Research IndicatorsGraph generated 01 September 2019 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
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: POU2F1 (cancer-related)
Yu B, Zhang M, Chen J, et al.Abnormality of hepatic triglyceride metabolism in Apc
Life Sci. 2019; 227:201-211 [PubMed
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AIMS: Colorectal cancer syndrome has been one of the greatest concerns in the world. Although several epidemiological studies have shown that hepatic low lipoprotein lipase (LPL) mRNA expression may be associated with dyslipidemia and tumor progression, it is still not known whether the liver plays an essential role in hyperlipidemia of Apc
MAIN METHODS: We measured the expression of metabolic enzymes that involved fatty acid uptake, de novo lipogenesis (DNL), β-oxidation and investigated hepatic triglyceride production in the liver of wild-type and Apc
KEY FINDINGS: We found that hepatic fatty acid uptake and DNL decreased, but there was no significant difference in fatty acid β-oxidation. Interestingly, the production of hepatic very low-density lipoprotein-triglyceride (VLDL-TG) decreased at 20 weeks of age, but marked steatosis was observed in the livers of the Apc
SIGNIFICANCE: Altogether, these findings highlighted a novel role of GPIHBP1 that might be responsible for hypertriglyceridemia in Apc
Kim TW, Han SR, Kim JT, et al.Differential expression of tescalcin by modification of promoter methylation controls cell survival in gastric cancer cells.
Oncol Rep. 2019; 41(6):3464-3474 [PubMed
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The EF‑hand calcium binding protein tescalcin (TESC) is highly expressed in various human and mouse cancer tissues and is therefore considered a potential oncogene. However, the underlying mechanism that governs TESC expression remains unclear. Emerging evidence suggests that TESC expression is under epigenetic regulation. In the present study, the relationship between the epigenetic modification and gene expression of TESC in gastric cancer was investigated. To evaluate the relationship between the methylation and expression of TESC in gastric cancer, the methylation status of CpG sites in the TESC promoter was analyzed using microarray with the Illumina Human Methylation27 BeadChip (HumanMethylation27_270596_v.1.2), gene profiles from the NCBI Dataset that revealed demethylated status were acquired, and real‑time methylation‑specific PCR (MSP) in gastric cancer cells was conducted. In the present study, it was demonstrated that the hypermethylation of TESC led to the downregulation of TESC mRNA/protein expression. In addition, 5‑aza‑2c‑deoxycytidine (5'‑aza‑dC) restored TESC expression in the tested gastric cancer cells except for SNU‑620 cells. ChIP assay further revealed that the methylation of the TESC promoter was associated with methyl‑CpG binding domain protein (MBD)1, histone deacetylase (HDAC)2, and Oct‑1 and that treatment with 5'‑aza‑dC facilitated the dissociation of MBD1, HDAC2, and Oct‑1 from the promoter of TESC. Moreover, silencing of TESC increased MBD1 expression and decreased the H3K4me2/3 level, thereby causing transcriptional repression and suppression of cell survival in NCI‑N87 cells; conversely, overexpression of TESC downregulated MBD1 expression and upregulated the H3K4me2 level associated with active transcription in SNU‑638 cells. These results indicated that the differential expression of TESC via the modification status of the promoter and histone methylation controled cell survival in gastric cancer cells. Overall, the present study provided a novel therapeutic strategy for gastric cancer.
Insulin-sensitizer treatment with metformin is widely used in polycystic ovary syndrome (PCOS). However, the treatment effectiveness shows individual differences in PCOS patients. Organic cation transporter (OCT) 1 and 2 have been reported to mediate metformin transport in the liver and kidney, respectively. In this study, we investigated the association between the polymorphisms of
Xie Q, Lin S, Zheng M, et al.Long noncoding RNA NEAT1 promotes the growth of cervical cancer cells via sponging miR-9-5p.
Biochem Cell Biol. 2019; 97(2):100-108 [PubMed
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Evidence has accumulated demonstrating that long noncoding RNAs (lncRNAs) participate in the initiation and progression of cancers. In this study, we found that the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) is significantly increased in both cervical cancer tissues and cell lines. Overexpression of NEAT1 promoted the proliferation and migration of cervical cancer cells. Molecular studies uncovered that NEAT1 functions as competitive endogenous RNA (ceRNA), binding the micro-RNA miR-9-5p and suppressing its expression. However, we consistently found that when NEAT1 was highly expressed, it attenuated the inhibitory effect of miR-9-5p on the expression of PTEN and POU2F1, which are the targets of miR-9-5p. Consistent with the negative regulation of NEAT1 on miR-9-5p, restoration of miR-9-5p inhibited the growth-promoting effects of NEAT1 on cervical cancer cells. Taken together, these results indicated that NEAT1 plays an important role in the regulation cervical cancer cell growth by targeting miR-9-5p. Our findings characterized the possible mechanism of NEAT1 in cervical cancer.
