Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: LCN2 (cancer-related)
Inokawa Y, Sonohara F, Kanda M, et al.Correlation Between Poor Prognosis and Lower TPPP Gene Expression in Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(9):4639-45 [PubMed
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BACKGROUND/AIM: Post-resection recurrence of hepatocellular carcinoma (HCC) tends to derive from multicentric origins, which indicates that the background liver microenvironment affects carcinogenesis.
MATERIALS AND METHODS: We obtained control liver samples [super normal (SN)] from 11 patients with secondary metastatic liver malignancies and used expression and methylation arrays to compare them with non-cancerous liver tissue from a patient with typical HCC with chronic hepatitis C (corresponding normal (CN)].
RESULTS: The expression array showed that gene expression of tubulin polymerization-promoting protein (TPPP) was lower in CN compared with SN. The methylation array showed a greater TPPP methylation index for CN than for SN. Transcripts of TPPP differed significantly among SN (n=11), CN (n=179), and tumor tissue of HCC (n=179) (median of 116, 4.60, and 2.63, respectively, p<0.001). Multivariate analysis showed lower TPPP expression in tumor than in normal tissue (ratio <0.3, n=57) to independently predict poor overall survival (p=0.031).
CONCLUSION: Significantly lower TPPP expression was found in HCC and CN tissue compared to SN and indicated poor prognosis.
Chiang KC, Hsu SY, Lin SJ, et al.PTEN Insufficiency Increases Breast Cancer Cell Metastasis In Vitro and In Vivo in a Xenograft Zebrafish Model.
Anticancer Res. 2016; 36(8):3997-4005 [PubMed
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BACKGROUND/AIM: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) insufficiency is commonly found in breast cancer patients with metastasis. We investigated the mechanisms by which PTEN affects breast cancer metastatic behavior.
MATERIALS AND METHODS: Migration and invasion assay, western blot, immunofluorescent staining and zebrafish animal model were applied.
RESULTS: We showed that PTEN insufficiency induced an increase in MCF-7 cell migration and invasion through induction of epithelial-mesenchymal transition (EMT), which was triggered by up-regulation of the EMT-inducing transcriptional factors Zeb1, Zeb2, Snail, Slug and Twist. Simultaneously, E-cadherin expression was inhibited and P-cadherin was up-regulated. Further, WNT1 inducible signaling pathway protein 1 (WISP1) and lipocalin-2 (LCN2) expressions were increased after PTEN knockdown in MCF-7 cells, which also exhibited increased filamentous actin (F-actin) synthesis and extracellular matrix metalloproteinase-2 (MMP-2) and MMP-9 expression. We further showed that PTEN knockdown in MCF-7 cells could increase cell migration in the xenograft zebrafish model.
CONCLUSION: Our findings reveal new therapeutic targets for breast cancer patients with PTEN insufficiency.
Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy.
Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃), the newly-synthesized 1α,25(OH)₂D₃ analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)₂D₃ and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)₂D₃ and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)₂D₃ induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)₂D₃ and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)₂D₃ and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC.
Three-dimensional multicellular spheroids (MCS) of human cells are important in cancer research. We investigated possible mechanisms of MCS formation of thyroid cells. Both, normal Nthy-ori 3-1 thyroid cells and the poorly differentiated follicular thyroid cancer cells FTC-133 formed MCS within 7 and 14 days of culturing on a Random Positioning Machine (RPM), while a part of the cells continued to grow adherently in each culture. The FTC-133 cancer cells formed larger and numerous MCS than the normal cells. In order to explain the different behaviour, we analyzed the gene expression of IL6, IL7, IL8, IL17, OPN, NGAL, VEGFA and enzymes associated cytoskeletal or membrane proteins (ACTB, TUBB, PFN1, CPNE1, TGM2, CD44, FLT1, FLK1, PKB, PKC, ERK1/2, Casp9, Col1A1) as well as the amount of secreted proteins (IL-6, IL-7, IL-8, IL-17, OPN, NGAL, VEGFA). Several of these components changed during RPM-exposure in each cell line. Striking differences between normal and malignant cells were observed in regards to the expression of genes of NGAL, VEGFA, OPN, IL6 and IL17 and to the secretion of VEGFA, IL-17, and IL-6. These results suggest several gravi-sensitive growth or angiogenesis factors being involved in 3D formation of thyroid cells cultured under simulated microgravity.
Mongre RK, Sodhi SS, Sharma N, et al.Epigenetic induction of epithelial to mesenchymal transition by LCN2 mediates metastasis and tumorigenesis, which is abrogated by NF-κB inhibitor BRM270 in a xenograft model of lung adenocarcinoma.
