that is possibly involved in passage to estrogen independence.

Sen A, Nelson TJ, Alkon DL
ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation.
J Neurosci. 2015; 35(19):7538-51 [PubMed] Related Publications
Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression. Amyloid-β (Aβ) oligomers, which have been implicated in AD, caused effects similar to ApoE4. Blocking low-density lipoprotein receptor-related protein 1 (LRP-1) receptor with receptor-associated protein (RAP) or LRP-1 siRNA abolished the ApoE effects. ApoE3 also induced expression of protein kinase C ε (PKCε) and PKCε retained HDACs in the cytosol. PKCε activation and ApoE3 supplementation prevented ApoE4-mediated BDNF downregulation. PKCε activation also reversed Aβ oligomer- and ApoE4-induced nuclear import of HDACs, preventing the loss in BDNF. ApoE4 induced HDAC6-BDNF promoter IV binding, which reduced BDNF exon IV expression. Nuclear HDAC4 and HDAC6 were more abundant in the hippocampus of ApoE4 transgenic mice than in ApoE3 transgenic mice or wild-type controls. Nuclear translocation of HDA6 was also elevated in the hippocampus of AD patients compared with age-matched controls. These results provide new insight into the cause of synaptic loss that is the most important pathologic correlate of cognitive deficits in AD.

Savitri E, Haryana MS
Expression of interleukin-8, interleukin-10 and Epstein-Barr viral-load as prognostic indicator in nasopharyngeal carcinoma.
Glob J Health Sci. 2015; 7(3):364-72 [PubMed] Related Publications
Interleukin-8 (IL-8) is angiogeneic chemokine that plays a potential role in both development and progression of many human malignancies including nasopharyngeal carcinoma (NPC). Epstein- Barr virus (EBV) is recognized to be an important etiologic agent of NPC as the viral gene products are frequently detected in NPC tissue along with the elevation of antibody titre to the viral protein (VCA-p18+ EBNA1) of IgA in the majority of patients. Elevated plasma of Viral Load is regarded as an important marker for the presence of the disease and for the monitoring of disease progression. However, other serum /plasma parameters such as the level of certain interleukins (IL-8 and IL-10) has also been implicated in NPC progression. The study aimed to investigate the correlations between plasma Viral Load and the level of interleukin (IL-8) and Interleukin (IL-10) in relating these parameters to the stages of NPC. In addition of Viral Load (VCA-p18+EBNA1) IgA, Interleukin-8 and Interleukin-10 before and after therapy will be investigated to seek the possible marker for disease progression. A total of 39 NPC patients and 29 healthy control individuals enrolled in this study. Plasma Viral Load was quantified using real-time quantitative PCR. The Level of plasma interleukins both IL-8 and IL-10 were analyzed using ELISA methods. Results indicated there was a significant decrease in viral load was detected in plasma of NPC patients following therapy. Plasma of viral load was shown to be a good prognosticator for disease progression. There were positive correlation between plasma of viral load and IL-8. These non invasive parameters expressed in blood, could be substitutes of viral load using brushing method, which is invasive. In conclusion that: Viral Load, (VCA-p18+EBNA1) IgA and IL-8 levels are promising markers for the presence of NPC and progression of the disease.

Przytulska J, Rogala N, Bednarek-Tupikowska G
Current and emerging therapies for adrenocortical carcinoma--review.
Adv Clin Exp Med. 2015 Mar-Apr; 24(2):185-93 [PubMed] Related Publications
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Patients may present with hormone excess or a local mass effect. The most common imaging techniques (CT and MRI) use both size and appearance to distinguish between benign and malignant tumors. Open surgery by an expert surgeon with R0 target is the treatment of choice. Mitotane (alone or in combination with cytotoxic drugs) may be administered after surgery or in patients not amenable to surgery. The role of radiotherapy as an adjuvant treatment is uncertain whereas targeted radionuclide therapy seems to be a promising option. New adjuvant treatment options, even after complete tumor removal, are desired because postoperative disease-free survival at 5 yrs is only around 30%. The establishment of detailed guidelines with the purpose of optimizing therapy with only mitotane but also in combination with other antineoplasmatic drugs is still a task to be done. Future advances in the management of ACC will probably be connected with better understanding of the molecular pathogenesis.