Ergun S, Güney S, Temiz E, et al.Significance of miR-15a-5p and CNKSR3 as Novel Prognostic Biomarkers in Non-Small Cell Lung Cancer.
Anticancer Agents Med Chem. 2018; 18(12):1695-1701 [PubMed
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BACKGROUND: In recent years, targeted cancer treatment methods at various molecular levels have been developed for Non-Small Cell Lung Cancer (NSCLC), one of two major subtypes of lung cancer. miRNAbased clinical trials are currently the preferred targeted therapeutic strategy. Also, ceRNAs (competing endogenous RNA) would be the newest and the most effective approach to uncover novel interactions between mRNAs and miRNAs in NSCLC carcinogenesis. There are many factors influencing the efficiency of a miRNA to suppress or silence translation of the target mRNA. The most effective event is the presence of other RNAs showing ceRNA activity. These RNAs contain binding sites for specific miRNAs and enable miRNAs to bind these pseudo targets, instead of the original binding sites on the target mRNA. Therefore, the mRNA of the target gene is less affected by this miRNA, while the amount of miRNA remains the same in the media.
METHOD: For this project, we determined that five clinically important different oncogenes (PDL1, FGFR1, DDX3X, SLC1A5, FXR1 ) are involved in the pathogenesis of NSCLC. For this purpose, we transfected model NSCLC cell line, A549, with miRNAs (miR-150-5p, miR-15a-5p, miR-503-5p) targeting these oncogenes to investigate whether these oncogenes will be suppressed at the mRNA level and also how the suppression efficiency of these miRNA on the oncogenes will be affected by possible ceRNA (CNKSR3, POU2F1, HIPK2) activities.
RESULTS: miR-15a-5p was determined to have the most suppressive effect on the five genes and three potential ceRNAs (p<0.05). Furthermore, CNKSR3 was the ceRNA most affected by all three miRNAs (p<0.05).
CONCLUSION: CNKSR3 was affected more than the oncogenes known to act on NSCLC and this might make it a stronger and novel marker for use in possible treatment regimens designed using miR-15a-5p silencing effect on oncogenes in NSCLC pathogenesis. According to the literature, this is the first study associating NSCLC with miR-15a-5p and CNKSR3.
Hekmatshoar Y, Ozkan T, Altinok Gunes B, et al.Characterization of imatinib-resistant K562 cell line displaying resistance mechanisms.
Cell Mol Biol (Noisy-le-grand). 2018; 64(6):23-30 [PubMed
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Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the t(9; 22) and the related oncogene, BCR-ABL. Tyrosine kinase activity of fusion protein BCR-ABL is the main cause of CML. Even if imatinib is used as a tyrosine kinase inhibitor (TKI) for CML therapy, drug resistance may occur in patients and the clinical failure of imatinib treatment in resistant patients had resulted with the use of another alternative TKIs. BCR-ABL dependent and independent molecular mechanisms have crucial roles in drug resistance. To reveal the underlying molecular mechanisms which play significant roles in imatinib resistance in CML, we established K562 imatinib-resistant cell line (K562r5) which was continuously exposed to (5µM) imatinib to investigate molecular mechanisms which play significant roles in drug resistance. First of all, we analyzed T315I, M351T, F315L and F359C/L/V mutations with DNA sequencing as a BCR-ABL dependent mechanism in our cell lines. Moreover, we investigated BCR-ABL independent mechanisms such as apoptosis, autophagy, drug transport and DNA repair which affect drug resistance in these cell lines. In vitro cell viability was determined by MTT assay. DNA sequencing analysis was performed to detect BCR-ABL mutations. The apoptotic effect of imatinib on CML cell lines was tested by flow cytometric Annexin V-PE staining and caspase activation assays. Apoptotic, autophagic, drug transporter and DNA repair genes expression levels were determined by RT-PCR. The conventional cytogenetic analysis was performed on K562s and K562r cells. Our results indicate that inhibition of apoptosis, induction of autophagy, overexpression of efflux gene MDR1 and down-regulation of influx gene OCT1 play crucial roles in the progression of imatinib resistance.
Rinaldetti S, Pfirrmann M, Manz K, et al.Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial.
Clin Lymphoma Myeloma Leuk. 2018; 18(4):266-271 [PubMed
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INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated.
MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated.
RESULTS: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (‰) was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.5‰ (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (≤4.5‰; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%).
CONCLUSION: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation.
