Research IndicatorsGraph generated 30 August 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 30 August, 2019 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: JUND (cancer-related)
Bhardwaj R, Suzuki A, Leland P, et al.Identification of a novel role of IL-13Rα2 in human Glioblastoma multiforme: interleukin-13 mediates signal transduction through AP-1 pathway.
J Transl Med. 2018; 16(1):369 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Previously, we have demonstrated that Interleukin 13 receptor alpha 2 (IL-13Rα2) is overexpressed in approximate 78% Glioblastoma multiforme (GBM) samples. We have also demonstrated that IL-13Rα2 can serve as a target for cancer immunotherapy in several pre-clinical and clinical studies. However, the significance of overexpression of IL-13Rα2 in GBM and astrocytoma and signaling through these receptors is not known. IL-13 can signal through IL-13R via JAK/STAT and AP-1 pathways in certain cell lines including some tumor cell lines. Herein, we have investigated a role of IL-13/IL-13Rα2 axis in signaling through AP-1 transcription factors in human glioma samples in situ.
METHODS: We examined the activation of AP-1 family of transcription factors (c-Jun, Fra-1, Jun-D, c-Fos, and Jun-B) after treating U251, A172 (IL-13Rα2 +ve) and T98G (IL-13Rα2 -ve) glioma cell lines with IL-13 by RT-qPCR, and immunocytochemistry (ICC). We also performed colorimetric ELISA based assay to determine AP-1 transcription factor activation in glioma cell lines. Furthermore, we examined the expression of AP-1 transcription factors in situ in GBM and astrocytoma specimens by multiplex-immunohistochemistry (IHC). Student t test and ANOVA were used for statistical analysis of the results.
RESULTS: We have demonstrated up-regulation of two AP-1 transcription factors (c-Jun and Fra-1) at mRNA and protein levels upon treatment with IL-13 in IL-13Rα2 positive but not in IL-13Rα2 negative glioma cell lines. Both transcription factors were also overexpressed in patient derived GBM specimens, however, in contrast to GBM cell lines, c-Fos is also overexpressed in patient derived specimens. Astrocytoma specimens showed lesser extent of immunostaining for IL-13Rα2 and three AP-1 factors compared to GBM specimens. By transcription factor activation assay, we demonstrated that AP-1 transcription factors (C-Jun and Fra-1) were activated upon treatment of IL-13Rα2 + GBM cell lines but not IL-13Rα2 - GBM cell line with IL-13. Our results demonstrate functional activity of AP-1 transcription factor in GBM cell lines in response to IL-13.
CONCLUSIONS: These results indicate that IL-13/IL-13Rα2 axis can mediate signal transduction in situ via AP-1 pathway in GBM and astrocytoma and may serve as a new target for GBM immunotherapy.
Background: Pancreatic cancer is a fatal malignancy with a poor prognosis. The interactions between tumor cells and stromal cells contribute to cancer progression. Pancreatic stellate cells (PSCs) play a key role in tumor-stroma crosstalk of pancreatic cancer. The in-depth exploration for tumor-stroma crosstalk is helpful to develop novel therapeutic strategies. Our aim was to identify the potential core genes and pathways in tumor-stroma crosstalk.
Methods: 3 microarray datasets were from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were screened through bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network were used to obtain the biological roles of DEGs. The top 15 DEGs were explored by principal component analysis. We validated the top 15 DEGs expression in the tumor-stroma crosstalk model in which PSCs were treated with the mixture of Aspc-1 and Panc-1 supernatant.
Results: A total of 221 genes were filtered as DEGs for tumor-stroma crosstalk. The results of principal component analysis for the top 15 DEGs can distinguish three groups. According to the KEGG enrichment, there were 8, 7, and 7 DEGs enriched in cancer related pathway, PI3K-Akt signaling pathway, and microRNAs, respectively. In the tumor-stroma crosstalk model, significant differences can be validated in the AKAP12, CLDN1, CP, FKBP1A, LAMB3, LSM4, MTMR3, PRKARIA, YWHAZ, and JUND expressions.
Conclusions: These results identified the potential core genes and pathways in pancreatic cancer for tumor-stroma crosstalk, which could provide potential targets for the treatment of pancreatic cancer.
AIM: To investigate survival rate and incidence of hepatocellular carcinoma (HCC) in patients with decompensated cirrhosis in the antiviral era.
METHODS: We used the Korean Health Insurance Review and Assessment. Korea's health insurance system is a public single-payer system. The study population consisted of 286871 patients who were prescribed hepatitis B antiviral therapy for the first time between 2007 and 2014 in accordance with the insurance guidelines. Overall, 48365 antiviral treatment-naïve patients treated between 2008 and 2009 were included, and each had a follow-up period ≥ 5 years. Data were analyzed for the 1
RESULTS: The mean patient age was 43.5 years. The annual mortality rates were 2.4%-19.1%, and 5-year cumulative mortality rate was 32.6% in 1
CONCLUSION: Long term outcome of decompensated cirrhosis treated with antiviral agent improved much, and incidence of hepatocellular carcinoma and mortality sharply decreased after one year treatment.
