Research IndicatorsGraph generated 16 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 16 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
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: PLK2 (cancer-related)
Gümus M, Ozgur A, Tutar L, et al.Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis.
Curr Pharm Biotechnol. 2016; 17(14):1231-1245 [PubMed
] Related Publications
BACKGROUND: Despite development of novel cancer drugs, invasive ductal breast carcinoma and its metastasis are still highly morbid. Therefore, new therapeutic approaches are being developed and Hsp90 is an important target for drug design. For this purpose, a series of benzodiazepine derivatives were designed and synthesized as novel Hsp90 inhibitor.
METHODS: Benzodiazepine derivatives anticancer activities were determined by XTT cell proliferation assay against human breast cancer cell line (MCF-7). Effects of the compounds on endothelial function were monitored on human vascular endothelium (HUVEC) cell line as well. In order to determine the anti-proliferative mechanism of the compounds, in silico molecular docking studies were performed between Hsp90 ATPase domain and the benzodiazepine derivatives. Further, these compounds perturbation on Hsp90 ATPase function were tested. Fluorescence binding experiments showed that the derivatives bind Hsp90 effectively. Expression analysis of known cancer drug target genes by PCR array experiments suggest that the benzodiazepine derivatives have remarkable anticancer activity.
RESULTS: A representative Benzodiazepine derivative D5 binds Hsp90 with Kd value of 3,93 μM and with estimated free energy of binding -7.99 (kcal/mol). The compound decreases Hsp90 ATPase function and inhibit Hsp90 client protein folding activity. The compound inhibits expression of both Hsp90 isoforms and key proteins (cell cycle receptors; PLK2 and TERT, kinases; PI3KC3 and PRKCE, and growth factors; IGF1, IGF2, KDR, and PDGFRA) on oncogenic pathways.
CONCLUSION: Benzodiazepine derivatives presented here display anticancer activity. The compounds effect on both breast cancer and endothelial cell lines show their potential as drug templates to inhibit breast cancer and its metastasis.
Zhao HB, Zhang XF, Shi F, et al.Comparison of the expression of human equilibrative nucleotide transporter 1 (hENT1) and ribonucleotide reductase subunit M1 (RRM1) genes in seven non-Hodgkin lymphoma cell lines.
Genet Mol Res. 2016; 15(2) [PubMed
] Related Publications
We investigated the variability in the expression of human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase subunit M1 (RRM1) in non-Hodgkin lymphoma cell lines. hENT1 and RRM1 mRNA expression levels in natural killer (NK) cells and seven non-Hodgkin lymphoma cell lines (YTS, SNK-6, Jeko-1, ly-1, Raji, Karpas, and Jurket) were studied using reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) and the results were compared using the Student t-test. mRNA expression of hENT1 was detectable in YTS, SNK-6, Jeko-1, ly-1, Raji, Karpas, Jurket, and NK cells, which revealed variability in gene expression. There were significant differences in the mRNA expression values of hENT1 (P = 0.021) and RRM1 (P = 0.002) compared to those in NK cells. mRNA expression of both hENT1 and RRM1 was closely associated with non-Hodgkin lymphoma cell proliferation. Differential expression analysis of hENT1 and RRM1 in non-Hodgkin lymphoma cell lines may provide novel drug leads for precision medicine.
Kim SJ, Kim JH, Ki CS, et al.Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin.
Ann Oncol. 2016; 27(3):508-13 [PubMed
] Related Publications
BACKGROUND: Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL).
PATIENTS AND METHODS: We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity.
RESULTS: A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study.
CONCLUSIONS: Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL.
TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53-null and p53-mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo-like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up-regulated by cisplatin. PLK2-phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up-regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73-enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73.
Gee HE, Buffa FM, Harris AL, et al.MicroRNA-Related DNA Repair/Cell-Cycle Genes Independently Associated With Relapse After Radiation Therapy for Early Breast Cancer.
Int J Radiat Oncol Biol Phys. 2015; 93(5):1104-14 [PubMed
] Related Publications
PURPOSE: Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo.
METHODS AND MATERIALS: With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis.
RESULTS: We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05).
CONCLUSIONS: Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.
Zhang X, Zhao L, Li X, et al.ATP-binding cassette sub-family C member 4 (ABCC4) is overexpressed in human NK/T-cell lymphoma and regulates chemotherapy sensitivity: Potential as a functional therapeutic target.
Leuk Res. 2015; 39(12):1448-54 [PubMed
] Related Publications
Nasal-type natural killer/T-cell (NK/T-cell) lymphomas are subtypes of non-Hodgkin's lymphoma (NHL), which are typically more clinically aggressive. There is, however relatively little understanding of nasal-type NK/T-cell lymphoma molecular pathogenesis. Thus, in this study we applied RNA sequencing to systematically screen for altered gene expression in human NK/T-cell lymphoma cell lines YTS and SNK-6 versus normal NK cells. We found that ATP-binding cassette sub-family C Member 4 (ABCC4) levels were significantly upregulated both in human NK/T-cell lymphoma YTS and SNK-6 cells, as compared with normal NK cells. These expression levels were further confirmed by real-time PCR. Protein levels of ABCC4 were also significantly higher in YTS and SNK-6 cells as compared with normal NK cells. Clinically relevant, ABCC4 expression levels were significantly higher in human NK/T-cell lymphoma tissues as compared with control nasal mucosa tissues, confirmed by immunohistochemical staining. In addition, we explored the biological function of such ABCC4 upregulation. Overexpression of ABCC4 by lentivirus transfection induced chemotherapy resistance to epirubicin (EPI) and cisplatin (DDP) in YTS cells. In contrast, knockdown of ABCC4 expression by shRNA contributed to chemotherapy sensitivity by both EPI and DDP. Furthermore, overexpression of ABCC4 inhibited, while downregulation of ABCC4 increased, YTS cell apoptosis following treatment by EPI or DDP. Therefore, the present study identified ABCC4 to be overexpressed in human NK/T-cell lymphoma cells, to regulate chemotherapy sensitivity to EPI and DDP, and possibly to be a functional therapeutic target. These findings may provide a basic rationale for new approaches in the effort to develop anti-tumor therapeutics for NK/T-cell lymphoma.