Buß I, Hamacher A, Sarin N, et al.Relevance of copper transporter 1 and organic cation transporters 1-3 for oxaliplatin uptake and drug resistance in colorectal cancer cells.
Metallomics. 2018; 10(3):414-425 [PubMed
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Oxaliplatin is a routinely used drug in the treatment of colorectal cancer. However, development of resistance is a major hurdle of the chemotherapy success. Defects in cellular accumulation represent a frequently reported feature of cells with acquired resistance to platinum drugs. Nevertheless, the mechanisms of oxaliplatin uptake and their role in oxaliplatin resistance remain poorly elucidated. The aim of this study was to investigate the relevance of copper transporter 1 (CTR1) and organic cation transporters 1-3 (OCT1-3) for oxaliplatin uptake and resistance to the drug in sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cells. Co-incubation with copper(ii) sulfate, a CTR1 substrate, significantly decreased oxaliplatin accumulation but not cytotoxicity in both cell lines. Pre- as well as co-incubation with the OCT1 inhibitor atropine led to a significant reduction in oxaliplatin accumulation in sensitive but not in resistant cells. However, oxaliplatin cytotoxicity was also decreased in the presence of atropine in both cell lines. Cimetidine, an inhibitor of OCT2, induced a significant reduction in the cellular accumulation and potency of oxaliplatin in sensitive and resistant cells. An inhibitor of OCT3, decynium-22, had no influence on oxaliplatin accumulation and cytotoxicity in either cell line. No differences in the transporter expressions were observed between the cell lines, drug-treated or not, either at the mRNA or protein levels. A fluorescent oxaliplatin derivative CFDA-oxPt co-localized with CTR1, OCT1 and OCT2 in sensitive cells, but only with CTR1 and OCT2 in the resistant cell line. Our results suggest that oxaliplatin is transported into the cell by CTR1 in both cell lines. However, contribution of CTR1-mediated uptake to resistance seems unlikely. Uptake of oxaliplatin via OCT1 appears to take place in the sensitive but not in the resistant cell line underscoring the transporter relevance for oxaliplatin resistance. OCT2 is likely to be involved in the uptake of oxaliplatin to a similar extent in both cell lines suggesting no major contribution of this transporter to resistance. In contrast, OCT3 appears to be irrelevant for oxaliplatin transport into the cell and resistance.
Pedersen AJT, Stage TB, Glintborg D, et al.The Pharmacogenetics of Metformin in Women with Polycystic Ovary Syndrome: A Randomized Trial.
Basic Clin Pharmacol Toxicol. 2018; 122(2):239-244 [PubMed
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily ± oral contraceptive pills (150 μg desogestrel + 30 μg ethinylestradiol). In the entire study population, treatment was associated with reduced weight (median weight change -2.4 kg, 25th-75th percentile -5.2 to 0.3 kg, p < 0.001) and increased triglycerides (0.2 mmol/L (0.0-0.6 mmol/L), p < 0.01) without significant changes in other lipid parameters or insulin sensitivity (insulin
Gaudelot K, Gibier JB, Pottier N, et al.Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.
Tumour Biol. 2017; 39(7):1010428317707372 [PubMed
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Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.
Zhong Y, Huang H, Chen M, et al.POU2F1 over-expression correlates with poor prognoses and promotes cell growth and epithelial-to-mesenchymal transition in hepatocellular carcinoma.
Oncotarget. 2017; 8(27):44082-44095 [PubMed
] Free Access to Full Article Related Publications
Despite recent efforts to understand activities of POU domain class 2 transcription factor 1 (POU2F1), little is known about the roles of POU2F1 in hepatocellular carcinoma (HCC) tumorigenesis and its correlation with any clinicopathological feature of HCC. In this study, we found that POU2F1 was significantly up-regulated in HCC specimens compared with adjacent non-cancerous liver specimens. The high POU2F1 protein expression level positively correlated with large tumor size, high histological grade, tumor metastasis and advanced clinical stage, and HCC patients with high POU2F1 levels exhibited poor prognoses. We further demonstrated that POU2F1 over-expression promoted HCC cell proliferation, colony formation, epithelial-to-mesenchymal transition (EMT), migration and invasion, while silencing of POU2F1 inhibited these malignant phenotypes. POU2F1 induced the expression of Twist1, Snai1, Snai2 and ZEB1 genes which are involved in the regulation of EMT. Furthermore, POU2F1 was up-regulated by AKT pathway in HCC, and POU2F1 over-expression reversed the inhibition of malignant phenotypes induced by AKT knock-down, indicating POU2F1 is a key down-stream effector of AKT pathway. Collectively, our results indicate that POU2F1 over-expression is positively associated with aggressive phenotypes and poor survival in patients with HCC, and POU2F1 regulated by AKT pathway promotes HCC aggressive phenotypes by regulating the transcription of EMT genes. POU2F1 may be employed as a new prognostic factor and therapeutic target for HCC.