To identify differences in gene expression profiles of infected cells between thyroid carcinoma (C), thyroid adenoma (A) and normal thyroid (N) epithelial cells, differentially expressed genes were identified using three pairwise comparisons with the GEO2R online tool. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were used to classify them at the functional level. The most significant cluster in the N vs. A pairwise comparison had four hub genes: Insulin-like growth factor 2, Von Willebrand factor (VWF), multimerin 1 (MMRN1) and complement factor D (CFD). In N vs. C, the most significant cluster had 19 genes: IGF2, early growth response 2, transcription factor 3, KIT proto‑oncogene receptor tyrosine kinase, SMAD family member 9, MLLT3 super elongation complex subunit, runt related transcription factor 1, CFD, actinin α 1, SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily a member 4, JunD proto‑oncogene AP‑1 transcription factor subunit, serum response factor (SRF), FosB proto‑oncogene, AP‑1 transcription factor subunit, connective tissue growth factor (CTGF), SRC proto‑oncogene, non‑receptor tyrosine kinase, MMRN1, SRY‑box 9, early growth response 3 and ETS variant 4. In A vs. C, the most significant cluster had 14 genes: BCL2-like 1, galectin 3, MCL1 BCL2 family apoptosis regulator, DNA damage inducible transcript 3, BCL2 apoptosis regulator, CTGF, matrix metallopeptidase 7, early growth response 1, kinase insert domain receptor, TIMP metallopeptidase inhibitor 1, apolipoprotein E, VWF, cyclin D1 and placental growth factor. Histological evidence was presented to confirm the makeup of the hubs prior to logistic regression analysis to differentiate benign and malignant neoplasms. The results of the present study may aid in the search for novel potential biomarkers for the differential diagnosis, prognosis and development of drug targets of thyroid neoplasm.
Andrs M, Pospisilova M, Seifrtova M, et al.Purin-6-one and pyrrolo[2,3-d]pyrimidin-4-one derivatives as potentiating agents of doxorubicin cytotoxicity.
Future Med Chem. 2018; 10(17):2029-2038 [PubMed
] Related Publications
AIM: DNA damage response plays an eminent role in patients' response to conventional chemotherapy and radiotherapy. Its inhibition is of great interest as it can overcome cancer cell resistance and reduce the effective doses of DNA damaging agents. Results & methodology: We have focused our research on phosphatidylinositol 3-kinase-related kinases and prepared 35 novel compounds through a scaffold hopping approach. The newly synthesized inhibitors were tested on a panel of nine cancer and one healthy cell lines alone and in combination with appropriate doses of doxorubicin.
CONCLUSION: Five novel compounds 4f, 10b, 15g, 7e and 15f in combination with doxorubicin showed significant antiproliferative effect on seven cancer cell lines while not affecting the cell growth alone.
Vanova N, Muckova L, Schmidt M, et al.Simultaneous determination of malondialdehyde and 3-nitrotyrosine in cultured human hepatoma cells by liquid chromatography-mass spectrometry.
Biomed Chromatogr. 2018; 32(12):e4349 [PubMed
] Related Publications
Although reactive oxygen/nitrogen species (ROS/RNS) have a fundamental role in physiological processes, enhanced ROS/RNS production induced by exogenous sources, including drugs and other xenobiotics, may result in serious damage to biomolecules. Oxidative/nitrosative stress is being intensively investigated and might be responsible for a variety of health side effects. The present liquid chromatography-tandem mass spectrometry (LC-MS/MS) method provides reliable and accurate simultaneous measurement of malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) in cultured human hepatoma (HepG2) cells. Sample preparation process involving ultrasonic homogenization, alkaline hydrolysis of protein-bound MDA and 3-NT, deproteination, derivatization of MDA by 2,4-dinitrophenylhydrazine and solid-phase extraction was optimized, ensuring the isolation and purification of desired analytes. Additionally, nonprotein thiols and nonprotein disulfides were measured using HPLC-UV. The established lower limit of quantification (0.025 nmol/mL for MDA; 0.0125 nmol/mL for 3-NT) allowed their LC-MS/MS determination in HepG2 cells exposed to model oxidizing agent, tert-butyl hydroperoxide (t-BOOH). The results show significant changes in MDA and 3-NT concentrations and alterations in thiol redox-state in dependence on the t-BOOH concentration and duration of its incubation in HepG2 cells. Concurrent evaluation of oxidative/nitrosative stress biomarkers in the in vitro model may significantly facilitate assessment of toxicity of newly developed drugs in preclinical trials and thus improve their safety profile.
Ishikawa C, Senba M, Mori NMitotic kinase PBK/TOPK as a therapeutic target for adult T‑cell leukemia/lymphoma.
Int J Oncol. 2018; 53(2):801-814 [PubMed
] Related Publications
Adult T‑cell leukemia/lymphoma (ATLL) is a disorder involving human T-cell leukemia virus type 1 (HTLV‑1)-infected T‑cells characterized by increased clonal neoplastic proliferation. PDZ-binding kinase (PBK) [also known as T‑lymphokine-activated killer cell-originated protein kinase (TOPK)] is a serine/threonine kinase expressed in proliferative cells and is phosphorylated during mitosis. In this study, the expression and phosphorylation of PBK/TOPK were examined by western blot analysis and RT‑PCR. We found that PBK/TOPK was upregulated and phosphorylated in HTLV‑1-transformed T‑cell lines and ATLL‑derived T‑cell lines. Notably, CDK1/cyclin B1, which phosphorylates PBK/TOPK, was overexpressed in these cells. HTLV‑1 infection upregulated PBK/TOPK expression in peripheral blood mononuclear cells (PBMCs) in co-culture assays. The potent PBK/TOPK inhibitors, HI‑TOPK‑032, and fucoidan from brown algae, decreased the proliferation and viability of these cell lines in a dose‑dependent manner. By contrast, the effect of HI‑TOPK‑032 on PBMCs was less pronounced. Treatment with HI‑TOPK‑032 resulted in G1 cell cycle arrest, and decreased CDK6 expression and pRb phosphorylation, which are critical determinants of progression through the G1 phase. In addition, HI‑TOPK‑032 induced apoptosis, as evidenced by morphological changes, the cleavage of poly(ADP-ribose) polymerase with the activation of caspase‑3, -8 and -9, and an increase in the sub‑G1 cell population and APO2.7-positive cells. Moreover, HI‑TOPK‑032 inhibited the expression of cellular inhibitor of apoptosis 2 (c-IAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin and myeloid cell leukemia‑1 (Mcl‑1), and induced the expression of Bak and interferon-induced protein with tetratricopeptide repeats (IFIT)1, 2 and 3. It is noteworthy that the use of this inhibitor led to the inhibition of the phosphorylation of IκB kinase (IKK)α, IKKβ, IκBα, phosphatase and tensin homolog (PTEN) and Akt, and to the decreased protein expression of JunB and JunD, suggesting that PBK/TOPK affects the nuclear factor-κB, Akt and activator protein‑1 signaling pathways. In vivo, the administration of HI‑TOPK‑032 suppressed tumor growth in an ATLL xenograft model. Thus, on the whole, this study on the identification and functional analysis of PBK/TOPK suggests that this kinase is a promising molecular target for ATLL treatment.