Bhullar KS, Jha A, Rupasinghe HPNovel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells.
Chem Biol Interact. 2015; 242:107-22 [PubMed
] Related Publications
Anticancer activity of a novel curcumin analog (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone (CUR3d) was studied using a human hepatocellular carcinoma cell line (HepG2). The results showed that CUR3d completely inhibits the tumor cell proliferation in a dose- and time-dependent manner. CUR3d at 100 μmol/L activated the pro-apoptotic caspase-3 along with downregulation of anti-apoptotic BIRC5 and Bcl2. CUR3d treatment controlled the cancer cell growth by downregulating the expression of PI3K/Akt (Akt1, Akt2) pathway along with NF-κB. CUR3d down-regulated the members of epidermal growth receptor family (EGFR, ERBB3, ERBB2) and insulin like growth receptors (IGF1, IGF-1R, IGF2). This correlated with the downregulation of G-protein (RHOA, RHOB) and RAS (ATF2, HRAS, KRAS, NRAS) pathway signaling. CUR3d also arrested cell cycle via inhibition of CDK2, CDK4, CDK5, CDK9, MDM2, MDM4 and TERT genes. Cell cycle essential aurora kinases (AURKα, AURKβ) and polo-like kinases (PLK1, PLK2, PLK3) were also modulated by CUR3d. Topoisomerases (TOP2α, TOP2β), important factors in cancer cell immortality, as well as HIF-1α were downregulated following CUR3d treatment. The expression of protein kinase-C family (PRKC-A, PRKC-D, PRKC-E) was also attenuated by CUR3d. The downregulation of histone deacetylases (Class I, II, IV) and PARP I further strengthened the anticancer efficacy of CUR3d. Downregulation of carcinogenic cathepsins (CTSB, CTSD) and heat shock proteins exhibited CUR3d's potency as a potential immunological adjuvant. Finally, the non-toxic manifestation of CUR3d in healthy liver and lung cells along with downregulation of drug resistant gene ABCC1 further warrant need for advance investigations.
Sun L, Zhao Y, Shi H, et al.LMP1 promotes nasal NK/T-cell lymphoma cell function by eIF4E via NF-κB pathway.
Oncol Rep. 2015; 34(6):3264-71 [PubMed
] Related Publications
Nasal natural killer T-cell lymphoma (NKTL) is a highly malignant tumor that is closely associated with Epstein-Barr virus (EBV) infection. Latent membrane protein 1 (LMP1) is encoded by EBV and plays an important role in EBV-induced cell transformation. Therefore, we assessed the function of LMP1 as a stimulant of NKTL progression and the underlying mechanism. A human EBV-positive NKTL cell line (SNK-6) was transfected with pcDNA3.1-LMP1, LV-LMP1 shRNA or LV-eukaryotic translation initiation factor 4E (eIF4E)-shRNA. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the proliferation of SNK-6 cells, and cell migration and invasion were analyzed by transwell chamber assay. Flow cytometry was used to analyze the cell cycle and apoptosis. The results showed LMP1 was highly expressed in SNK-6 cells compared with control groups. Following pretreatment with LMP1 shRNA, the proliferation of SNK-6 cells was inhibited and resulted in a G0/G1 phase arrest. A reduction in invasion and migration was also observed. LMP1 silencing promoted cell apoptosis. Further mechanistic analysis suggested that LMP1 overexpression induced the expression of eIF4E, while eIF4E-shRNA dramatically attenuated the increase in cell proliferation, invasion, migration and the inhibition of apoptosis triggered by LMP-1 upregulation. Moreover, the effect of LMP1 on eIF4E expression was mediated by the NF-κB pathway. Therefore, this finding may provide a potential target against NKTL.
Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.
BACKGROUND: Extranodal NK/T-cell lymphoma (ENKL) is an aggressive hematological malignancy associated with Epstein-Barr virus (EBV) infection. It is often resistant to conventional chemotherapy and has a poor prognosis. Icaritin, a compound derived from Chinese herbal medicine, Herba Epimedii, has been reported to exert antitumor effects on a variety of cancer cell lines. In the present study, we investigated the cytotoxic effects of Icaritin on the two EBV-positive ENKL cell lines SNK-10 and SNT-8, along with the underlying molecular mechanisms.
METHODS: ENKL cell lines SNK-10 and SNT-8 were exposed to different concentrations of Icaritin for the indicated time. Treated cells were analyzed for cell proliferation, cell cycle, and cell apoptosis. Phosphorylation of Stat3 and Akt proteins in signaling pathways and the EBV-encoded LMP1 proteins were measured by Western blot. Expression of EBV genes was assessed by Real-Time PCR.