Int J Oncol. 2016; 48(1):84-98 [PubMed
] Free Access to Full Article Related Publications
Tumor initiating cancer stem-like cells (TICSCs) have recently become the object of intensive study. Human-Lipocalin-2 (hLCN2) acts as a biomarker for cancers. The aim of the present study was to explore new insights regarding the potential role of LCN2 in inducing epithelial to mesenchymal transition (EMT) by transfecting LCN2 into CD133+-A549-TICSCs and its cross-talk with the NF-κB signaling pathway in adenocarcinoma of the lung. Furthermore, EMT was confirmed by transcriptomic analysis, immunoblotting and immunocyto/histochemical analyses. Tumorigenesis and metastasis were confirmed by molecular therapeutics tracer 2DG infrared optical probe in BALB/cSIc-nude mice. It was observed that the CD133+-expressing-LCN2-A549 TICSCs population increased in adenocarcinoma of the lung compared to the normal lung tissue. The expressions of genes involved in stemness, adhesion, motility and drug efflux was higher in these cells than in their non-LCN2 expressing counterparts. The present study revealed that elevated expression of LCN2 significantly induced metastasis via EMT. Overexpression of LCN2 significantly increased stemness and tumor metastasis by modulating NF-κB cellular signaling. BRM270, a novel inhibitor of NF-κB plays a significant role in the EMT reversal. BRM270, a naturaceutical induces cell shrinkage, karyorrhexis and programmed cell death (PCD) which were observed by Hoechst 33342 staining while flow cytometry analysis showed significant (P<0.05) decrease in cell population from G0-G1 phases. Also, 2DG guided in vivo model revealed that BRRM270 significantly (P<0.0003) reduced tumor metastasis and increased percent survival in real-time with complete resection. An elaborate study on the novel concept with respect to linking of naturaceutics as selective and potential anticancer agent that eliminates the elevated LCN2 induced EMT and tumor dissemination through cooperation with the NF-κB signaling as the baseline data for the planning of new therapeutic strategies was conducted for the first time. Our results also illustrate a molecular mechanistic approach for 2DG-guided molecular imaging-based cancer therapy using BRM270 as a novel cancer therapeutic drug to enhance the effect of doxorubicin (Dox)-resistant LCN2 induced metastasis of solid tumors in nude mice.
Wang L, Chen C, Li F, et al.Down-regulation of neutrophil gelatinase-associated lipocalin in head and neck squamous cell carcinoma correlated with tumorigenesis, not with metastasis.
Int J Clin Exp Pathol. 2015; 8(8):8857-68 [PubMed
] Free Access to Full Article Related Publications
To examine the significance of the Neutrophil gelatinase-associated lipocalin (NGAL) in diagnosing head and neck squamous cell carcinoma (HNSCC) and predicting regional metastasis. We first used GEO dataset to analyze the NGAL gene expression in HNSCC. Then, we summarized the characteristics of patients retrospectively selected in clinic. Expression of NGAL protein in human HNSCC tumor, lymph node and normal samples were analyzed using immunohistochemistry. Next, we further investigated the NGAL expression in a tissue microassay to analyze the relationship between NGAL protein expression and TNM stage. Finally, we tested the NGAL protein expression in head and neck cancer cell lines. Analysis of GEO dataset concluded that NGAL gene expression in HNSCC was lower than that in normal tissue (P<0.01). There was no statistically significant difference of NGAL gene expression between T-stage and N-stage (P>0.05). NGAL protein expression in tumor was lower than that in normal tissue (P<0.01). There was no statistically significant difference of NGAL protein expression between metastasis group and non-metastasis group (P>0.05). Expression of NGAL protein was not correlated with TNM stage of HNSCC. Aggressive HNSCC cell lines have lower NGAL protein expression. Our data demonstrated that the expression of NGAL protein was correlated with tumorigenesis of HNSCC, but not with regional metastasis. It may serve as a novel biomarker for prognostic evaluation of patients with HNSCC.
Suzuki-Muromoto S, Hino-Fukuyo N, Haginoya K, et al.A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
Brain Dev. 2016; 38(2):257-60 [PubMed
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We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16 years old. She presented dysmorphic facial features, growth retardation and severe psychomotor retardation associated with 3p deletion syndrome. We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located. Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma. She showed no other tumors associated VHL disease till 24 years old. This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease. Repeat imaging studies were recommended for the patients with 3p deletion syndrome.
TRAIL (TNF-related apoptosis-inducing ligand) is a member of the tumor necrosis factor superfamily that can induce tumor selective death by up-regulating death receptor 4 (DR4) and DR5 expression. The study aimed to explore the role of RIP and c-FLIP genes in TRAIL induced liver cancer cell HepG2 and Hep3B apoptosis and related mechanism. RIP and c-FLIP silenced HepG2 and Hep3B cell model were established through siRNA. Western blot was applied to test c-FLIP, RIP, DR4, DR5, FADD, Caspase-3/8/9, ERK1/2, and DFF45 protein expression. Caspase-8 kit was used to detect Caspase-8 expression. Flow cytometry was performed to measure cell apoptosis rate. Acid phosphatase method was applied to determine cell cycle. TRAIL had no significant effect on Caspase-3/8/9, DR4, DR5, ERK1/2, and DFF45 protein expression, but up-regulated c-FLIP and RIP protein expression and reduced FADD expression level. After treated by the chemotherapy drug mitomycin and adriamycin, c-FLIP and RIP expression decreased significantly, while FADD increased. After knockout c-FLIP and RIP gene, HepG2 and Hep3B cell apoptosis rate induced by TRAIL increased obviously. Meanwhile, cell subG1 percentage increased markedly and exhibited G1 phase growth retardation. In addition, after two kinds of gene knockout, Caspase-8 was activated and produce Caspase-3 P20 and P24, leading DFF45 appeared DNA fragment P17 and P25. c-FLIP and RIP can inhibit Caspase-8 activation and prompting HepG2 and Hep3B resistant to cell apoptosis induced by TRAIL.