Cervical cancer is an infectious cancer and the most common gynecologic cancer worldwide. E6/E7, the early genes of the high-risk mucosal human papillomavirus type, play key roles in the carcinogenic process of cervical cancer. However, little was known about its roles in modulating tumor microenvironment, particular extracellular matrix (ECM). In this study, we found that E6/E7 could regulate multiple ECM proteins, especially collagen triple helix repeat containing 1 (CTHRC1). CTHRC1 is highly expressed in cervical cancer tissue and serum and closely correlated with clinicopathological parameters. CTHRC1 promotes cervical cancer cell migration and invasion in vitro and metastasis in vivo. E6/E7 regulates the expression of CTHRC1 in cervical cancer by E6/E7-p53-POU2F1 (POU class 2 homeobox 1) axis. Futhermore, CTHRC1 activates Wnt/PCP signaling pathway. Take together, E6/E7-p53-POU2F1-CTHRC1 axis promotes cervical cancer cell invasion and metastasis and may act as a potential therapeutic target for interventions against cervical cancer invasion and metastasis.
Ben Hassine I, Gharbi H, Soltani I, et al.hOCT1 gene expression predict for optimal response to Imatinib in Tunisian patients with chronic myeloid leukemia.
Cancer Chemother Pharmacol. 2017; 79(4):737-745 [PubMed
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PURPOSE: Imatinib mesylate (IM) is considered as a highly effective therapy for chronic myeloid leukemia (CML) patients. However, a minority of patients fail to achieve optimal response due to impaired bioavailability of IM. The human organic cation transporter 1 (OCT1; SLC22A1) has been reported to be the main influx transporter involved in IM uptake into CML cells. Genetic variants and/or hOCT1 expression changes may influence IM response. In this study, we aimed to investigate the impact of both hOCT1 polymorphisms located in exon 7 and hOCT1 mRNA levels on the clinical outcome in CML patients.
METHODS: hOCT1 expression profile was determined using the quantitative real-time polymerase chain reaction in 69 CML patients treated with IM (35 responders to IM patients and 34 IM-resistant patients), while genotyping of 69 cases and 51 controls for hOCT1 polymorphisms was performed by direct sequencing after amplification of exon7.
RESULTS: Our results showed that the hOCT1 gene was significantly downregulated in the samples of the IM-resistant group when compared with the IM-responder group (p = 0.0211). Moreover, sequencing data show an association in all cases between the SNP 408V>M (g.1222G>A) and an intronic 8 bp (base pairs) insertion of GTAAGTTG (rs36056065) at the 3' end of exon 7. The genotype and allele distribution of the different SNPs did not differ significantly between the two groups of patients.
CONCLUSIONS: hOCT1 mRNA expression may serve as a clinical biomarker of response to imatinib and could be useful to predict IM therapy outcome of CML patients.
The androgen receptor (AR) is a member of the nuclear receptor superfamily of transcription factors and is central to prostate cancer (PCa) progression. Ligand-activated AR engages androgen response elements (AREs) at androgen-responsive genes to drive the expression of gene batteries involved in cell proliferation and cell fate. Understanding the transcriptional targets of the AR has become critical in apprehending the mechanisms driving treatment-resistant stages of PCa. Although AR transcription regulation has been extensively studied, the signaling networks downstream of AR are incompletely described. Semaphorin 3C (SEMA3C) is a secreted signaling protein with roles in nervous system and cardiac development but can also drive cellular growth and invasive characteristics in multiple cancers including PCa. Despite numerous findings that implicate SEMA3C in cancer progression, regulatory mechanisms governing its expression remain largely unknown. Here we identify and characterize an androgen response element within the SEMA3C locus. Using the AR-positive LNCaP PCa cell line, we show that SEMA3C expression is driven by AR through this element and that AR-mediated expression of SEMA3C is dependent on the transcription factor GATA2. SEMA3C has been shown to promote cellular growth in certain cell types so implicit to our findings is the discovery of direct regulation of a growth factor by AR. We also show that FOXA1 is a negative regulator of SEMA3C. These findings identify SEMA3C as a novel target of AR, GATA2, and FOXA1 and expand our understanding of semaphorin signaling and cancer biology.
Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants are bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression are positively correlated in prostate tumours. TET2 is expressed in normal prostate tissue and reduced in a subset of tumours from the Cancer Genome Atlas (TCGA). Small interfering RNA-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression network identified using TCGA prostate tumour RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. Decreased TET2 mRNA expression in TCGA PCa tumours is strongly associated with reduced patient survival, indicating reduced expression in tumours may be an informative biomarker of disease progression and perhaps metastatic disease.