RESULTS: Our results showed that Icaritin dose-dependently inhibits ENKL cell proliferation and induces apoptosis and cell cycle arrest at G2/M phase. Additionally, Icaritin upregulates Bax, downregulates Bcl-2 and pBad, and activates caspase-3 and caspase-9. The anti-proliferative and pro-apoptotic effects of Icaritin are likely mediated by inhibition of Stat3 and Akt pathways through LMP1 downregulation. Importantly, Icaritin induces EBV lytic gene expression in ENKL cells, and the combination of Icaritin and the antiviral drug ganciclovir (GCV) is more effective in inducing ENKL cells apoptosis than Icaritin or GCV alone.
CONCLUSIONS: These findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.
Sun L, Zhao Y, Shi H, et al.LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma.
Oncol Rep. 2015; 33(5):2253-60 [PubMed
] Related Publications
The latent membrane protein-1 (LMP-1) is essential for Epstein-Barr virus (EBV)-induced nasal natural killer/T-cell lymphoma (NKTL). The aim of the present study was to evaluate the role of LMP-1 in NKTL. Two human EBV-positive NKTL cell lines (SNK-6 and SNT-8) were transfected with pcDNA3.1-LMP-1 or LMP-1 siRNA. Compared with the blank control, the cell apoptosis rates were decreased by 10.31 and 12.05% after pcDNA3.1-LMP-1 transfection and increased by 41.48 and 35.63% after lentiviral LMP-1 siRNA infection in the SNK-6 and SNT-8 cells. Survivin expression was induced by LMP-1, and the effect was attenuated by inhibitors of survivin, NF-κB and PI3K/Akt. Reduction in cell apoptosis by LMP-1 was also inhibited by inhibitors of survivin, NF-κB and PI3K/Akt. For the in vivo assay, tumor-bearing mice were established by subcutaneous injection with differentially treated SNT-8 cells into the back of the nude mice, and the tumor growth in the different groups was recorded. The results revealed that tumor formation and growth were also inhibited by treatment with survivin, NF-κB and PI3K/Akt inhibitors. Collectively, LMP-1-induced survivin expression inhibited cell apoptosis through the NF-κB and PI3K/Akt pathways, and survivin may be a new target for the treatment of NKTL induced by EBV.
Liu LY, Wang W, Zhao LY, et al.Silencing of polo-like kinase 2 increases cell proliferation and decreases apoptosis in SGC-7901 gastric cancer cells.
Mol Med Rep. 2015; 11(4):3033-8 [PubMed
] Related Publications
Polo‑like kinase 2 (PLK2) is a serine/threonine protein kinase, which has vital roles during mitosis and the centrosome cycle. In acute myeloblastic leukemia and hepatocarcinogenesis, PLK2 acts as a tumor suppressor; however, the function of PLK2 in gastric cancer remains to be elucidated. In the present study, PLK2 was overexpressed in gastric cancer tissues and three types of gastric cancer cells, SGC‑7901, MKN‑45 and BGC‑823. Transfection of SGC‑7901 gastric cancer cells with small interfering (si)RNA against PLK2 exerted no effect on the ratio of cells at different stages of the cell cycle compared with that of the untransfected and control siRNA‑transfected cells. In addition, silencing of PLK2 significantly enhanced the growth of SGC‑7901 cells through inhibiting apoptosis. Furthermore, apoptosis‑associated genes Bax and caspase 3 were found to be downregulated at the protein level. In conclusion, these results suggested that PLK2 may act as a tumor suppressor in gastric cancer, therefore indicating its therapeutic potential.
Ji WG, Zhang XD, Sun XD, et al.miRNA-155 modulates the malignant biological characteristics of NK/T-cell lymphoma cells by targeting FOXO3a gene.
J Huazhong Univ Sci Technolog Med Sci. 2014; 34(6):882-8 [PubMed
] Related Publications
This study investigated the effects of miRNA-155 on malignant biological characteristics of NK/T-cell lymphoma cell lines and the possible mechanism. The expression of miRNA-155 was detected in lymphoma cell lines from different sources (SNK-6, YTS, Jurkat and DOHH2) by real-time PCR. Lentiviral vectors (pLL3.7) that could overexpress or downexpress miRNA-155 were constructed. Recombinant lentiviral particles were prepared and purified, and their titers determined. The expression of miRNA-155 in the infected SNK-6 cells and the cell proliferation were detected by PCR and CCK-8, respectively. Flow cytometry was used to determine the apoptosis of infected SNK-6 cells. The target of miRNA155 was predicted from Targetscan website. The effect of miRNA155 on FOXO3a expression was examined by Western blotting. The results showed that among the human NK/T-cell lymphoma cell lines SNK-6, YTS, Jurkat and DOHH2, the expression of miRNA-155 was highest in SNK-6. The infection efficiency of the recombinant lentivirus in SNK-6 was more than 70% at multiplicity of infection (MOI) of 100. The expression of miRNA-155 was significantly increased in SNK-6 cells infected by lentivirus vectors with high expression of miRNA-155 (4 times higher than the control group), and profoundly decreased in those infected with lentiviruses with low expression of miRNA-155. The proliferation of letivirus-infected SNK-6 cells was decreased as the expression of miRNA-155 reduced. The apoptosis rate was increased with the reduction in the expression of miRNA-155. FOXO3a was found to be a possible target of miRNA155, as suggested by Targetscan website. Western blotting showed that the expression of FOXO3a was significantly elevated in SNK-6 cells with miRNA-155 inhibition. It was concluded that reduction in miRNA-155 expression can inhibit the proliferation of SNK-6 lymphoma cells and promote their apoptosis, which may be associated with regulation of FOXO3a gene.