Chen VL, Yeh ML, Le AK, et al.Anti-viral therapy is associated with improved survival but is underutilised in patients with hepatitis B virus-related hepatocellular carcinoma: real-world east and west experience.
Aliment Pharmacol Ther. 2018; 48(1):44-54 [PubMed
] Related Publications
BACKGROUND: Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis.
METHODS: This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death.
RESULTS: Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P < 0.001) while patients receiving anti-viral therapy had increased 5-year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti-viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001).
CONCLUSIONS: Anti-viral therapy improved overall survival in patients with HBV-related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti-viral therapy in HBV-related HCC and better linkage-to-care for HBV patients are needed.
Ryu TK, Baek SW, Kang RH, et al.Photodynamic and photothermal tumor therapy using phase-change material nanoparticles containing chlorin e6 and nanodiamonds.
J Control Release. 2018; 270:237-245 [PubMed
] Related Publications
This paper describes the fabrication and evaluation of phase-change material (PCM) nanoparticles containing chlorin e6 (Ce6) and nanodiamonds (NDs) for photodynamic and photothermal approaches for tumor therapy, respectively. The temperature of the PCM nanoparticles containing NDs (ND/PCM, 0.5mg/mL in water) is increased to 45°C during laser exposure for 5min. The singlet oxygen generation intensity of PCM nanoparticles containing Ce6 and NDs (Ce6/ND/PCM) is gradually increased with respect to the laser exposure time. Also, the release of Ce6 from Ce6/ND/PCM can be controlled in an on-and-off manner using laser. Cell ablation tests reveal that Ce6/ND/PCM greatly ablates KB cells upon laser exposure, which is attributed to both the temperature increase in the media and singlet oxygen generation by the released Ce6. In an animal model, tumor volume is notably reduced over time after the intratumoral injection of Ce6/ND/PCM and subsequent laser exposure with a higher efficiency compared to ND/PCM. The Ce6/ND/PCM can be a promising nanomedicine for tumor therapy.
BACKGROUND: Nonalcoholic fatty liver disease, the hepatic manifestation of metabolic syndrome, is associated with increased risk of colorectal adenoma, a precursor of colorectal cancer. Because nonalcoholic fatty liver disease and colorectal adenoma share many common risk factors of metabolic syndrome, the association between these 2 pathological findings has been investigated in multiple studies, but the results have been conflicting.
OBJECTIVE: The present study aimed to assess the relationship between the fatty liver index, a predictor of nonalcoholic fatty liver disease, and the prevalence of colorectal adenomas.
DESIGN: This is a retrospective observational study.
SETTINGS: This study was conducted at a single expert center.
PATIENTS: A total of 2976 consecutive subjects over 40 years of age undergoing routine checkups including abdominal ultrasonography and colonoscopy at Chung-Ang University Hospital Health Care Center were included.
MAIN OUTCOME MEASURES: The primary outcome measured was the prevalence of colorectal adenomas according to fatty liver index.
RESULTS: Among these subjects, 932 (31.3%) had colorectal adenoma, 691 (23.2%) had metabolic syndrome, and 1512 (50.8%) had fatty liver on ultrasonography. In multivariate analysis, fatty liver index ≥30 was associated with an increased risk of colorectal adenoma (OR, 1.269; 95% CI, 1.06-1.49; p = 0.008). The fatty liver index-high group (fatty liver index ≥30) had more colorectal adenomas and more advanced colorectal adenomas than the fatty liver index-low group (fatty liver index <30) (p < 0.001 and p = 0.042). The prevalence of colorectal adenomas increased with increasing quartile of fatty liver index (p < 0.05).
LIMITATIONS: The study was limited by a relatively healthy Asian population.
CONCLUSION: The high fatty liver index may be a useful predictor of colorectal adenoma. See Video Abstract at http://links.lww.com/DCR/A478.
Ahn SB, Wu WH, Lee JH, et al.Fermented Soymilk Alleviates Lipid Accumulation by Inhibition of SREBP-1 and Activation of NRF-2 in the Hepatocellular Steatosis Model.