Wu S, Wang S, Fu Y, et al.A novel mechanism of rs763110 polymorphism contributing to cervical cancer risk by affecting the binding affinity of C/EBPβ and OCT1 complex to chromatin.
Int J Cancer. 2017; 140(4):756-763 [PubMed
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Recently, several studies have showed that FAS (rs2234767, rs1800682) and FASL (rs763110) functional single nucleotide polymorphisms (SNPs) were associated with the risk of various cancers. However, the association between cervical cancer risk and the three SNPs above remained inconclusive. In this work, we performed a two-stage case-control study on 1155 cervical cancer patients and 1252 matched healthy controls to determine the roles of the mentioned SNPs in cervical cancer susceptibility. We genotyped the FAS rs2234767, rs1800682, and FASL rs763110 polymorphisms using PCR-TaqMan assays. Results revealed that the rs763110 TT genotype significantly increased the risk of cervical cancer compared with the CC/CT genotype (adjusted OR = 1.70, 95% CI = 1.19-2.42). However, we did not observe any association between the cervical cancer risk and the rs2234767 and rs1800682 polymorphisms. The immunohistochemistry assay showed that patients carrying the rs763110 TT genotype presented a lower cancerous FASL expression than that of the CC/CT genotypes. Chromatin immunoprecipitation (ChIP) and Sequential Chromatin immunoprecipitation assays also demonstrated that OCT1 was recruited to the FASL promoter region and regulated the FASL gene transcription by interacting with C/EBPβ. In conclusion, this study provided evidence indicating that the rs763110 variant in the FASL promoter was associated with the risk of cervical cancer by affecting the binding affinity of the C/EBPβ/OCT1 complex to chromatin.
Xie CH, Cao YM, Huang Y, et al.Long non-coding RNA TUG1 contributes to tumorigenesis of human osteosarcoma by sponging miR-9-5p and regulating POU2F1 expression.
Tumour Biol. 2016; 37(11):15031-15041 [PubMed
] Related Publications
Recent studies have shown that long non-coding RNAs (lncRNAs) have critical roles in tumorigenesis, including osteosarcoma. The lncRNA taurine-upregulated gene 1 (TUG1) was reported to be involved in the progression of osteosarcoma. Here, we investigated the role of TUG1 in osteosarcoma cells and the underlying mechanism. TUG1 expression was measured in osteosarcoma cell lines and human normal osteoblast cells by quantitative real-time PCR (qRT-PCR). The effects of TUG1 on osteosarcoma cells were studied by RNA interference in vitro and in vivo. The mechanism of competing endogenous RNA (ceRNA) was determined using bioinformatic analysis and luciferase assays. Our data showed that TUG1 knockdown inhibited cell proliferation and colony formation, and induced G0/G1 cell cycle arrest and apoptosis in vitro, and suppressed tumor growth in vivo. Besides, we found that TUG1 acted as an endogenous sponge to directly bind to miR-9-5p and downregulated miR-9-5p expression. Moreover, TUG1 overturned the effect of miR-9-5p on the proliferation, colony formation, cell cycle arrest, and apoptosis in osteosarcoma cells, which involved the derepression of POU class 2 homeobox 1 (POU2F1) expression. In conclusion, our study elucidated a novel TUG1/miR-9-5p/POU2F1 pathway, in which TUG1 acted as a ceRNA by sponging miR-9-5p, leading to downregulation of POU2F1 and facilitating the tumorigenesis of osteosarcoma. These findings may contribute to the lncRNA-targeted therapy for human osteosarcoma.
Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25-30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity. MATE1 mainly mediates the cellular uptake of imatinib into targeted cells and thereby controls the intracellular effectiveness of imatinib. Importantly, MATE1 but not OCT1 expression is reduced in total bone marrow cells of imatinib-non-responding CML patients compared with imatinib-responding patients, indicating that MATE1 but not OCT1 determines the therapeutic success of imatinib. We thus propose that imatinib non-responders could be identified early before starting therapy by measuring MATE1 expression levels.
Portseva TN, Pankratova EV, Stepchenko AG, Georgieva SGIncreased level of Oct-1 protein in tumor cells modulates cellular response to anticancer drugs.
Dokl Biochem Biophys. 2016; 469(1):269-72 [PubMed
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The effect of overexpression of Oct-1 protein isoforms on the cell response to two anticancer drugs camptothecin and dexamethasone was studied. The effect of Oct-1 isoforms on regulated gene transcription was estimated by the difference in the level of mRNA in Burkitt's lymphoma cells (Namalwa line) untransfected and stably transfected with Oct-1 isoforms. The response to anticancer drugs of the Oct-1 target genes involved in the development of apoptosis depended, firstly, on the type of drug, secondly, on the concentration of Oct-1 in cells. and, thirdly, on the Oct-1 isoform with which these cells were transfected.