Ward A, Sivakumar G, Kanjeekal S, et al.The deregulated promoter methylation of the Polo-like kinases as a potential biomarker in hematological malignancies.
Leuk Lymphoma. 2015; 56(7):2123-33 [PubMed
] Related Publications
Deregulation of Polo-like kinase (PLK) transcription via promoter methylation results in perturbations at the protein level, which has been associated with oncogenesis. Our objective was to further characterize the methylation profile for PLK1-4 in bone marrow aspirates displaying blood neoplasms as well as in cells grown in vitro. Clinically, we have determined that more than 70% of lymphoma and myelodysplastic syndrome (MDS)/leukemia bone marrow extracts display a hypermethylated PLK4 promoter region in comparison to the normal. Decreased PLK4 protein expression due to promoter hypermethylation was negatively correlated with JAK2 overexpression, a common occurrence in hematological malignancies. In vitro examination of the PLKs under biologically relevant condition of 5% O2 revealed that the highly conserved PLKs respond to lower oxygen tension at both the DNA and the protein level. These findings suggest that PLK promoter methylation status correlates with disease and tumorigenesis in blood neoplasms and could serve as a biomarker.
BACKGROUND: miRNA-27a has been confirmed as an important regulator in carcinogenesis and other pathological processes. Whether and how it plays a role in the laryngeal carcinoma is unknown.
METHODS: Mature miRNA-27a expression in laryngeal cancer was detected by qRT-PCR. Gain-of-function studies using mature miR-27a were performed to investigate cell proliferation and apoptosis in the Hep2 cells. In silico database analysis and luciferase reporter assay were applied to predict and validate the direct target, respectively. Loss-of-function assays were performed to investigate the functional significance of the miR-27a target gene. qRT-PCR and Western blot were used to evaluate mRNA and protein levels of the target, respectively.
RESULTS: miR-27a was significantly up-regulated in the laryngeal tumor tissues compared to the adjacent non-tumor tissues. In silico database analysis result revealed that PLK2 is a potential target of miR-27a. luciferase reporter assay result showed the direct inhibition of miR-27a on PLK2-3'UTR. In the cases with miR-27a up-regulation, PLK2 protein expression level was significantly lower in cancer tissues than that in the adjacent non-tumor tissues, which showed a negative correlation with miR-27a expression level. Both miR-27a and knockdown of PLK2 caused the increase of the cell viability and colony formation and inhibition of the late apoptosis in the Hep2 cell lines. Moreover, miR-27a but not PLK2 also repressed the early apoptosis in the Hep2 cells. Additionally, no alteration of the Hep2 cell cycle induced by miR-27a was detected.
CONCLUSIONS: miR-27a acts as an oncogene in laryngeal squamous cell carcinoma through down-regulation of PLK2 and may provide a novel clue into the potential mechanism of LSCC oncogenesis or serve as a useful biomarker in diagnosis and therapy in laryngeal cancer.
Liu LY, Wang W, Zhao LY, et al.Mir-126 inhibits growth of SGC-7901 cells by synergistically targeting the oncogenes PI3KR2 and Crk, and the tumor suppressor PLK2.
Int J Oncol. 2014; 45(3):1257-65 [PubMed
] Related Publications
MicroRNA (miRNA)-126 (miR-126) was reported to be downregulated and to act as a tumor suppressor in cancers of the lung, cervix, bladder and prostate. However, the functions of miR-126 in gastric cancer appear to be diverse and are largely unknown. MiR-126 was reported to act as a tumor suppressor by targeting the Crk gene, or as an oncogene by targeting the SOX2 gene in gastric cancer. We identified that the expression of miR-126 was decreased in gastric cancer cell lines and tissues. PLK2, a tumor suppressor gene, was directly regulated by miR-126 in SGC-7901 cells. Overexpression of miR-126 not only suppressed the growth and clone formation of SGC-7901 cells, but also induced apoptosis in vitro, whereas inhibition of miR-126 slightly promoted SGC-7901 cell proliferation. The cell cycle was not affected by miR-126. Moreover, miR-126 suppressed tumor growth in vivo in a xenograft model. PLK2, PI3KR2 and Crk were regulated by miR-126 in SGC-7901 cells. We infer that the functions of miR-126 in gastric cancer depend on synergistic targeting balance between oncogenes and anti-oncogenes. Our study indicates that miR-126 is a tumor suppressor, which in the future may become a therapeutic target for gastric cancer.
Li Y, Zhang X, Hu T, et al.Asparagine synthetase expression and its potential prognostic value in patients with NK/T cell lymphoma.