J Microbiol Biotechnol. 2018; 28(2):236-245 [PubMed
] Related Publications
Ingredients of soy and fermented soy products have been widely utilized as food supplements for health-enhancing properties. The aim of this study was to evaluate the effects of fermented soymilk (FSM) and soymilk (SM) on free fatty acid-induced lipogenesis in the hepatocellular steatosis model. HepG2 cells were incubated with palmitic acid (PA) for 24 h to induce lipogenesis and accumulation of intracellular lipid contents. The PA-treated cells were co-incubated with FSM, SM, genistein, and estrogen, respectively. Lipid accumulation in the PA-treated HpG2 cells was significantly decreased by co-incubation with FSM. Treatment of HepG2 cells with PA combined with genistein or estrogen significantly increased the expression of SREBP-1. However, FSM co-incubation significantly attenuated SREBP-1 expression in the PA-treated HepG2 cells; in addition, expression of NRF-2 and phosphorylation of ERK were significantly increased in the PA and FSM co-incubated cells. PA-induced ROS production was significantly reduced by FSM and SM. Our results suggested that the bioactive components of FSM could protect hepatocytes against the lipid accumulation and ROS production induced by free fatty acids. These effects may be mediated by the inhibition of SREBP-1 and the activation of NRF-2 via the ERK pathway in HepG2 cells.
Ishikawa C, Mori NIn vitro and in vivo anti-primary effusion lymphoma activities of fucoidan extracted from Cladosiphon okamuranus Tokida.
Oncol Rep. 2017; 38(5):3197-3204 [PubMed
] Related Publications
Primary effusion lymphoma (PEL) caused by Kaposi's sarcoma-associated herpesvirus (KSHV) is characterized by lymphomatous effusion in body cavities and poor prognosis. There is still no effective treatment for PEL. Fucoidan, a major sulfated polysaccharide isolated from brown seaweeds, has an attractive array of bioactivities such as cancer inhibition. However, the effects of fucoidan on PEL cells remain unclear. We investigated the anti-PEL effects of fucoidan obtained from Cladosiphon okamuranus Tokida cultivated in Okinawa. Fucoidan dose-dependently inhibited the proliferation of KSHV-infected PEL cell lines, and provoked G1 cell cycle arrest, which was accompanied by CDK4 and CDK6 downregulation. Fucoidan also induced apoptosis of PEL cells through caspase-3, -8 and -9 activation; this occurred partly through the downregulation of anti-apoptotic Bcl-xL, Mcl-1 and XIAP proteins. Fucoidan also suppressed nuclear factor-κB, activator protein-1 (AP-1), and T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling pathways through inhibition of phosphorylation of IκBα and TOPK, and the expression of AP-1 family proteins, JunB and JunD. Oral administration of fucoidan effectively inhibited the development of PEL cells and ascites in a xenograft SCID mouse model, with minimal serious adverse effects. Notably, native fucoidan exhibited a more efficient anti-PEL effect than nanoparticle fucoidan. These preclinical findings highlight the anti-PEL actions of fucoidan, suggesting it could be potentially useful for the prevention and treatment of PEL.
Chang Y, Choe WH, Sinn DH, et al.Nucleos(t)ide Analogue Treatment for Patients With Hepatitis B Virus (HBV) e Antigen-Positive Chronic HBV Genotype C Infection: A Nationwide, Multicenter, Retrospective Study.
J Infect Dis. 2017; 216(11):1407-1414 [PubMed
] Related Publications
Background: Antiviral treatment for hepatitis B virus (HBV) e antigen (HBeAg)-positive chronic HBV infection is still controversial. We assessed whether antiviral treatment reduces the risk of liver disease progression in these patients.
Methods: This study included consecutive patients in 8 large-volume hospitals in Korea who tested positive for HBeAg and had an HBV DNA level of >20000 IU/mL, an alanine aminotransferase (ALT) level of <40 IU/L, and no evidence of cirrhosis. The primary end point was the development of hepatocellular carcinoma (HCC), and the secondary end point was the development of cirrhosis.
Results: A total of 484 patients were included: 87 were in the antiviral treatment group, and 397 were in the control group. Baseline liver function was significantly more favorable for the control group. After matching for propensity score to overcome those differences, the antiviral treatment group had a significantly reduced risk for HCC (hazard ratio [HR], 0.234; log-rank P = .046) and cirrhosis (HR, 0.235; log-rank P = .015), compared with the control group. After balancing the baseline characteristics by using inverse probability weighting, antiviral therapy significantly decreased the risk of HCC (HR, 0.189; log-rank P = .004) and cirrhosis (HR, 0.347; log-rank P = .036).
Conclusion: Antiviral therapy for patients with HBeAg-positive chronic HBV infection and have a high HBV load reduces the risk of HCC, even if the ALT level is below the upper limit of normal.
Hsu FF, Chiang MT, Li FA, et al.Acetylation is essential for nuclear heme oxygenase-1-enhanced tumor growth and invasiveness.
Oncogene. 2017; 36(49):6805-6814 [PubMed
] Related Publications
Overexpression of heme oxygenase-1 (HO-1), an endoplasmic reticulum-anchored enzyme, is observed in many cancers. HO-1 nuclear translocation has been shown to correlate with progression of several cancers. We recently reported that HO-1 is susceptible to intramembrane proteolysis and translocates to the nucleus to promote cancer growth and invasiveness without depending on its enzymatic activity. In the present study, we show that the HO-1 lacking C-terminal transmembrane segment (t-HO-1) was susceptible to acetylation by p300 and CREB-binding protein (CBP) histone acetyltransferase in the nucleus. Mass spectrometry analysis of HO-1 isolated from human embryonic kidney cells 293T (HEK293T) cells overexpressing CBP and t-HO-1 revealed two acetylation sites located at K243 and K256. Mutation of both lysine residues to arginine (R) abolished t-HO-1-enhanced tumor cell growth, migration and invasion. However, mutation of the lysine residues to glutamine (Q), a mimic of acetylated lysine, had no significant effect on t-HO-1-mediated tumorigenicity. Mechanistic studies demonstrated that transcriptional factor JunD interacted with wild-type (WT) t-HO-1 and mutant carrying K243/256Q but not K243/256 R mutation. Moreover, JunD-induced AP-1 transcriptional activity was significantly enhanced by coexpression with WT and acetylation-mimic but not acetylation-defective t-HO-1. Consistent with the in vitro observations, the implication of K243/256 acetylation in t-HO-1-enhanced tumorigenicity was also demonstrated in xenograft models. Immunohistochemistry performed with a specific antibody against acetyl-HO-1 showed the positive acetyl-HO-1 nuclear staining in human lung cancer tissues but not in the corresponding non-tumor tissues, supporting its clinical significance. Collectively, our findings highlight the importance of nuclear HO-1 post-translational modification in the induction of cancer progression.