Koh SA, Lee KHHGF mediated upregulation of lipocalin 2 regulates MMP9 through nuclear factor-κB activation.
Oncol Rep. 2015; 34(4):2179-87 [PubMed
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Lipocalin 2 (LCN2) is a member of lipocalin family that binds and transports a small lipophilic ligand, sharing a highly conserved tertiary structure and can be found as a monomer, homodimer, heterodimer with matrix metalloproteinase 9 (MMP9). The high molecule LCN2/MMP9 complex was found in several cancer types. Yet, the mechanisms of regulation between LCN2 with MMP9 in tumorigenesis is unclear. The aims of the present study were to identify the function of LCN2 associated with MMP9 in gastric cancer growth and metastasis. First, we confirmed that the expression level of LCN2 and MMP9 was upregulated by hepatocyte growth factor (HGF). To identify the association pathway of HGF-induced LCN2, the cells were treated with PI3-kinase inhibitor (LY294002), or MEK inhibitor (PD098059), or p38 inhibitor (SB203580) and then analyzed using western blotting. The HGF-mediated LCN2 protein level was decreased with LY294002. Also, the HGF-mediated MMP9 was decreased with LY294002. The role for LCN2 with HGF mediated MMP9 was determined by knockdown of LCN2. LCN2-sh RNA cells showed a decreased level of HGF-mediated MMP9. The HGF-mediated LCN2 protein level was decreased with treatment of the NFκB inhibitor. We confirmed the role of HGF-mediated LCN2. HGF-mediated cell proliferation and in vitro invasion was decreased in LCN2 knockdown cell. In conclusion, the present study showed that LCN2 upregulated MMP9 through PI3K/AKT/NFκB pathway in gastric cancer. LCN2 has a role in cell proliferation and cell invasion in gastric cancer, which may be a possible target for developing gastric cancer therapy.
Meka Pb, Jarjapu S, Nanchari SR, et al.LCN2 Promoter Methylation Status as Novel Predictive Marker for Microvessel Density and Aggressive Tumor Phenotype in Breast Cancer Patients.
Asian Pac J Cancer Prev. 2015; 16(12):4965-9 [PubMed
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LCN2 (Lipocalin 2) is a 25 KD secreted acute phase protein, reported to be a novel regulator of angiogenesis in breast cancer. Up regulation of LCN2 had been observed in multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. However, the role of LCN2 promoter methylation in the formation of microvessels is poorly understood. The aim of this study was to analyze the association of LCN 2 promoter methylation with microvessel formation and tumor cell proliferation in breast cancer patients. The LCN2 promoter methylation status was studied in 64 breast cancer tumors by methylation specific PCR (MSP). Evaluation of microvessel density (MVD) and Ki67 cell proliferation index was achieved by immunohistochemical staining using CD34 and MIB-1 antibodies, respectively. LCN2 promoter unmethylation status was observed in 43 (67.2%) of breast cancer patients whereas LCN2 methylation status was seen in 21 (32.8%). Further, LCN2 promoter unmethylation status was associated with aggressive tumor phenotype and elevated mean MVD in breast cancer patients.
López-Ayllón BD, de Castro-Carpeño J, Rodriguez C, et al.Biomarkers of erlotinib response in non-small cell lung cancer tumors that do not harbor the more common epidermal growth factor receptor mutations.
Int J Clin Exp Pathol. 2015; 8(3):2888-98 [PubMed
] Free Access to Full Article Related Publications
Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers, which are the leading cause of cancer-related deaths in the world. Tyrosine kinase inhibitors such as erlotinib represent one therapeutic options presently recommended for tumors produced by activating mutations in the gene coding of epidermal growth factor receptor (EGFR). The aim of this study is the identification of possible biomarkers for tumor sensitivity to erlotinib in the absence of the main EGFR mutations. The erlotinib sensitivity of cells isolated from 41 untreated NSCLC patients was determined and compared with the presence of the more frequent EGFR mutations. Several patients had tumor cells highly sensitive to erlitinib in the absence of the EGFR mutations analyzed. The gene expression profile of 3 erlotinib-sensitive tumors was compared with that of 4 resistant tumors by DNA microarray hybridization. Sixteen genes were expressed at significantly higher levels in the resistant tumors than in the sensitive tumors. The possible correlation between erlotinib sensitivity and the expression of these genes was further analyzed using the data for the NSCLC, breast cancer and colon cancer cell lines of the NCI60 collection. The expression of these genes was correlated with the overall survival of 5 patients treated with erlotinib, according to The Cancer Genome Atlas (TCGA) database. Overlapping groups of 7, 5 and 3 genes, including UGT1A6, TRIB3, MET, MMP7, COL17A1, LCN2 and PTPRZ1, whose expression correlated with erlotinib activity was identified. In particular, low MET expression levels showed the strongest correlation.
Higuchi M, Sasaki S, Kawadoko S, et al.Epstein-Barr virus-positive diffuse large B-cell lymphoma following acute myeloid leukemia: a common clonal origin indicated by chromosomal translocation t(3;4)(p25;q21).