Oncol Rep. 2014; 32(2):853-9 [PubMed
] Related Publications
Natural killer (NK)/T cell lymphoma usually shows a highly aggressive clinical course and the overall prognosis is poor. At present, there are no standard therapeutic regimens for this disease. Although chemotherapeutic protocols containing L-asparaginase (L-Asp) or pegaspargase (PEG‑Asp) have improved the efficacy of treatment, some patients are resistant to L-Asp or PEG-Asp. Previous studies demonstrated that the elevated expression of asparagine synthetase (ASNS) is correlated with the resistance to L-Asp or PEG-Asp and may also affect the prognosis in some types of tumors, but the expression level and clinical significance of ASNS in NK/T cell lymphoma remain unknown. Therefore, we investigated the expression and clinical significance of ASNS in lymphoma cell lines and patients with NK/T cell lymphoma. Firstly, we detected PEG-Asp and L-Asp activity using MTT assay and expression of ASNS using real-time PCR in the 7 lymphoma cell lines. Secondly, we used branched DNA-liquidchip technology (bDNA-LCT) for detecting ASNS mRNA in formalin-fixed, paraffin-embedded tissue sections in 50 cases of NK/T cell lymphoma and in 12 cases of nasal polyps and chronic rhinitis. Moreover, we analyzed the correlations between the expression of ASNS and the sensitivity to L-Asp and PEG-Asp in 7 lymphoma cell lines and with clinicopathological features and prognosis of NK/T cell lymphoma patients who used chemotherapy containing L-Asp and PEG-Asp. There was a marked difference in the sensitivity to L-Asp and PEG-Asp of the 7 lymphoma cell lines. YTS and SNK-6 cells were highly sensitive to PEG-Asp and had relatively low levels of ASNS mRNA expression. Hut-78, Jurkat and Karpas 299 cells were naturally resistant to PEG-Asp, and the ASNS expression levels were extremely high. The expression level of ASNS was relatively low in the NK/T cell lymphoma tissue compared to levels in the nasal polyps and chronic rhinitis (0.480±0.307 vs. 0.739±0.267; P=0.009). ASNS expression level was associated with III-IV tumor stage (P=0.041) and a high International Prognostic Index (P=0.018) in patients with NK/T cell lymphoma. The NK/T cell lymphoma patients with higher ASNS expression had a reduced median survival time when compared with the survival of patients with low ASNS expression (P=0.033). Cox regression test showed that the ASNS expression level is an independent prognostic factor for NK/T cell lymphoma patients. In conclusion, the expression of ASNS was closely related with the sensitivity of lymphoma cell lines to L-Asp and PEG-Asp in vitro and also had a certain effect on the survival of NK/T cell lymphoma patients. In conclusion, high ASNS expression in NK/T cell lymphoma is correlated with worse clinicopathological features.
Komabayashi Y, Kishibe K, Nagato T, et al.Downregulation of miR-15a due to LMP1 promotes cell proliferation and predicts poor prognosis in nasal NK/T-cell lymphoma.
Am J Hematol. 2014; 89(1):25-33 [PubMed
] Related Publications
Nasal NK/T-cell lymphoma (NNKTL) is an Epstein-Barr virus (EBV)-associated malignancy and has distinct clinical and histological features. However, its genetic features are hitherto unclear. MicroRNAs (miRNAs) play a crucial role in the pathogenesis of several malignancies via regulating gene expression. In this study, we investigated whether the specific microRNAs were related to the tumor behaviors in NNKTL. MiRNA array and Quantitative RT-PCR analyses revealed that miR-15a was expressed at a much lower level in NNKTL cells (SNK-1, SNK-6, and SNT-8) than in normal peripheral NK cells and EBV-negative NK cell line KHYG-1. Quantitative PCR and western blot analyses showed that the expression of MYB and cyclin D1, which are validated targets of miR-15a, was higher in NNKTL cells. Transfection of NNKTL cells (SNK-6 and SNT-8) with a miR-15a precursor decreased MYB and cyclin D1 levels, thereby blocking G1/S transition and cell proliferation. Knockdown of EBV-encoded latent membrane protein 1 (LMP1) significantly increased miR-15a expression in SNK-6 cells. In NNKTL tissues, we found that reduced miR-15a expression, which correlated with MYB and cyclin D1 expression, was associated with poor prognosis of NNKTL patients. These data suggest that downregulation of miR-15a, possibly due to LMP1, implicates in the pathogenesis of NNKTL by inducing cell proliferation via MYB and cyclin D1. Thus, miR-15a could be a potential target for antitumor therapy and a prognostic predictor for NNKTL.
Pezuk JA, Brassesco MS, Morales AG, et al.Polo-like kinase 1 inhibition causes decreased proliferation by cell cycle arrest, leading to cell death in glioblastoma.
Cancer Gene Ther. 2013; 20(9):499-506 [PubMed
] Related Publications
Glioblastoma (GBM) is one of the most aggressive central nervous system tumors with a patient's median survival of <1 year. Polo-like kinases (PLKs) are a family of serine/threonine kinases that have key roles in cell cycle control and DNA-damage response. We evaluated PLK1, 2, 3 and 4 gene expression in 8 GBM cell lines and 17 tumor samples, and analyzed the effect of the PLK1 inhibition on SF188 and T98G GBM cell lines and 13 primary cultures. Our data showed PLK1 overexpression and a variable altered expression of PLK2, 3 and 4 genes in GBM tumor samples and cell lines. Treatments with nanomolar concentrations of BI 2536, BI 6727, GW843682X or GSK461364 caused a significant decrease in GBM cells proliferation. Colony formation was also found to be inhibited (P<0.05), whereas apoptosis rate and mitotic index were significantly increased (P<0.05) after PLK1 inhibition in both GBM cell lines. Cell cycle analysis showed an arrest at G2 (P<0.05) and cell invasion was also decreased after PLK1 inhibition. Furthermore, simultaneous combinations of BI 2536 and temozolomide produced synergistic effects for both the cell lines after 48 h of treatment. Our findings suggest that PLK1 might be a promising target for the treatment of GBMs.