There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the
Background/Aims: To investigate the use of measurements of liver stiffness (LS) by two-dimensional real-time shear wave elastography (SWE) for predicting the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).
Methods: We retrospectively collected data on 291 enrolled patients with CHB whose LS had been measured using SWE.
Results: The mean age of the patients was 46.8 years; males predominated (67%), and 40 of the patients (14%) had clinical cirrhosis. Among the patients, 165 (56.7%) received antiviral treatment. The median LS value was 7.4 kPa, and the median follow-up period was 35.8 months (range, 3.0 to 52.8 months). During follow-up, HCC developed in 13 patients (4.5%), and the cumulative incidence rates of HCC at 1, 2, and 4 years were 1.1%, 3.6%, and 8.4%, respectively. Based on a multivariate analysis, older age (≥50 years) and higher LS value (≥10 kPa) were independently associated with the risk of developing HCC (hazard ratio [HR], 4.53, p=0.023; and HR, 4.08, p=0.022). The cumulative incidence rate of HCC was significantly higher in patients with higher LS values (≥10 kPa) than in those with lower LS values (<10 kPa) (p=0.001).
Conclusions: Increased LS measured by SWE at any time point regardless of antiviral treatment is associated with an increased risk of HCC in patients with CHB.
Ishikawa C, Senba M, Mori NButein inhibits NF-κB, AP-1 and Akt activation in adult T-cell leukemia/lymphoma.
Int J Oncol. 2017; 51(2):633-643 [PubMed
] Related Publications
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) but there is no effective treatment for HTLV-1-associated diseases. Herein, we determined the effect of butein, a bioactive plant polyphenol, on cell growth, apoptosis and signaling pathways in HTLV-1-infected T-cell lines and on tumor growth in SCID mice. Treatment with butein caused a decrease in viability of HTLV-1-infected T-cell lines. T cells cultured with butein showed obvious apoptosis morphology, and cleavage of poly(ADP-ribose) polymerase with activation of caspase-3, -8 and -9. Pretreatment of cells with caspase inhibitor partially blocked butein-induced inhibition of cell viability. Butein also resulted in cell cycle arrest at G1 phase. Butein markedly downregulated the protein expression levels of CDK4, CDK6, cyclin D1, cyclin D2, cyclin E, survivin, XIAP, c-IAP2 and phospho-pRb. Butein also inhibited i) total and phospho-protein levels of IκB kinase (IKK)α and IKKβ, ii) degradation and phosphorylation of IκBα, iii) JunB and JunD, iv) total and phospho-protein levels of Akt, v) phosphorylation of RelA, vi) heat shock protein 90, and vii) DNA-binding activity of NF-κB and AP-1. In mice harboring ATLL xenograft tumors, butein caused a significant inhibition of tumor growth and reduced serum levels of soluble interleukin-2 receptor α chain and soluble cluster of differentiation 30. Considered together, the results indicated that butein has antiproliferative and proapoptotic properties through the suppression of NF-κB, AP-1 and Akt signaling in HTLV-1-infected T cells, both in vitro and in vivo, suggesting its therapeutic potential against HTLV-1-associated diseases including ATLL.
Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome with neuroendocrine tumorigenesis of the parathyroid glands, pituitary gland, and pancreatic islet cells. The MEN1 gene codes for the canonical tumor suppressor protein, menin. Its protein structure has recently been crystallized, and it has been investigated in a multitude of other tissues. In this review, we summarize recent advancements in understanding the structure of the menin protein and its function as a scaffold protein in histone modification and epigenetic gene regulation. Furthermore, we explore its role in hepatobiliary autoimmune diseases, cancers, and metabolic diseases. In particular, we discuss how menin expression and function are regulated by extracellular signaling factors and nuclear receptor activation in various hepatic cell types. How the many signaling pathways and tissue types affect menin's diverse functions is not fully understood. We show that small-molecule inhibitors affecting menin function can shed light on menin's broad role in pathophysiology and elucidate distinct menin-dependent processes. This review reveals menin's often dichotomous function through analysis of its role in multiple disease processes and could potentially lead to novel small-molecule therapies in the treatment of cholangiocarcinoma or biliary autoimmune diseases.
Calip GS, Xing S, Jun DH, et al.Polypharmacy and Adherence to Adjuvant Endocrine Therapy for Breast Cancer.
J Oncol Pract. 2017; 13(5):e451-e462 [PubMed
] Related Publications
PURPOSE: Many patients with breast cancer are treated for other conditions and experience polypharmacy with multiple concurrent medications. Our aim was to evaluate polypharmacy in relation to adherence to adjuvant endocrine therapy (AET) in breast cancer.
METHODS: We conducted a retrospective cohort study of women with incident, invasive breast cancer initiating AET (tamoxifen, letrozole, anastrozole, exemestane) between 2009 and 2013 in the Truven Health MarketScan Database. Polypharmacy and pill burden were measured for commonly used concurrent medications, including lipid-lowering drugs, antihypertensives, oral diabetes medications, insulin analogs, antidepressants, anxiolytics/antipsychotics, and opioid-containing analgesics. Polypharmacy was defined as frequent use (three or more dispensings) of a given medication class and by pill burden (total dispensings). Medication possession ratios (MPR) were estimated for subsequent 12-month intervals. Multivariable generalized estimating equation models were used to calculate odds ratios (ORs) and robust 95% CIs for associations with AET adherence (MPR ≥ 0.80).