Int J Hematol. 2015; 102(4):482-7 [PubMed
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Secondary non-Hodgkin lymphoma following acute myeloid leukemia (AML) is extremely rare. We here describe a unique case involving a patient who developed Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) during complete remission (CR) of AML. A 75-year-old Japanese man was initially diagnosed with AML with maturation (FAB M2), bearing chromosomal translocation t(3,4)(p25;q21). After intensive chemotherapy, bone marrow aspiration revealed normal karyotype, and he achieved CR. Six years and 4 months later, he was still in CR from AML, but developed DLBCL presenting in the terminal ileum. Cytogenetic analysis of the DLBCL cells showed the same translocation as the previous AML. The rearrangements of the immunoglobulin heavy chain genes of the two malignancies were examined using polymerase chain reaction amplification, and the rearrangement patterns were found to differ from each other. Our data thus suggest that, in the present case, the AML and DLBCL arose from a common progenitor cell, as indicated by the clonal abnormality t(3,4)(p25;q21), and that different immunoglobulin heavy chain gene rearrangements occurred during each course of clonal evolution.
The thyroid hormone, 3,3',5-triiodo-L-thyronine (T3), regulates cell growth, development and differentiation via interactions with thyroid hormone receptors (TR), but the mechanisms underlying T3-mediated modulation of cancer progression are currently unclear. Lipocalin 2 (LCN2), a tumor-associated protein, is overexpressed in a variety of cancer types. Oligonucleotide microarray, coupled with proteomic analysis, has revealed that LCN2 is positively regulated by T3/TR. However, the physiological role and pathway of T3-mediated regulation of LCN2 in hepatocellular carcinogenesis remain to be characterized. Upregulation of LCN2 after T3 stimulation was observed in a time- and dose-dependent manner. Additionally, TRE on the LCN2 promoter was identified at positions -1444/-1427. Overexpression of LCN2 enhanced tumor cell migration and invasion, and conversely, its knockdown suppressed migration and invasion, both in vitro and in vivo. LCN2-induced migration occurred through activation of the Met/FAK cascade. LCN2 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively correlated with TRα levels. Both TRα and LCN2 showed similar expression patterns in relation to survival rate, tumor grade, tumor stage and vascular invasion. Our findings collectively support a potential role of T3/TR in cancer progression through regulation of LCN2 via the Met/FAK cascade. LCN2 may thus be effectively utilized as a novel marker and therapeutic target in HCC.
Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer of thyroid C-cells, for which few treatment options are available. We have recently reported a role for cyclin-dependent kinase 5 (CDK5) in MTC pathogenesis. We have generated a mouse model, in which MTC proliferation is induced upon conditional overexpression of the CDK5 activator, p25, in C-cells, and arrested by interrupting p25 overexpression. Here, we identify genes and proteins that are differentially expressed in proliferating versus arrested benign mouse MTC. We find that downstream target genes of the tumor suppressor, retinoblastoma protein, including genes encoding cell cycle regulators such as CDKs, cyclins and CDK inhibitors, are significantly upregulated in malignant mouse tumors in a CDK5-dependent manner. Reducing CDK5 activity in human MTC cells down-regulated these cell cycle regulators suggesting that CDK5 activity is critical for cell cycle progression and MTC proliferation. Finally, the same set of cell cycle proteins was consistently overexpressed in human sporadic MTC but not in hereditary MTC. Together these findings suggest that aberrant CDK5 activity precedes cell cycle initiation and thus may function as a tumor-promoting factor facilitating cell cycle protein expression in MTC. Targeting aberrant CDK5 or its downstream effectors may be a strategy to halt MTC tumorigenesis.
Harati MD, Amiri F, Jaleh F, et al.Targeting delivery of lipocalin 2-engineered mesenchymal stem cells to colon cancer in order to inhibit liver metastasis in nude mice.
Tumour Biol. 2015; 36(8):6011-8 [PubMed
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One of the major obstacles in cancer therapy is the lack of anticancer agent specificity to tumor tissues. The strategy of cell-based therapy is a promising therapeutic option for cancer treatment. The specific tumor-oriented migration of mesenchymal stem cells (MSCs) makes them a useful vehicle to deliver anticancer agents. In this study, we genetically manipulated bone marrow-derived mesenchymal stem cells with their lipocalin 2 (Lcn2) in order to inhibit liver metastasis of colon cancer in nude mice. Lcn2 was successfully overexpressed in transfected MSCs. The PCR results of SRY gene confirmed the presence of MSCs in cancer liver tissue. This study showed that Lcn2-engineered MSCs (MSC-Lcn2) not only inhibited liver metastasis of colon cancer but also downregulated the expression of vascular endothelial growth factor (VEGF) in the liver. Overall, MSCs by innate tropism toward cancer cells can deliver the therapeutic agent, Lcn2, and inhibit cancer metastasis. Hence, it could be a new modality for efficient targeted delivery of anticancer agent to liver metastasis.