Ren Y, Yin Z, Li K, et al.
TGFβ-1 and TGFBR2 polymorphisms, cooking oil fume exposure and risk of lung adenocarcinoma in Chinese nonsmoking females: a case control study.
BMC Med Genet. 2015; 16:22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Transforming growth factor-β (TGF-β) plays an important role in regulating cellular functions, and many studies have demonstrated important roles for TGF-β in various cancers. Single nucleotide polymorphisms (SNPs) of TGF-β may influence lung carcinogenesis. The aim of this study was to test whether TGF-β1 C509T and TGF-β receptor II (TGFBR2) G-875A polymorphisms were associated with lung adenocarcinoma in nonsmoking females.
METHODS: A hospital-based case-control study was performed in Chinese nonsmoking females. Genotyping was performed using TaqMan SNP genotyping assay, and demographic data and environmental exposure were collected by trained interviewers after informed consents were obtained.
RESULTS: A total of 272 (95.4%) cases and 313 (99.4%) controls were successfully genotyped, and the results showed that the polymorphic allele frequencies of C509T and G875A were similar among lung adenocarcinoma patients and controls (P=0.589 and 0.643, respectively). However, when the data were stratified for cooking oil fume exposure, the TT genotype of the TGFB1 C509T polymorphism showed a significantly decreased risk for lung adenocarcinoma compared with the CC genotype (adjusted OR=0.362, 95% CI=0.149-0.878, P=0.025).
CONCLUSIONS: TGF-β1 gene C509T polymorphism might be associated with decreased risk of lung adenocarcinoma in Chinese females exposed to cooking oil fumes, but no association was observed TGFBR2 gene G875A polymorphism.

Wang S, Sun H, Jia Y, et al.
Association of 42 SNPs with genetic risk for cervical cancer: an extensive meta-analysis.
BMC Med Genet. 2015; 16:25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A large number of single nucleotide polymorphisms (SNPs) associated with cervical cancer have been identified through candidate gene association studies and genome-wide association studies (GWAs). However, some studies have yielded different results for the same SNP. To obtain a more comprehensive understanding, we performed a meta-analysis on previously published case-control studies involving the SNPs associated with cervical cancer.
METHODS: Electronic searches of PubMed and Embase were conducted for all publications about the association between gene polymorphisms and cervical cancer. One-hundred and sixty-seven association studies were included in our research. For each SNP, three models (the allele, dominant and recessive effect models) were adopted in the meta-analysis. For each model, the effect summary odds ratio (OR) and 95% CI were calculated. Heterogeneity between studies was evaluated by Cochran's Q test. If the p value of Q test was less than 0.01, a random effect model was used; otherwise, a fixed effect model was used.
RESULTS: The results of our meta-analysis showed that: (1) There were 8, 2 and 8 SNPs that were significantly associated with cervical cancer (P < 0.01) in the allele, dominant and recessive effect models, respectively. (2) rs1048943 (CYP1A1 A4889G) showed the strongest association with cervical cancer in the allele effect model (1.83[1.57, 2.13]); in addition, rs1048943 (CYP1A1 A4889G) had a very strong association in the dominant and recessive effect model. (3) 15, 11 and 10 SNPs had high heterogeneity (P < 0.01) in the three models, respectively. (4) There was no published bias for most of the SNPs according to Egger's test (P < 0.01) and Funnel plot analysis. For some SNPs, their association with cervical cancer was only tested in a few studies and, therefore, might have been subjected to published bias. More studies on these loci are required.
CONCLUSION: Our meta-analysis provides a comprehensive evaluation of cervical cancer association studies.

Arcand SL, Akbari MR, Mes-Masson AM, et al.
Germline TP53 mutational spectrum in French Canadians with breast cancer.
BMC Med Genet. 2015; 16:24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.
METHODS: TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.
RESULTS: Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.
CONCLUSIONS: In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.

Yang J, AlTahan AM, Hu D, et al.
The role of histone demethylase KDM4B in Myc signaling in neuroblastoma.
J Natl Cancer Inst. 2015; 107(6):djv080 [PubMed] Related Publications
BACKGROUND: Epigenetic alterations, such as histone methylation, modulate Myc signaling, a pathway central to oncogenesis. We investigated the role of the histone demethylase KDM4B in N-Myc-mediated neuroblastoma pathogenesis.
METHODS: Spearman correlation was performed to correlate MYCN and KDM4B expression. RNA interference, microarray analysis, gene set enrichment analysis, and real-time polymerase chain reaction were used to define the functions of KDM4B. Immunoprecipitation and immunofluorescence were used to assess protein-protein interactions between N-Myc and KDM4B. Chromatin immunoprecipitation was used to assess the binding of Myc targets. Constitutive and inducible lentiviral-mediated KDM4B knockdown with shRNA was used to assess the effects on tumor growth. Kaplan-Meier survival analysis was used to assess the prognostic value of KDM4B expression. All statistical tests were two-sided.
RESULTS: KDM4B and MYCN expression were found to be statistically significantly correlated in a variety of cancers, including neuroblastoma (R = 0.396, P < .001). Functional studies demonstrated that KDM4B regulates the Myc pathway. N-Myc was found to physically interact with and recruit KDM4B. KDM4B was found to regulate neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo (5 mice/group, two-tailed t test, P ≤ 0.001). Finally, together with MYCN amplification, KDM4B was found to stratify a subgroup of poor-prognosis patients (122 case patients, P < .001).
CONCLUSIONS: Our findings provide insight into the epigenetic regulation of Myc via histone demethylation and proof-of-concept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma.