RESULTS: Among 40,009 women, 74% were adherent in year +1 and continued to have high mean adherence (MPR = 0.79) among those continuing AET through year +3. Increasing polypharmacy ( P < .001) and pill burden ( P < .001) were associated with greater adherence, but effects differed by medication class. Frequent use of lipid-lowering drugs (OR, 1.42; 95% CI, 1.36 to 1.49) and antihypertensives (OR, 1.15; 95% CI, 1.10 to 1.20) were associated with higher odds of adherence; frequent use of opioid-containing analgesics (OR, 0.80; 95% CI, 0.77 to 0.83), anxiolytics/antipsychotics (OR, 0.95; 95% CI, 0.91 to 0.99), antidepressants (OR, 0.85; 95% CI, 0.82 to 0.89), and insulin therapy (OR, 0.82; 95% CI, 0.72 to 0.95) were associated with lower odds of adherence.
CONCLUSION: Associations between polypharmacy and adherence in breast cancer may be better characterized by understanding specific classes of medications used concurrently. Comprehensive medication therapy management, including ongoing pain evaluation and psychoactive therapies, is warranted.
Terol M, Gazon H, Lemasson I, et al.HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression.
Leukemia. 2017; 31(10):2235-2243 [PubMed
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Human T-cell leukemia virus type 1 (HTLV-1) basic-leucine zipper (bZIP) factor (HBZ) is a key player in proliferation and transformation of HTLV-1-infected cells, thus contributing to adult T-cell leukemia (ATL) development. HBZ deregulates gene expression within the host cell by interacting with several cellular partners. Through its C-terminal ZIP domain, HBZ is able to contact and activate JunD, a transcription factor of the AP-1 family. JunD mRNA is intronless but can generate two protein isoforms by alternative translation initiation: JunD full-length and Δ JunD, an N-terminal truncated form unresponsive to the tumor suppressor menin. Using various cell lines and primary T-lymphocytes, we show that after serum deprivation HBZ induces the expression of Δ JunD isoform. We demonstrate that, unlike JunD, Δ JunD induces proliferation and transformation of cells. To decipher the mechanisms for Δ JunD production, we looked into the translational machinery and observed that HBZ induces nuclear retention of RPS25 mRNA and loss of RPS25 protein expression, a component of the small ribosomal subunit. Therefore, HBZ bypasses translational control of JunD uORF and favors the expression of Δ JunD. In conclusion, we provide strong evidences that HBZ induces Δ JunD expression through alteration of the cellular translational machinery and that the truncated isoform Δ JunD has a central role in the oncogenic process leading to ATL.
Prior studies established constitutively active AP-1, NF-κB, and STAT3 signaling in oral cancer. Differential expression/activation of specific members of these transcription factors has been documented in HPV-positive oral lesions that respond better to therapy. We performed a comprehensive analysis of differentially expressed, transcriptionally active members of these pivotal signaling mediators to develop specific signatures of HPV-positive and HPV-negative oral lesions by immunohistochemical method that is applicable in low-resource settings. We examined a total of 31 prospective and 30 formalin-fixed, paraffin-embedded tissues from treatment-naïve, histopathologically and clinically confirmed cases diagnosed as oral or oropharyngeal squamous cell carcinoma (OSCC/OPSCC). Following determination of their HPV status by GP5 + /GP6 + PCR, the sequential sections of the tissues were evaluated for expression of JunB, JunD, c-Fos, p50, p65, STAT3, and pSTAT3(Y705), along with two key regulatory proteins pEGFR and p16 by IHC. Independent analysis of JunB and p65 showed direct correlation with HPV positivity, whereas STAT3 and pSTAT3 were inversely correlated. A combined analysis of transcription factors revealed a more restrictive combination, characterized by the presence of AP-1 and NF-κB lacking involvement of STAT3 that strongly correlated with HPV-positive tumors. Presence of STAT3/pSTAT3 with NF-κB irrespective of the presence or absence of AP-1 members was present in HPV-negative lesions. Expression of pSTAT3 strongly correlated with all the AP-1/NF-κB members (except JunD), its upstream activator pEGFR
BACKGROUND & AIMS: Single large (>5 cm) hepatocellular carcinoma (HCC) is classified as Barcelona Liver Clinic (BCLC) stage early stage (A). Yet, controversies exist whether single large HCC can be considered as early stage. We have analyzed long-term outcome to see which stage is appropriate for these patients.
METHODS: From 2005 to 2006, 1,546 consecutive patients who were newly diagnosed as HCC (BCLC A or B) at four tertiary hospitals in Korea were analyzed. BCLC A was sub-classified into A1 (single 2-5 cm), A2 (2-3 nodules ≤3 cm), and A3 (single >5 cm). BCLC B1 included patients beyond-Milan criteria, and within up-to-7 criterion. Survival prediction between subgroupings (1: A1 + A2 + A3 vs. B1 and 2: A1 + A2 vs. A3 + B1) was compared based on c-index and Akaike information criterion (AIC).