Intrinsic and acquired resistance to the monoclonal antibody drug trastuzumab is a major problem in the treatment of HER2-positive breast cancer. A deeper understanding of the underlying mechanisms could help to develop new agents. Our intention was to detect genes and single nucleotide polymorphisms (SNPs) affecting trastuzumab efficiency in cell culture. Three HER2-positive breast cancer cell lines with different resistance phenotypes were analyzed. We chose BT474 as model of trastuzumab sensitivity, HCC1954 as model of intrinsic resistance, and BTR50, derived from BT474, as model of acquired resistance. Based on RNA-Seq data, we performed differential expression analyses on these cell lines with and without trastuzumab treatment. Differentially expressed genes between the resistant cell lines and BT474 are expected to contribute to resistance. Differentially expressed genes between untreated and trastuzumab treated BT474 are expected to contribute to drug efficacy. To exclude false positives from the candidate gene set, we removed genes that were also differentially expressed between untreated and trastuzumab treated BTR50. We further searched for SNPs in the untreated cell lines which could contribute to trastuzumab resistance. The analysis resulted in 54 differentially expressed candidate genes that might be connected to trastuzumab efficiency. 90% of 40 selected candidates were validated by RT-qPCR. ALPP, CALCOCO1, CAV1, CYP1A2 and IGFBP3 were significantly higher expressed in the trastuzumab treated than in the untreated BT474 cell line. GDF15, IL8, LCN2, PTGS2 and 20 other genes were significantly higher expressed in HCC1954 than in BT474, while NCAM2, COLEC12, AFF3, TFF3, NRCAM, GREB1 and TFF1 were significantly lower expressed. Additionally, we inferred SNPs in HCC1954 for CAV1, PTGS2, IL8 and IGFBP3. The latter also had a variation in BTR50. 20% of the validated subset have already been mentioned in literature. For half of them we called and analyzed SNPs. These results contribute to a better understanding of trastuzumab action and resistance mechanisms.
Mochizuki K, Kondo T, Oishi N, et al.Low frequency of PAX8-PPARγ rearrangement in follicular thyroid carcinomas in Japanese patients.
Pathol Int. 2015; 65(5):250-3 [PubMed
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Paired-box gene 8 (PAX8)-peroxisome proliferator-activated receptor-γ (PPARγ) gene fusion has been identified at significant frequency in follicular thyroid carcinomas (FTCs) with cytogenetically detectable translocation t(2;3)(q13;p25). This represents a possible specific molecular marker for follicular carcinoma. In this study, we examined PAX8-PPARγ rearrangement in 24 FTC samples from Japanese patients by reverse transcribed-polymerase chain reaction (RT-PCR) using two upstream PAX8 primers located in exons 7 and 8 and a downstream primer in exon 1 of PPARγ. The fusion gene was detected in only one of 24 FTCs (4%). The FTC with PAX8-PPARγ rearrangement from a 56-year-old man showed a product consistent with fusion between exon 8 of PAX8 and exon 1 of PPARγ. It was confirmed by direct sequencing. This FTC was histologically encapsulated, composed of trabeculae and small follicles and had complete penetration of the capsule by tumor tissues (minimally invasive type). The frequency of the fusion gene in this study was much lower than the 29-63% noted in reports from other countries suggesting that FTCs in Japanese patients may have a special genetic background, and that the high iodine intake from a typical Japanese diet might influence the frequency of the fusion gene in FTCs.
Ruiz-Morales JM, Dorantes-Heredia R, Arrieta O, et al.Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in lung adenocarcinoma.
Tumour Biol. 2015; 36(5):3601-10 [PubMed
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Prognosis in patients with lung cancer is poor. Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) are proteins involved in the invasion and metastases of cancer. The objective of this study is to determine if there is a relationship between tumor expression of NGAL and MMP-9 in lung adenocarcinoma patients with prognosis and overall survival. Retrospective analysis was made of patients with lung adenocarcinoma treated at Medica Sur Hospital between 2005 and 2013. Tumor tissue was analyzed for NGAL and MMP-9 expression by immunohistochemistry. We identified 41 patients. Mean overexpression in tumoral tissue of NGAL was 70 % and 30 % for MMP-9. Univariate analysis revealed that prognostic factors associated with overall survival (OS) were NGAL expression and stage at diagnosis. Median OS for NGAL expression < 70 % was 45.7 months (95 % CI; 15.2-76.2) and for patients with ≥ 70 % 4.6 months (95 % CI; 0.5-18.8; P < 0.0001), and for stage at diagnosis (stages I and II mean not reached), stage III mean OS 15.57 months (95 % CI; 9.8-21.2) and stage IV 9.6 months (95 % CI; 0.8-18.4. P = 0.002). No differences in OS were found for expression of MMP-9. Multivariate analysis revealed significance for OS in NGAL expression (HR 5.01 [95 % CI; 1.68-14.93] P = 0.004) and stage at diagnosis (HR 2.05 [95 % CI 1.30-3.22] P = 0.002). Tumoral tissue expression of NGAL ≥ 70 % confers a worse prognosis compared to those who did not. NGAL is an independent prognostic factor of stage at diagnosis.
Srdelić Mihalj S, Kuzmić-Prusac I, Zekić-Tomaš S, et al.Lipocalin-2 and matrix metalloproteinase-9 expression in high-grade endometrial cancer and their prognostic value.
Histopathology. 2015; 67(2):206-15 [PubMed
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AIMS: To demonstrate lipocalin-2 (LCN-2) immunohistochemical expression together with matrix metalloproteinase-9 (MMP-9) protein in high-grade endometrial cancer and determine their correlations with FIGO (International Federation of Gynecology and Obstetrics) stage, histological subtype, presence of vascular invasion, patient age and overall and disease-free survival.