Obinata D, Takayama K, Fujiwara K, et al.Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth.
Oncogene. 2016; 35(49):6350-6358 [PubMed
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Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.
Lubecka K, Kurzava L, Flower K, et al.Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity.
Carcinogenesis. 2016; 37(7):656-68 [PubMed
] Free Access to Full Article Related Publications
DNA hypomethylation was previously implicated in cancer progression and metastasis. The purpose of this study was to examine whether stilbenoids, resveratrol and pterostilbene thought to exert anticancer effects, target genes with oncogenic function for de novo methylation and silencing, leading to inactivation of related signaling pathways. Following Illumina 450K, genome-wide DNA methylation analysis reveals that stilbenoids alter DNA methylation patterns in breast cancer cells. On average, 75% of differentially methylated genes have increased methylation, and these genes are enriched for oncogenic functions, including NOTCH signaling pathway. MAML2, a coactivator of NOTCH targets, is methylated at the enhancer region and transcriptionally silenced in response to stilbenoids, possibly explaining the downregulation of NOTCH target genes. The increased DNA methylation at MAML2 enhancer coincides with increased occupancy of repressive histone marks and decrease in activating marks. This condensed chromatin structure is associated with binding of DNMT3B and decreased occupancy of OCT1 transcription factor at MAML2 enhancer, suggesting a role of DNMT3B in increasing methylation of MAML2 after stilbenoid treatment. Our results deliver a novel insight into epigenetic regulation of oncogenic signals in cancer and provide support for epigenetic-targeting strategies as an effective anticancer approach.
Qian X, Zhao FQRegulatory roles of Oct proteins in the mammary gland.
Biochim Biophys Acta. 2016; 1859(6):812-9 [PubMed
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The expression of Oct-1 and -2 and their binding to the octamer motif in the mammary gland are developmentally and hormonally regulated, consistent with the expression of milk proteins. Both of these transcription factors constitutively bind to the proximal promoter of the milk protein gene β-casein and might be involved in the inhibition or activation of promoter activity via interactions with other transcription factors or cofactors at different developmental stages. In particular, the lactogenic hormone prolactin and glucocorticoids induce Oct-1 and Oct-2 binding and interaction with both the signal transducer and activator of transcription 5 (STAT5) and the glucocorticoid receptor on the β-casein promoter to activate β-casein expression. In addition, increasing evidence has shown the involvement of another Oct factor, Oct-3/4, in mammary tumorigenesis, making Oct-3/4 an emerging prognostic marker of breast cancer and a molecular target for the gene-directed therapeutic intervention, prevention and treatment of breast cancer. This article is part of a Special Issue entitled: The Oct Transcription Factor Family, edited by Dr. Dean Tantin.
The metazoan-specific POU domain transcription factor family comprises activities underpinning developmental processes such as embryonic pluripotency and neuronal specification. Some POU family proteins efficiently bind an 8-bp DNA element known as the octamer motif. These proteins are known as Oct transcription factors. Oct1/POU2F1 is the only widely expressed POU factor. Unlike other POU factors it controls no specific developmental or organ system. Oct1 was originally described to operate at target genes associated with proliferation and immune modulation, but more recent results additionally identify targets associated with oxidative and cytotoxic stress resistance, metabolic regulation, stem cell function and other unexpected processes. Oct1 is pro-oncogenic in multiple contexts, and several recent reports provide broad evidence that Oct1 has prognostic and therapeutic value in multiple epithelial tumor settings. This review focuses on established and emerging roles of Oct1 in epithelial tumors, with an emphasis on mechanisms of transcription regulation by Oct1 that may underpin these findings. This article is part of a Special Issue entitled: The Oct Transcription Factor Family, edited by Dr. Dean Tantin.
BACKGROUND: The polyspecific organ cation transporter 1 (OCT1) is one of the most important active influx pumps for drugs like the kinase inhibitor sorafenib. The aim of this retrospective study was the definition of the role of intratumoral OCT1 mRNA expression in hepatocellular carcinoma (HCC) as a biomarker in systemic treatment with sorafenib.
METHODS: OCT1 mRNA expression levels were determined in biopsies from 60 primary human HCC by real time PCR. The data was retrospectively correlated with clinical parameters.