RESULTS: The 5-year overall survival (OS) rate was 62.3, 58.6, 36.8, and 42.0% for A1, A2, A3 and B1, respectively. In multivariate Cox-regression analysis, OS was significantly different between A3 + B1 vs. A1 + A2 (hazard ratio [HR] 1.85; P<0.001), but not between A1 + A2 + A3 vs. B1 (HR 1.19; P = 0.258). For A3, surgical resection showed superior OS over transarterial chemoembolization. Survival prediction was superior in subgrouping 2 (AIC 5727.2; c-index 0.652) than subgrouping 1 (AIC 5766.3; c-index 0.619) even after inverse probability weighting.
CONCLUSIONS: This large scale long-term follow-up data shows that single large tumor should be considered as intermediate stage in terms of prognosis. However, in terms of treatment, resection might be the first line treatment option.
Objective To examine if hypoxia inducible factor-1α (HIF-1α) can induce the upregulation of the purinergic receptor P2Y2 (P2Y2) and thereby promote the viability of human hepatocellular carcinoma (HCC) cells under hypoxic conditions. Methods Archival HCC tumour specimens and corresponding non-cancerous tissues were examined immunohistochemically for P2Y2 protein. A series of in vitro experiments were undertaken using HCC cell lines to determine the effect of hypoxia on HIF-1α and P2Y2 levels, the effect of HIF-1α upregulation on P2Y2 levels, and the effect of P2Y2 upregulation on cell viability under hypoxic conditions. Results Human HCC specimens were positive for P2Y2. Hypoxia and upregulated HIF-1α both upregulated the P2Y2 levels in HCC cell lines. P2Y2 upregulation using plasmid transfection resulted in enhanced cell viability under hypoxia. Treatment of HepG2 cells with the selective P2Y2 antagonist MRS2312 downregulated P2Y2 and reduced cell viability in five HCC cell lines. P2Y2 knockdown reduced HepG2 cell viability under hypoxia. Conclusions These present results suggest that HCC cells upregulate P2Y2 levels during hypoxia, which in turn promotes their growth. P2Y2 could be a potential therapeutic target for treating HCC.
Jun DH, Kim BJ, Park JH, et al.Preoperative Body Mass Index May Determine the Prognosis of Advanced Gastric Cancer.
Nutr Cancer. 2016 Nov-Dec; 68(8):1295-1300 [PubMed
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Radical gastrectomy followed by adjuvant chemotherapy for advanced gastric cancer causes serious nutritional impairment. Our study evaluated the clinical impact of body mass index (BMI) on the long-term outcomes of advanced gastric cancer (stage II and III). We analyzed 211 cases of stage II and III gastric cancer between January 2005 and December 2010 at Chung-Ang University Hospital, Seoul, Korea. Patients were divided into four groups according to BMI: underweight, normal, overweight, and obese. In addition, we divided patients into two groups: BMI-High (BMI ≥ 23 kg/m
Tak E, Hwang S, Lee HC, et al.Apoptosis of Hepatitis B Virus-expressing Liver Tumor Cells Induced by a High Concentration of Nucleos(t)ide Analogue.
Anticancer Res. 2016; 36(11):6059-6069 [PubMed
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BACKGROUND/AIM: We investigated the expression of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and HBV X protein (HBx) in human hepatocellular carcinoma (HCC) and evaluated the effect of high-concentration nucleos(t)ide analogs (NUCs) on liver tumor cell lines.
MATERIALS AND METHODS: This study consisted of three parts: part I used human blood and non-tumor liver tissues; part II used human HCC and adjacent liver tissues; and part III used an HBV-expressing liver tumor cell line.
RESULTS: There were close correlations among blood and liver HBV DNA and liver cccDNA. HBV cccDNA and HBx were highly up-regulated in HCC compared to adjacent liver tissues despite NUC therapy. HBV cccDNA and HBx were highly up-regulated in the cccDNA-expressing HepG2.2.15 cell line. Their expression was down-regulated and apoptosis was induced by a very high concentration of NUCs in dose- and time-dependent manner.
CONCLUSION: Very high concentrations of NUCs may have a novel potential to kill replicating HBV-expressing liver tumor cells.
Lim SW, Lee HL, Lee KN, et al.A Case of Myeloid Sarcoma of Intestine.
Korean J Gastroenterol. 2016; 68(3):148-51 [PubMed
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Myeloid sarcoma (MS) is an extramedullary involvement of immature myeloid proliferation. An isolated MS is defined as a myeloblastic tumor when it arises without any concomitant circulating disease. A diagnosis of MS is established using pathologic features including infiltration of myeloblasts and strong myeloperoxidase expression with negative cytokeratin immunohistochemical staining. We report a rare case of colonic MS without any peripheral blood abnormality. If the affected patient were left untreated, the MS could evolve into acute myeloid leukemia (AML) within one year. Several studies recommend the same regimens of chemotherapy as used for circulating AML to treat isolated MS. We focused on the diagnosis of MS in this study. The correct diagnosis of MS is important for adequate treatment. In conclusion, MS should be considered in the differential diagnosis of intestinal tumor.
BACKGROUND: Activator Protein-1 (AP-1) family (cJun, JunB, JunD, cFos, FosB, Fra1, and Fra2) plays a central role in the transcriptional regulation of many genes that are associated with cell proliferation, differentiation, migration, metastasis, and survival. Many oncogenic signaling pathways converge at the AP-1 transcription complex. Transforming growth factor beta (TGF-β) is a multifunctional regulatory cytokine that regulates many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival.
METHODS: This study investigated, the role of FOS proteins in TGF-β signaling in prostate cancer cell proliferation, migration, and invasion. Steady state expression levels of FOS mRNA and proteins were determined using RT-PCR and western blotting analyses. DU145 and PC3 prostate cancer cells were exposed to TGF-β1 at varying time and dosage, RT-PCR, western blot, and immunofluorescence analyses were used to determine TGF-β1 effect on FOS mRNA and protein expression levels as well as FosB subcellular localization. Transient silencing of FosB protein was used to determine its role in cell proliferation, migration, and invasion.