METHODS AND RESULTS: Immunohistochemical staining was performed using LCN-2 and MMP-9 antibodies on high-grade endometrial cancer (n = 85) diagnosed at Split University Hospital Centre during 1998-2010. Immunohistochemical expression was determined on archived paraffin-embedded samples and scored semiquantitatively. Survival time was analysed using the Kaplan-Meier method, and the log-rank test was used to assess between-group differences. The Cox proportional hazard regression model was used on multivariate survival analysis. Patients were followed from the time of primary surgery until death or last follow-up until December 2012. LCN-2 and MMP-9 were highly expressed in high-grade endometrial cancer. Univariate analysis showed positive immunohistochemical staining for LCN-2 and MMP-9 to be associated with shorter survival in patients with high-grade endometrial cancer. Multivariate analysis showed LCN-2 overexpression to be associated with shorter overall and disease-free survival in high-grade endometrial cancer.
CONCLUSIONS: Our findings suggest that LCN-2 expression may be an important independent indicator of shorter survival in patients with high-grade endometrial cancer.
Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.
Hypoxic tumors have been identified as appropriate indicators of tumor malignancy. However, no convenient plasma marker for hypoxic tumors has been described. Therefore, to identify a novel, convenient plasma marker for hypoxic tumors, we used microarray analysis to compare gene expression profiles of normoxic and hypoxic tumor tissues of mice bearing melanomas. Among the upregulated genes detected in hypoxic tumors, we chose to study the secretory protein lipocalin2 (LCN2) as a marker for hypoxic tumors. LCN2 protein levels in the plasma of mice bearing hypoxic tumors were significantly increased compared with those in mice bearing normoxic tumors. Interestingly, LCN2 mRNA levels were 17-fold higher in HIF-1α-positive hypoxic tumors than in HIF-1α-negative normoxic tumors. Furthermore, LCN2 mRNA levels were significantly higher in the B16-F1 cells and various human tumor cells cultured under hypoxic conditions than in cells cultured under normoxic conditions, while no changes in mRNA expression were observed in nontumor NIH-3T3 cells, even under hypoxic conditions. In cultured cells, the expression pattern of LCN2 was mostly consistent with that of HIF-1α, whereas that of a conventional hypoxic marker, carbonic anhydrase IX, was not. Collectively, our data suggested that LCN2 was a useful plasma marker for hypoxic tumors.
OBJECTIVE: Obesity is an established risk factor for colorectal cancer (CRC) incidence and it is also linked to CRC recurrence and survival. Polymorphisms located in obesity-related genes are associated with an increased risk of developing several cancer types including CRC. We evaluated whether single-nucleotide polymorphisms in obesity-related genes may predict tumor recurrence in colon cancer patients.
MATERIALS AND METHODS: Genotypes were obtained from germline DNA from 207 patients with stage II or III colon cancer at the Norris Comprehensive Cancer Center. Nine polymorphisms in eight obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA, and DSCR1) were evaluated. The primary endpoint of the study was the 3-year recurrence rate. Positive associations were also tested in an independent Japanese cohort of 350 stage III CRC patients.
RESULTS: In univariate analysis, for PPARrs1801282, patients with a CC genotype had significantly lower recurrence probability (29 ± 4% SE) compared with patients with a CG genotype (48 ± 8% SE) [hazard ratio (HR): 1.77; 95% confidence interval (CI), 1.01-3.10; P = 0.040]. For DSCR1rs6517239, patients with an AA genotype had higher recurrence probability than patients carrying at least one allele G (37 ± 4% SE vs. 15 ± 6% SE) (HR: 0.51; 95% CI, 0.27-0.94; P = 0.027). This association was stronger in the patients bearing a left-sided tumor (HR: 0.34; 95% CI, 0.13-0.88; P = 0.018). In the Japanese cohort, no associations were found.
CONCLUSION: This hypothesis-generating study suggests a potential influence of polymorphisms within obesity-related genes in the recurrence probability of colon cancer. These interesting results should be evaluated further.
Du ZP, Wu BL, Wang SH, et al.Shortest path analyses in the protein-protein interaction network of NGAL (neutrophil gelatinase-associated lipocalin) overexpression in esophageal squamous cell carcinoma.
Asian Pac J Cancer Prev. 2014; 15(16):6899-904 [PubMed
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NGAL (neutrophil gelatinase-associated lipocalin) is a novel cancer-related protein involves multiple functions in many cancers and other diseases. We previously overexpressed NGAL to analyze its role in esophageal squamous cell carcinoma (ESCC). In this study, a protein-protein interaction (PPI) was constructed and the shortest paths from NGAL to transcription factors in the network were analyzed. We found 28 shortest paths from NGAL to RELA, most of them obeying the principle of extracellular to cytoplasm, then nucleus. These shortest paths were also prioritized according to their normalized intensity from the microarray by the order of interaction cascades. A systems approach was developed in this study by linking differentially expressed genes with publicly available PPI data, Gene Ontology and subcellular localizaton for the integrated analyses. These shortest paths from NGAL to DEG transcription factors or other transcription factors in the PPI network provide important clues for future experimental identification of new pathways.
Wu BL, Li CQ, Du ZP, et al.Functional analysis of the mRNA profile of neutrophil gelatinase‑associated lipocalin overexpression in esophageal squamous cell carcinoma using multiple bioinformatic tools.