Protein kinases represent the most effective class of therapeutic targets in cancer; therefore, determination of kinase aberrations is a major focus of cancer genomic studies. Here, we analyzed transcriptome sequencing data from a compendium of 482 cancer and benign samples from 25 different tissue types, and defined distinct "outlier kinases" in individual breast and pancreatic cancer samples, based on highest levels of absolute and differential expression. Frequent outlier kinases in breast cancer included therapeutic targets like ERBB2 and FGFR4, distinct from MET, AKT2, and PLK2 in pancreatic cancer. Outlier kinases imparted sample-specific dependencies in various cell lines, as tested by siRNA knockdown and/or pharmacologic inhibition. Outlier expression of polo-like kinases was observed in a subset of KRAS-dependent pancreatic cancer cell lines, and conferred increased sensitivity to the pan-PLK inhibitor BI-6727. Our results suggest that outlier kinases represent effective precision therapeutic targets that are readily identifiable through RNA sequencing of tumors.
Berg T, Bug G, Ottmann OG, Strebhardt KPolo-like kinases in AML.
Expert Opin Investig Drugs. 2012; 21(8):1069-74 [PubMed
] Related Publications
New therapies targeting critical elements of the cell cycle open novel and attractive avenues for the treatment of cancer patients. At present, the number of clinical trials that are registered with the European Organization for Research and Treatment of Cancer (EORTC) and with the US National Cancer Institute, which investigate the efficacy of Polo-like kinase 1 (Plk1) inhibitors against solid tumors and different types of leukemia is growing. Plks are important regulators of mitotic progression. Plk1, the best characterized mammalian Plk, has become an attractive target for cancer drug development, because most types of cancer appear to be addicted to the non-oncogene Plk1. Here, the authors discuss the role of Plk1 and the potential tumor suppressor gene Plk2 in acute myeloid leukemia (AML).
The polo-like kinase PLK2 has recently been identified as a potential theranostic marker in the management of chemotherapy sensitive cancers. The methylation status of the PLK2 CpG island varies with sensitivity to paclitaxel and platinum in ovarian cancer cell lines. Importantly, extrapolation of these in vitro data to the clinical setting confirms that the methylation status of the PLK2 CpG island predicts outcomes in patients treated with carboplatin and paclitaxel chemotherapy. A second cell cycle regulator, p57Kip2, is also subject to epigenetic silencing in carboplatin resistance in vitro and in vivo, emphasising that cell cycle regulators are important determinants of sensitivity to chemotherapeutic agents and providing insights into the phenomenon of collateral drug sensitivity in oncology. Understanding the mechanistic basis and identification of robust biomarkers to predict collateral sensitivity may inform optimal use of chemotherapy in patients receiving multiple lines of treatment.
Shen T, Li Y, Yang L, et al.Upregulation of Polo-like kinase 2 gene expression by GATA-1 acetylation in human osteosarcoma MG-63 cells.
Int J Biochem Cell Biol. 2012; 44(2):423-9 [PubMed
] Related Publications
Polo-like kinase 2 (Plk2) is a member of the serine/threonine protein kinase family involved in cell-cycle regulation and cellular response to stresses. It is of great interest to investigate the molecular mechanisms that control the expression of Plk2. Here, using real-time PCR and Western blot assays, we show that trichostatin A (TSA), a histone deacetylase inhibitor, upregulated Plk2 mRNA and protein expression in the human osteosarcoma MG-63 cell line. Luciferase activity analysis of the truncated Plk2 promoter indicated that the region from -1220 to -830 of the Plk2 promoter was sensitive to TSA. Moreover, using the electrophoresis mobility shift assay and chromatin immunoprecipitation assay, we identified two GATA-1 responsive elements at positions -1051 and -949, to which GATA-1 binding was enhanced by TSA under in vitro and in vivo conditions. Immunoprecipitation and Western blot showed that the levels of acetylated GATA-1 were increased with TSA in MG-63 cells, consistent with their binding affinities to the GATA-1 responsive elements. In summary, these data demonstrate that acetylation plays a crucial role in Plk2 expression and acetylation of GATA-1 by TSA treatment may upregulate their DNA-binding affinities, resulting in the activation of Plk2 promoter. These results may contribute to the understanding of the molecular mechanism of Plk2 regulation.
Valenti F, Fausti F, Biagioni F, et al.Mutant p53 oncogenic functions are sustained by Plk2 kinase through an autoregulatory feedback loop.
Cell Cycle. 2011; 10(24):4330-40 [PubMed
] Related Publications
Aberrant activation of kinases has emerged to be a key event along with tumor progression, maintenance of tumor phenotype and response to anticancer treatments. This study documents the existence of an oncogenic auto-regulatory feedback loop that includes the Polo-like kinase-2 (Snk/Plk2) and mutant p53 proteins. Plk2 protein binds to and phosphorylates mutant p53, thereby potentiating its oncogenic activities. Phosphorylated mutant p53 binds more efficiently to p300 consequently strengthening its own transcriptional activity. Plk2 gene is regulated at a transcriptional level by both wt- and mutant p53 proteins. This leads to growth suppression or enhanced cell proliferation and chemo-resistance, respectively. In turn, the siRNA-mediated knock down of either mutant p53 or Plk2 proteins significantly curtails the growth properties of tumor cells and their chemo-resistance to anticancer treatments. Therefore, this paper identifies a novel tumor network including Plk2 and mutant p53 proteins whose triggering in response to DNA damage might disclose important implications for the treatment of human cancers.