RESULTS: Intratumoral OCT1 mRNA expression is a significant positive prognostic factor for patients treated with sorafenib according to Cox regression analysis (HR 0.653, 95%-CI 0.430-0.992; p = 0.046). Under treatment with sorafenib, a survival benefit could be shown using the lower quartile of intratumoral OCT1 expression as a cut-off. Macrovascular invasion (MVI) was slightly more frequent in patients with low OCT1 mRNA expression (p = 0.037). Treatment-induced AFP response was not associated with intratumoral OCT1 mRNA expression levels (p = 0.633).
CONCLUSIONS: This study indicates a promising role for intratumoral OCT1 mRNA expression as a prognostic biomarker in therapeutic algorithms in HCC. Further prospective studies are warranted on this topic.
The mechanism of resistance of hepatocellular carcinoma (HCC) to sorafenib is unknown and no useful predictive biomarker for sorafenib treatment has been reported. Accordingly, we established sorafenib-resistant HCC cells and investigated the underlying mechanism of resistance to sorafenib. Sorafenib-resistant cell lines were established from the HCC cell line PLC/PRF5 by cultivation under continuous exposure to increasing concentration of sorafenib. The IC50 values of the 2 resistant clones PLC/PRF5-R1 and PLC-PRF5-R2 were 9.2±0.47 μM (1.8-fold) and 25±5.1 μM (4.6-fold) respectively, which were significantly higher than that of parental PLC/PRF5 cells (5.4±0.17 μM) (p < 0.01 respectively), as determined by MTT assay. Western blot analysis of signal transduction-related proteins showed no significant differences in expression of AKT/pAKT, mTOR/pmTOR, or ERK/pERK between the 2 resistant clones versus parent cells, suggesting no activation of an alternative signal transduction pathway. Likewise, when expression of membrane transporter proteins was determined, there were no significant differences in expression levels of BSEP, MDR1, MRP2, BCRP, MRP4 and OCT1 between resistant clones and parent cells. However, the expression levels of MRP3 in the 2 resistant clones were significantly higher than that of parent cells. When MRP3 gene was knocked down by siRNA in PLC-PRF5-R2 cells, the sensitivity of the cells to sorafenib was restored. In the analysis of gene mutation, there was no mutation in the activation segment of Raf1 kinase in the resistant clones. Our data clearly demonstrate that the efflux transporter MRP3 plays an important role in resistance to sorafenib in HCC cells.
Francis J, Dubashi B, Sundaram R, et al.A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients.
Cancer Chemother Pharmacol. 2015; 76(6):1185-9 [PubMed
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PURPOSE: Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for better management of imatinib therapy. The present study was framed to explore the influence of common drug transporter gene polymorphisms of ABCB1, ABCG2, OCT1 and trough level concentration on commonly occurring adverse events in CML patients treated with imatinib mesylate.
METHODS: A total number of 111 patients in chronic phase (Philadelphia chromosome +ve) were included in the study. The plasma drug concentration of imatinib was estimated using LC-MS/MS method.
RESULTS: The mean ± SD trough level concentration of imatinib mesylate was found to be 1430.7 ± 438.7 ng/ml. The trough level concentration at steady state (Cmin.ss) was significantly higher in patients with grade 2-4 thrombocytopenia compared with patients without the adverse event (P value 0.033).
CONCLUSION: The drug level of imatinib in plasma correlates with the severity of thrombocytopenia, which adds to the utility of TDM in the management of CML patients.
Octamer transcription factor 1 (OCT1) was found to influence the genesis and progression of numerous cancers except for colorectal cancer (CRC). This study tried to explore the role of OCT1 in CRC and clarify the association between its expression and patients' clinical outcome. Transcriptional and post-transcriptional expression of OCT1 was detected in CRC cancerous tissues and paired normal mucosae by real-time PCR as well as immunohistochemistry. Moreover, the effect of OCT1 knockdown on CRC cell proliferation was investigated both in vitro and in vivo using Cell Counting Kit-8 assay, colony-forming assay, and mouse tumorigenicity assay. Expression of OCT1 was found to be elevated in CRC. Suppression of OCT1 significantly inhibited CRC cell proliferation both in vitro and in vivo. Furthermore, upregulated level of OCT1 was significantly associated with N stage, M stage, and American Joint Committee on Cancer (AJCC) stage (P = 0.027, 0.014, and 0.002, respectively) as well as differential degree (P = 0.022). By using multivariate Cox hazard model, OCT1 was also shown to be a factor independently predicting overall survival (OS; P = 0.013, hazard ratio = 2.747, 95 % confidence interval 1.125 to 3.715) and disease-free survival (DFS; P = 0.004, hazard ratio = 2.756, 95 % confidence interval 1.191 to 4.589) for CRC patients. Our data indicate that OCT1 carries weight in colorectal carcinogenesis and functions as a novel prognostic indicator and a promising target of anti-cancer therapy for CRC.