Mol Med Rep. 2014; 10(4):1800-12 [PubMed
] Free Access to Full Article Related Publications
Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin superfamily; dysregulated expression of NGAL has been observed in several benign and malignant diseases. In the present study, differentially expressed genes, in comparison with those of control cells, in the mRNA expression profile of EC109 esophageal squamous cell carcinoma (ESCC) cells following NGAL overexpression were analyzed by multiple bioinformatic tools for a comprehensive understanding. A total of 29 gene ontology (GO) terms associated with immune function, chromatin structure and gene transcription were identified among the differentially expressed genes (DEGs) in NGAL overexpressing cells. In addition to the detected GO categories, the results from the functional annotation chart revealed that the differentially expressed genes were also associated with 101 functional annotation category terms. A total of 59 subpathways associated locally with the differentially expressed genes were identified by subpathway analysis, a markedly greater total that detected by traditional pathway enrichment analysis only. Promoter analysis indicated that the potential transcription factors Snail, deltaEF1, Mycn, Arnt, MNB1A, PBF, E74A, Ubx, SPI1 and GATA2 were unique to the downregulated DEG promoters, while bZIP910, ZNF42 and SOX9 were unique for the upregulated DEG promoters. In conclusion, the understanding of the role of NGAL overexpression in ESCC has been improved through the present bioinformatic analysis.
LCN2 (lipocalin 2) is a member of the lipocalin family of proteins that transport small, hydrophobic ligands. LCN2 is elevated in various cancers including esophageal squamous cell carcinoma (ESCC). In this study, LCN2 was overexpressed in the EC109 ESCC cell line and we applied integrated analyses of the gene expression data to identify protein-protein interactions (PPI) network to enhance our understanding of the role of LCN2 in ESCC. Through further mining of PPI sub-networks, hundreds of differentially expressed genes (DEGs) were identified to interact with thousands of other proteins. Subcellular localization analyses found the DEGs and their directly or indirectly interacting proteins distributed in multiple layers, which was applied to analyze the possible paths between two DEGs. Gene Ontology annotation generated a functional annotation map and found hundreds of significant terms, especially those associated with the known and potential roles of LCN2 protein. The algorithm of Random Walk with Restart was applied to prioritize the DEGs and identified several cancer-related DEGs ranked closest to LCN2 protein. These analyses based on PPI network have greatly expanded our understanding of the mRNA expression profile of LCN2 overexpression for future examination of the roles and mechanisms of LCN2.
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D, a pro-hormone, is getting popular due to its hormone-like functions after converted to its active form, 1α,25(OH)2D3. Here, we show that dietary supplementation with 6 IU/g of vitamin D greatly suppressed ICC initiation and progression without apparent toxicity in a chemically induced rat model. Microarray analysis of rat ICC tissues showed vitamin D supplementation modulated the expressions of several unique genes, including lipocalin 2 (Lcn2), confirmed by RT-qPCR and immunohistochemical (IHC) staining. Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC. As human ICC SNU1079 cells were treated by 1α,25(OH)2D3, LCN2 expression and cell proliferation were attenuated. The downregulation of LCN2 expression was blunted when vitamin D receptor (VDR) was knocked down, implicating that the in vivo Lcn2 downregulation is a direct consequence of vitamin D supplementation Our results support the prevailing concept that vitamin D status is negatively associated with cancer incidence and mortality and suggest LCN2 may be a potential target against ICC. Further studies of application of vitamin D or its analog against ICC are warranted.
Li CF, Huang HY, Wu WR, et al.Clinical aggressiveness of myxofibrosarcomas associates with down-regulation of p12CDK2AP1: prognostic implication of a putative tumor suppressor that induces cell cycle arrest and apoptosis via mitochondrial pathway.
Ann Surg Oncol. 2014; 21 Suppl 4:S711-20 [PubMed
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BACKGROUND: Attenuated endogenous protein levels of cyclin-dependent kinase 2 associated protein 1 (p12(CDK2AP1)) and its active homodimer p25(CDK2AP1) were found in myxofibrosarcoma-derived cell lines. Clinical and biological significances of this putative tumor suppressor in myxofibrosarcoma were studied.
METHODS: Plasmids carrying the CDK2AP1 gene and small hairpin RNA interference (shRNAi) targeting CDK2AP1 were transfected into NMFH-1 and/or OH931 cells to evaluate the effects on the CDK2, active caspase 3 (CASP3), cleaved-CASP8 and -CASP9 levels, cell cycle regulation, and/or apoptotic responses. Immunostaining of p12(CDK2AP1) was interpretable in 102 primary myxofibrosarcomas and correlated with clinicopathological variables, CDK2, Ki-67 and active CASP3 protein levels, and disease-specific survival.
RESULTS: Exogenous expression of p12(CDK2AP1) in NMFH-1 and OH931 cells significantly induced G0/G1 cell cycle arrest and down-regulated CDK2 protein level. In NMFH-1 cells, these aspects were reversed by shRNAi targeting CDK2AP1 gene. Increased active CASP3 and cleaved-CASP9, but not -CASP8, were detected after CDK2AP1 overexpression, suggesting the cellular apoptosis were induced through the mitochondrial pathway. Immunostains of p12(CDK2AP1) were aberrantly decreased in 56.9 % of cases; positively and negatively correlated with protein levels of CDK2 (p = 0.023), Ki-67 (p = 0.001) and active CASP3 (p < 0.001), respectively. Following by high histological grades, p12(CDK2AP1) down-regulation was predictive of worse disease-specific survival in univariate (p = 0.003) and multivariate (p = 0.004) analyses.