Sequist LV, Soria JC, Goldman JW, et al.
Rociletinib in EGFR-mutated non-small-cell lung cancer.
N Engl J Med. 2015; 372(18):1700-9 [PubMed] Related Publications
BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.
METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.
RESULTS: A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).
CONCLUSIONS: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

Kwan ML, Bernard PS, Kroenke CH, et al.
Breastfeeding, PAM50 tumor subtype, and breast cancer prognosis and survival.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
BACKGROUND: Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown.
METHODS: We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided.
RESULTS: Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes.
CONCLUSIONS: History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity.

Amankwatia EB, Chakravarty P, Carey FA, et al.
MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms.
Br J Cancer. 2015; 112(9):1480-90 [PubMed] Article available free on PMC after 28/04/2016 Related Publications
BACKGROUND: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients.
METHODS: We used TaqMan low-density array (TLDA) qRT-PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion.
RESULTS: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells.
CONCLUSIONS: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers.

Yoshii M, Tanaka H, Ohira M, et al.
Regulation of neutrophil infiltration into peritoneal cavity by laparoscopic gastrectomy.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):546-50 [PubMed] Related Publications
BACKGROUND/AIMS: Laparoscopic surgery is a minimally invasive operation developed for treating gastrointestinal malignancies. We aimed to characterize the differences in the intra-abdominal environment following open and laparoscopic surgeries.
METHODOLOGY: We investigated data of 48 patients who underwent gastrectomy between 2010 and 2012. We analyzed the mRNA expression of chemokines, indoleamine 2, 3-dioxygenase (IDO), and so on in peritoneal lavage fluid with real-time RT-PCR. We also determined the leukocyte population and calculated the granulocyte/lymphocyte (G/L) ratio in peritoneal lavage fluid using flow cytometry.
RESULTS: CCL3 mRNA was significantly upregulated, whereas IDO mRNA was significantly downregulated, in the open group compared to the laparoscopic surgery group. Flow cytometry revealed that the G/L ratio was significantly higher in the open group.
CONCLUSIONS: We suggest that the production of chemokines and neutrophil infiltration into the abdominal cavity may be suppressed in the laparoscopic surgery. Thus, laparoscopic surgery may be beneficial in preserving local immunity.

Jian T, Chen Y
Regulatory mechanisms of transcription factors and target genes on gastric cancer by bioinformatics method.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):524-8 [PubMed] Related Publications
BACKGROUND/AIMS: Gastric cancer is one of the most lethal diseases and has caused a global health problem. We aimed to elucidate the major mechanisms involved in the gastric cancer progression.
METHODOLOGY: The expression profile GSE13911 was downloaded from GEO database, composing of 31 normal and 38 tumor samples. The transcription factor (TF)--target gene regulatory network and protein-protein interaction (PPI) network related to gastric cancer were obtained from TRED and TRANSFAC databases. After combining the two networks, we constructed an integrated network.
RESULTS: In total, 5255 DEGs in tumor samples were identified, which were mainly enriched in 12 pathways including cell cycle. The integrated network of TF--target gene--protein interaction included 7 genes related to cell cycle, in which E2F1 was predicted to mediate the expression of MCM4, MCM5 and CDC6 through regulating the expression of its target gene MCM3.
CONCLUSION: In gastric cancer progression, E2F1 may play vital roles in the involvement of cell cycle pathway through regulating its target gene MCM3, which might interact with MCM4, MCM5 and MCM7. Besides, STAT1 was another potentially critical transcription factor which could regulate multiple target genes.

Wang D, Tan J, Xu Y, et al.
Identification of MicroRNAs and target genes involvement in hepatocellular carcinoma with microarray data.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):378-82 [PubMed] Related Publications
The aim of the study is to identify the differentially expressed microRNAs (miRNAs) between hepatocellular carcinoma (HCC) samples and controls and provide new diagnostic potential miRNAs for HCC. The miRNAs expression profile data GSE20077 included 7 HCC samples, 1 HeLa sample and 3 controls. Differentially expressed miRNAs (DE-miRNAs) were identified by t-test and wilcox test. The miRNA with significantly differential expression was chosen for further analysis. Target genes for this miRNA were selected using TargetScan and miRbase database. STRING software was applied to construct the target genes interaction network and topology analysis was carried out to identify the hub gene in the network. And we identified the mechanism for affecting miRNA function. A total of 54 differentially expressed miRNAs were identified, in which there were 13 miRNAs published to be related to HCC. The differentially expressed hsa-miR-106b was chosen for further analysis and PTPRT (Receptor-type tyrosine-protein phosphatase T) was its potential target gene. The target genes interaction network was constructed among 33 genes, in which PTPRT was the hub gene. We got the conclusion that the differentially expressed hsa-miR-106b may play an important role in the development of HCC by regulating the expression of its potential target gene PT-PRT.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. LRP1, Cancer Genetics Web: http://www.cancer-genetics.org/LRP1.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 27 August, 2015     Cancer Genetics Web, Established 1999