RESULTS: Our data show that FOS mRNA and proteins were differentially expressed in human prostate epithelial (RWPE-1) and prostate cancer cell lines (LNCaP, DU145, and PC3). TGF-β1 induced the expression of FosB at both the mRNA and protein levels in DU145 and PC3 cells, whereas cFos and Fra1 were unaffected. Immunofluorescence analysis showed an increase in the accumulation of FosB protein in the nucleus of PC3 cells after treatment with exogenous TGF-β1. Selective knockdown of endogenous FosB by specific siRNA did not have any effect on cell proliferation in PC3 and DU145 cells. However, basal and TGF-β1- and EGF-induced cell migration was significantly reduced in DU145 and PC3 cells lacking endogenous FosB. TGF-β1- and EGF-induced cell invasion were also significantly decreased after FosB knockdown in PC3 cells.
CONCLUSION: Our data suggest that FosB is required for migration and invasion in prostate cancer cells. We also conclude that TGF-β1 effect on prostate cancer cell migration and invasion may be mediated through the induction of FosB. Prostate 77:72-81, 2017. © 2016 Wiley Periodicals, Inc.
Papoudou-Bai A, Hatzimichael E, Barbouti A, Kanavaros PExpression patterns of the activator protein-1 (AP-1) family members in lymphoid neoplasms.
Clin Exp Med. 2017; 17(3):291-304 [PubMed
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The activator protein-1 (AP-1) is a dimeric transcription factor composed of proteins belonging to the Jun (c-Jun, JunB and JunD), Fos (c-Fos, FosB, Fra1 and Fra2) and activating transcription factor protein families. AP-1 is involved in various cellular events including differentiation, proliferation, survival and apoptosis. Deregulated expression of AP-1 transcription factors is implicated in the pathogenesis of various lymphomas such as classical Hodgkin lymphomas, anaplastic large cell lymphomas, diffuse large B cell lymphomas and adult T cell leukemia/lymphoma. The main purpose of this review is the analysis of the expression patterns of AP-1 transcription factors in order to gain insight into the histophysiology of lymphoid tissues and the pathology of lymphoid malignancies.
Millena AC, Vo BT, Khan SAJunD Is Required for Proliferation of Prostate Cancer Cells and Plays a Role in Transforming Growth Factor-β (TGF-β)-induced Inhibition of Cell Proliferation.
J Biol Chem. 2016; 291(34):17964-76 [PubMed
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TGF-β inhibits proliferation of prostate epithelial cells. However, prostate cancer cells in advanced stages become resistant to inhibitory effects of TGF-β. The intracellular signaling mechanisms involved in differential effects of TGF-β during different stages are largely unknown. Using cell line models, we have shown that TGF-β inhibits proliferation in normal (RWPE-1) and prostate cancer (DU145) cells but does not have any effect on proliferation of prostate cancer (PC3) cells. We have investigated the role of Jun family proteins (c-Jun, JunB, and JunD) in TGF-β effects on cell proliferation. Jun family members were expressed at different levels and responded differentially to TGF-β treatment. TGF-β effects on JunD protein levels, but not mRNA levels, correlated with its effects on cell proliferation. TGF-β induced significant reduction in JunD protein in RWPE-1 and DU145 cells but not in PC3 cells. Selective knockdown of JunD expression using siRNA in DU145 and PC3 cells resulted in significant reduction in cell proliferation, and forced overexpression of JunD increased the proliferation rate. On the other hand, knockdown of c-Jun or JunB had little, if any, effect on cell proliferation; overexpression of c-Jun and JunB decreased the proliferation rate in DU145 cells. Further studies showed that down-regulation of JunD in response to TGF-β treatment is mediated via the proteasomal degradation pathway. In conclusion, we show that specific Jun family members exert differential effects on proliferation in prostate cancer cells in response to TGF-β, and inhibition of cell proliferation by TGF-β requires degradation of JunD protein.
Kuribayashi W, Takizawa K, Sugata K, et al.Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model.
Oncotarget. 2016; 7(32):51027-51043 [PubMed
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Adult T-cell leukemia (ATL) is a malignant disease caused by human T-lymphotropic virus type 1. In aggressive ATL, the response to chemotherapy is extremely poor. We hypothesized that this poor response is due to the existence of chemotherapy-resistant cells, such as leukemic stem cells. Previously, we successfully identified an ATL stem cell (ATLSC) candidate as the c-kit+/CD38-/CD71- cells in an ATL mouse model using Tax transgenic mice. Here, with a new ATL mouse model using HBZ-transgenic mice, we further discovered that the functional ATLSC candidate, which commonly expresses c-kit, is drug-resistant and has the ability to initiate tumors and reconstitute lymphomatous cells. We characterized the ATLSCs as c-kit+/CD4-/CD8- cells and found that they have a similar gene expression profile as T cell progenitors. Additionally, we found that AP-1 gene family members, including Junb, Jund, and Fosb, were up-regulated in the ATLSC fraction. The results of an in vitro assay showed that ATLSCs cultured with cytokines known to promote stem cell expansion, such as stem cell factor (SCF), showed highly proliferative activity and maintained their stem cell fraction. Inhibition of c-kit-SCF signaling with the neutralizing antibody ACK2 affected ATLSC self-renewal and proliferation. Experiments in Sl/Sld mice, which have a mutation in the membrane-bound c-kit ligand, found that ATL development was completely blocked in these mice. These results clearly suggest that the c-kit-SCF signal plays a key role in ATLSC self-renewal and in ATL initiation and disease progression.