CONCLUSIONS: Through down-regulation of CDK2, high p12(CDK2AP1) level induced cell cycle arrest and the mitochondrial-dependent apoptotic pathway. Low p12(CDK2AP1) level represents a poor prognostic factor in patients with myxofibrosarcoma.
Wang L, Huang J, Jiang M, et al.CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) by biocomputation.
Cell Biochem Biophys. 2014; 70(2):1011-6 [PubMed
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We data-analyzed and constructed the high-expression CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) compared with low-expression (fold change ≥ 2) no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) in GEO data set, using integration of gene regulatory network inference method with gene ontology (GO). Our result showed that CAMK1 transport subnetwork upstream KCNQ3, LCN2, NKX2_5, NUP62, SORT1, STX1A activated CAMK1, and downstream CAMK1-activated AFP, ENAH, KPNA2, SLC4A3; CAMK1 signal subnetwork upstream BRCA1, DKK1, GPSM2, LEF1, NR5A1, NUP62, SORT1, SSTR5, TBL3 activated CAMK1, and downstream CAMK1-activated MAP2K6, SFRP4, SSTR5, TSHB, UBE2C in HCC. We proposed that CAMK1 activated network enhanced endosome to lysosome transport, endosome transport via multivesicular body sorting pathway, Golgi to endosome transport, intracellular protein transmembrane transport, intracellular protein transport, ion transport, mRNA transport, plasma membrane to endosome transport, potassium ion transport, protein transport, vesicle-mediated transport, anion transport, intracellular transport, androgen receptor signaling pathway, cell surface receptor-linked signal transduction, hormone-mediated signaling, induction of apoptosis by extracellular signals, signal transduction by p53 class mediator resulting in transcription of p21 class mediator, signal transduction resulting in induction of apoptosis, phosphoinositide-mediated signaling, Wnt receptor signaling pathway, as a result of inducing phosphoinositide signal-mediated protein sorting, and transport in HCC. Our hypothesis was verified by CAMK1 functional regulation subnetwork containing positive regulation of calcium ion transport via voltage gated calcium channel, cell proliferation, DNA repair, exocytosis, I-kappaB kinase/NF-kappaB cascade, immunoglobulin-mediated immune response, mast cell activation, natural killer cell-mediated cytotoxicity directed against tumor cell target, protein ubiquitination, sodium ion transport, survival gene product activity, T cell-mediated cytotoxicity, transcription, transcription from RNA polymerase II promoter, transcription initiation from RNA polymerase II promoter, transcription via serum response element binding, exit from mitosis, ubiquitin ligase activity during mitotic cell cycle, regulation of angiogenesis, apoptosis, cell growth, cell proliferation, cyclin-dependent protein kinase activity, gene expression, insulin secretion, steroid biosynthesis, transcription from RNA polymerase II promoter, transcription from RNA polymerase III promoter, cell cycle, cell migration, DNA recombination, and protein metabolism; also by CAMK1 negative functional regulation subnetwork including negative regulation of apoptosis, cell proliferation, centriole replication, fatty acid biosynthesis, lipoprotein lipase activity, MAPK activity, progression through cell cycle, transcription, transcription from RNA polymerase II promoter, cell growth, phosphorylation, and ubiquitin ligase activity during mitotic cell cycle in HCC.
Zuccotti P, Colombrita C, Moncini S, et al.hnRNPA2/B1 and nELAV proteins bind to a specific U-rich element in CDK5R1 3'-UTR and oppositely regulate its expression.
Biochim Biophys Acta. 2014; 1839(6):506-16 [PubMed
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Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, a specific activator of cyclin-dependent kinase 5 (CDK5). CDK5 and p35 have a fundamental role in neuronal migration and differentiation during CNS development. Both the CDK5R1 3'-UTR's remarkable size and its conservation during evolution strongly indicate an important role in post-transcriptional regulation. We previously validated different regulatory elements in the 3'-UTR of CDK5R1, which affect transcript stability, p35 levels and cellular migration through the binding with nELAV proteins and miR-103/7 miRNAs. Interestingly, a 138 bp-long region, named C2.1, was identified as the most mRNA destabilizing portion within CDK5R1 3'-UTR. This feature was maintained by a shorter region of 73 bp, characterized by two poly-U stretches. UV-CL experiments showed that this region interacts with protein factors. UV-CLIP assays and pull-down experiments followed by mass spectrometry analysis demonstrated that nELAV and hnRNPA2/B1 proteins bind to the same U-rich element. These RNA-binding proteins (RBPs) were shown to oppositely control CDK5R1 mRNA stability and p35 protein content at post-trascriptional level. While nELAV proteins have a positive regulatory effect, hnRNPA2/B1 has a negative action that is responsible for the mRNA destabilizing activity both of the C2.1 region and of the full-length 3'-UTR. In co-expression experiments of hnRNPA2/B1 and nELAV RBPs we observed an overall decrease of p35 content. We also demonstrated that hnRNPA2/B1 can downregulate nELAV protein content but not vice versa. This study, by providing new insights on the combined action of different regulatory factors, contributes to clarify the complex post-transcriptional control of CDK5R1 gene expression.