Our previous study shows that Calpain 6 (CAPN6) expression is regulated by PI3K-Akt in liver cancer through POU2F1 and CAPN6 which promote cell proliferation and inhibit apoptosis of liver cancer cells. microRNAs (miRNAs) plays important roles in regulation of gene expression. However, whether miRNAs regulates CAPN6 expression and its cellular function is still unknown. This study aims to investigate how miRNAs regulate liver cancer apoptosis through POU2F1-CAPN6. It was verified that POU2F1 could promote cell proliferation and inhibit apoptosis through CAPN6. Using methods of bioinformatics, miR-449a was predicted as a potential regulator of both CAPN6 and POU2F1. It was verified that CAPN6 and POU2F1 were the target genes of miR-449a by luciferase assay. CAPN6 and POU2F1 protein and mRNA levels decreased in liver cancer cells with miR-449a overexpression using western blot and real time RT-PCR assays. miR-449a expression was lower in liver cancer tissues compared with their normal ones, so did the cells. Overexpression of miR-449a inhibited cell proliferation, induced G1 phase arrest and cell apoptosis in liver cancer. Further research demonstrated that miR-449a inhibited cancer cell proliferation and induced apoptosis via suppressing both POU2F1 and CAPN6. The study indicated that miR-449a functions as a tumor inhibitor in liver cancer by decreasing POU2F1 and CAPN6 expression in liver cancer.
Malhotra H, Sharma P, Malhotra B, et al.Molecular response to imatinib & its correlation with mRNA expression levels of imatinib influx & efflux transporters in patients with chronic myeloid leukaemia in chronic phase.
Indian J Med Res. 2015; 142(2):175-82 [PubMed
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BACKGROUND & OBJECTIVES: Imatinib is the standard first-line treatment for chronic myeloid leukaemia (CML) patients. About 20 to 30 per cent patients develop resistance to imatinib and fail imatinib treatment. One of the mechanisms proposed is varying expression levels of the drug transporters. This study was aimed to determine the expression levels of imatinib transporter genes (OCT1, ABCB1, ABCG2) in CML patients and to correlate these levels with molecular response.
METHODS: Sixty three CML chronic phase patients who were on 400 mg/day imatinib for more than two years were considered for gene expression analysis study for OCT1, ABCB1 and ABCG2 genes. These were divided into responders and non-responders. The relative transcript expression levels of the three genes were compared between these two categories. The association between the expression values of these three genes was also determined.
RESULTS: No significant difference in the expression levels of OCT1, ABCB1 and ABCG2 was found between the two categories. The median transcript expression levels of OCT1, ABCB1 and ABCG2 genes in responders were 26.54, 10.78 and 0.64 versus 33.48, 7.09 and 0.53 in non-responders, respectively. A positive association was observed between the expression of the ABCB1 and ABCG2 transporter genes (r=0.407, P<0.05) while no association was observed between the expression of either of the ABC transporter genes with the OCT1 gene.
INTERPRETATION & CONCLUSIONS: Our findings demonstrated that the mRNA expression levels of imatinib transporter genes were not correlated with molecular response in CML patients. Further studies need to be done on a large sample of CML patients to confirm these findings.
He T, Qi F, Jia L, et al.Tumor cell-secreted angiogenin induces angiogenic activity of endothelial cells by suppressing miR-542-3p.
Cancer Lett. 2015; 368(1):115-125 [PubMed
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Therapeutic strategies for targeting angiogenesis have been proven as successful treatments for divergent cancers. We previously discovered an anti-angiogenic miR-542-3p, which directly targeted the key angiogenesis-promoting protein Angiopoietin-2 to inhibit tumor angiogenesis in breast cancer models. In this study, to further investigate the mechanism of miR-542-3p induced angiogenic inhibition, we screened for tumor cell derived factors which were responsible for miR-542-3p alteration in endothelial cells. We found that tumor cell-derived angiogenin downregulated miR-542-3p in endothelial cells. Overexpression of angiogenin in tumor cells facilitated angiogenic activation in both in vitro and in vivo models via inhibition of miR-542-3p. Furthermore, our results showed that angiogenin could suppress CEBPB and POU2F1, which were transcription factors for miR-542-3p, suggesting a novel tumor cell-endothelial cell signal pathway. In addition, the level of angiogenin in primary breast carcinomas correlated with clinical progression. Serum levels of angiogenin were associated with metastatic development of breast cancer patients. Together, these findings reveal a novel regulatory pathway whereby tumor-derived angiogenin directly activates angiogenesis through inhibition of miR-542-3p, suggesting that angiogenin may represent a promising target for anti-angiogenic therapy and a potential marker for monitoring disease progression.