Zhang X, Zhao L, Hang Z, et al.Evaluation of HSV-1 and adenovirus vector-mediated infection, replication and cytotoxicity in lymphoma cell lines.
Oncol Rep. 2011; 26(3):637-44 [PubMed
] Related Publications
Lymphoma is not a common focus for viral therapy as many researchers do not consider lymphoma as a suitable target for viral vectors. In the present study, the infection, replication and cytotoxicity of herpes simplex virus (HSV) and adenovirus vectors were screened and evaluated in different lymphoma cell lines. Three recombinant viruses, BAC-HSV-1-eGFP, Adv-eGFP and an NV1020-like oncolytic HSV-1 virus strain named BAC-HSV-1-eGFP-delIRs, inserted with green fluorescent protein (GFP) as a reporter, were applied to evaluate the efficiency of viral infection and replication and cytotoxicity to lymphoma cells. Four types of lymphoma cell lines (SNK-6, Jurkat, Raji and Hut 78) were examined. We found that the HSV-1 vector, BAC-HSV-1-eGFP, was able to infect and replicate in the three lymphoma cell lines (Jurkat, Raji and Hut 78) and inhibit the growth of these cells more efficiently than adenovirus vector Adv-eGFP. The sensitivity of the four types of lymphoma cell lines to the viral vectors was different. The human cutaneous TL cell line Hut 78 was more sensitive to the viral vectors than the other cell lines. However, the human NK/T lymphoma cell line SNK-6 was not infected by any of the viral vectors and did not allow replication of the viruses. In conclusion, lymphoma may be a potential target for HSV-1 vector-mediated viral therapy.
Syed N, Coley HM, Sehouli J, et al.Polo-like kinase Plk2 is an epigenetic determinant of chemosensitivity and clinical outcomes in ovarian cancer.
Cancer Res. 2011; 71(9):3317-27 [PubMed
] Related Publications
Resistance to platinum- and taxane-based chemotherapy remains a major clinical impediment to effective management of epithelial ovarian cancer (EOC). To gain insights into resistance mechanisms, we compared gene and confirmed expression patterns of novel EOC cell lines selected for paclitaxel and carboplatin resistance. Here, we report that resistance can be conferred by downregulation of the Polo-like kinase Plk2. Mechanistic investigations revealed that downregulation occurred at the level of transcription via associated DNA methylation of the CpG island in the Plk2 gene promoter in cell lines, primary tumors, and patient sera. Inhibitory RNA (RNAi)-mediated knockdown and ectopic overexpression established a critical functional role for Plk2 in determining apoptotic sensitivity to paclitaxel and carboplatin. In drug-resistant human EOC cell lines, Plk2 promoter methylation varied with the degree of drug resistance and transcriptional silencing of the promoter. RNAi-dependent knockdown of Plk2 abrogated G(2)-M cell-cycle blockade by paclitaxel, conferring resistance to both paclitaxel and platinum. Conversely, ectopic expression of Plk2 restored sensitivity to G(2)-M cell-cycle blockade and cytotoxicity triggered by paclitaxel. In clinical cases, DNA methylation of the Plk2 CpG island in tumor tissue was associated with a higher risk of relapse in patients treated postoperatively with carboplatin and paclitaxel (P = 0.003). This trend was also reflected in the analysis of matched serum samples. Taken together, our results implicate Plk2 as a clinically important determinant of chemosensitivity, in support of the candidacy of Plk2 as a theranostic marker to inform EOC management.
Benetatos L, Dasoula A, Hatzimichael E, et al.Polo-like kinase 2 (SNK/PLK2) is a novel epigenetically regulated gene in acute myeloid leukemia and myelodysplastic syndromes: genetic and epigenetic interactions.
Ann Hematol. 2011; 90(9):1037-45 [PubMed
] Related Publications
Polo-like kinase 2 (SNK/PLK2), a transcriptional target for wild-type p53 and is hypermethylated in a high percentage of multiple myeloma and B cell lymphomas patients. Given these data, we sought to study the methylation status of the specific gene in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and to correlate it with clinical and genetic features. Using methylation-specific PCR MSP, we analyzed the methylation profile of 45 cases of AML and 43 cases of MDS. We also studied the distribution of MTHFR A1298C and MTHFR C677T polymorphisms and FLT3 mutations in AML patients and correlated the results with hypermethylation in the SNK/PLK2 CpG island. The SNK/PLK2 CpG island was hypermethylated in 68.9% and 88.4% of AML and MDS cases, respectively. Cases with hypermethylation had a trend towards more favorable overall survival (OS). There was no association between different MTHFR genotypes and susceptibility to develop AML. SNK/PLK2 hypermethylation combined with the MTHFR AA1298 genotype was associated with a tendency for a better OS. Similarly, patients with SNK/PLK2 hypermethylation combined with the MTHFR CT677 polymorphism had a better OS (HR = 0.34; p = 0.017). SNK/PLK2 methylation associated with unmutated FLT3 cases had a trend for better OS compared to patients with mutated FLT3 gene. SNK/PLK2 is a novel epigenetically regulated gene in AML and MDS, and methylation occurs at high frequency in both diseases. As such, SNK/PLK2 could represent a potential pathogenetic factor, although additional studies are necessary to verify its exact role in disease pathogenesis.
The NR4A subfamily of nuclear receptors (NR4A1, NR4A2, and NR4A3) function as transcription factors that transduce diverse extracellular signals into altered gene transcription to coordinate apoptosis, proliferation, cell cycle arrest, and DNA repair. We previously discovered that 2 of these receptors, NR4A1 and NR4A3, are potent tumor suppressors of acute myeloid leukemia (AML); they are silenced in human AML, and abrogation of both genes in mice leads to rapid postnatal development of AML. Reduced expression of NR4As is also a common feature of myelodysplastic syndromes (MDSs). Here we show that reduced gene dosage of NR4A1 and NR4A3 in hypoallelic (NR4A1(+/-)NR4A3(-/-) or NR4A1(-/-)NR4A3(+/-)) mice below a critical threshold leads to a chronic myeloid malignancy that closely recapitulates the pathologic features of mixed myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) with progression to AML in rare cases. Enhanced proliferation and excessive apoptosis of hematopoietic stem cells and myeloid progenitors, together with elevated DNA damage, contribute to MDS/MPN disease. We identify the myeloid tumor suppressor genes Egr1 and JunB and the DNA damage checkpoint kinase, polo-like kinase 2 (Plk2) as deregulated genes whose disrupted signaling probably contributes to MDS/MPN. These mice provide a novel model to elucidate the molecular pathogenesis of MDS/MPN and for therapeutic evaluation.
Hatzimichael E, Dasoula A, Benetatos L, et al.Study of specific genetic and epigenetic variables in multiple myeloma.
Leuk Lymphoma. 2010; 51(12):2270-4 [PubMed
] Related Publications
Few studies have examined the association between methylenetetrahydrofolate reductase (MTHFR) SNPs, epigenetic changes, and multiple myeloma (MM). We wished to determine genotype distributions for MTHFR 1298AC SNP in cases of MM and healthy controls and to examine whether there is any correlation between the methylation status of the CpG island of CDKN2A and Snk/Plk2 and MTHFR genotypes and with overall survival (OS) and other relevant clinical parameters. Bone marrow and peripheral blood were obtained from 45 patients with MM and 77 controls, respectively. The frequencies of the MTHFR 1298AA, 1298AC, and 1298CC genotypes were 53.3%, 40%, and 6.7% for the patient population and 50.6%, 41.6%, and 7.8% for the controls. No statistically significant difference was found in genotype distribution between cases and controls. No correlation was noted between MTHFR genotypes and OS, disease stage, bone disease, anemia, and extramedullary disease. Regarding CDKN2A and Snk/Plk2 CpG island methylation analysis, we found 12 of 45 patients and 27 of 45, respectively, to be methylated. CDKN2A and Snk/Plk2 methylation did not correlate with MTHFR genotypes. Herein, we report the identification of Snk/Plk2 as a novel methylated gene in MM and show that methylation is not influenced in this CpG island or in that of a previously described methylated gene, CDKN2A, in MM. Further evaluation in a larger sample of patients is needed in order to better define the prognostic and clinical value, if any, of MTHFR 1298 polymorphisms and CDKN2A and Snk/Plk2 methylation in the pathogenesis of MM.
Pellegrino R, Calvisi DF, Ladu S, et al.Oncogenic and tumor suppressive roles of polo-like kinases in human hepatocellular carcinoma.
Hepatology. 2010; 51(3):857-68 [PubMed
] Related Publications
UNLABELLED: Polo-like kinase (PLK) proteins play critical roles in the control of cell cycle progression, either favoring or inhibiting cell proliferation, and in DNA damage response. Although either overexpression or down-regulation of PLK proteins occurs frequently in various cancer types, no comprehensive analysis on their function in human hepatocellular carcinoma (HCC) has been performed to date. In the present study, we define roles for PLK1, PLK2, PLK3, and PLK4 during hepatocarcinogenesis. Levels of PLK1, as assessed by means of real-time reverse-transcription PCR and western blot analysis, were progressively increased from nonneoplastic surrounding liver tissues to HCC, reaching the highest expression in tumors with poorer outcome (as defined by the length of patients' survival) compared with normal livers. In sharp contrast, PLK2, PLK3, and PLK4 messenger RNA and protein expression gradually declined from nontumorous liver to HCC, with the lowest levels being detected in HCC with shorter survival. In liver tumors, PLK2-4 down-regulation was paralleled by promoter hypermethylation and/or loss of heterozygosity at the PLK2-4 loci. Subsequent functional studies revealed that PLK1 inhibition led to suppression of cell growth in vitro, whereas opposite effects followed PLK2-4 silencing in HCC cell lines. In particular, suppression of PLK1 resulted in a block in the G2/M phase of the cell cycle and in massive apoptosis of HCC cells in vitro regardless of p53 status.
CONCLUSION: PLK1-4 proteins are aberrantly regulated and possess different roles in human HCC, with PLK1 acting as an oncogene and PLK2-4 being presumably tumor suppressor genes. Thus, therapeutic approaches aimed at inactivating PLK1 and/or reactivating PLK2-4 might be highly useful in the treatment of human liver cancer.