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Publisher: Biomed Central Ltd.   (Total: 302 journals)

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Showing 1 - 200 of 302 Journals sorted alphabetically
Acta Neuropathologica Communications     Open Access   (Followers: 1, SJR: 2.683, CiteScore: 5)
Acta Veterinaria Scandinavica     Open Access   (Followers: 1, SJR: 0.655, CiteScore: 1)
Addiction Science & Clinical Practice     Open Access   (Followers: 8, SJR: 1.224, CiteScore: 3)
Advances in Rheumatology     Open Access  
Advances in Simulation     Open Access   (Followers: 4)
Agriculture & Food Security     Open Access   (Followers: 16, SJR: 0.575, CiteScore: 2)
AIDS Research and Therapy     Open Access   (Followers: 14, SJR: 1.08, CiteScore: 2)
Algorithms for Molecular Biology     Open Access   (Followers: 4, SJR: 1.333, CiteScore: 2)
Allergy, Asthma and Clinical Immunology     Open Access   (Followers: 25, SJR: 0.732, CiteScore: 2)
Alzheimer's Research & Therapy     Open Access   (Followers: 3, SJR: 2.449, CiteScore: 6)
Animal Biotelemetry     Open Access   (Followers: 1, SJR: 1.067, CiteScore: 2)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 11, SJR: 1.104, CiteScore: 3)
Annals of General Psychiatry     Open Access   (Followers: 24, SJR: 0.784, CiteScore: 2)
Annals of Occupational and Environmental Medicine     Open Access   (Followers: 10, SJR: 0.452, CiteScore: 1)
Annals of Surgical Innovation and Research     Open Access   (Followers: 3, SJR: 0.328, CiteScore: 1)
Antimicrobial Resistance and Infection Control     Open Access   (Followers: 8, SJR: 1.573, CiteScore: 3)
Applied Cancer Research     Open Access   (Followers: 1)
Archives of Physiotherapy     Open Access   (Followers: 11)
Archives of Public Health     Open Access   (Followers: 12, SJR: 1.244, CiteScore: 3)
Arthritis Research & Therapy     Open Access   (Followers: 14, SJR: 2.154, CiteScore: 4)
Asia Pacific Family Medicine     Open Access   (Followers: 1, SJR: 0.538, CiteScore: 1)
Asthma Research and Practice     Open Access   (Followers: 1)
Basic and Clinical Andrology     Open Access   (SJR: 0.564, CiteScore: 2)
Behavioral and Brain Functions     Open Access   (Followers: 3, SJR: 0.986, CiteScore: 3)
Big Data Analytics     Open Access   (Followers: 27)
BioData Mining     Open Access   (Followers: 5, SJR: 0.982, CiteScore: 2)
Bioelectronic Medicine     Open Access   (Followers: 1)
Biological Procedures Online     Open Access   (SJR: 1.352, CiteScore: 4)
Biological Research     Open Access   (SJR: 0.654, CiteScore: 2)
Biology Direct     Open Access   (Followers: 7, SJR: 1.694, CiteScore: 3)
Biology of Mood & Anxiety Disorders     Open Access   (Followers: 5)
Biology of Sex Differences     Open Access   (Followers: 2, SJR: 1.902, CiteScore: 4)
Biomarker Research     Open Access   (Followers: 2)
Biomaterials Research     Open Access   (Followers: 4, SJR: 0.735, CiteScore: 3)
Biomedical Dermatology     Open Access  
BioMedical Engineering OnLine     Open Access   (Followers: 7, SJR: 0.542, CiteScore: 2)
BioPsychoSocial Medicine     Open Access   (Followers: 7, SJR: 0.416, CiteScore: 1)
Biotechnology for Biofuels     Open Access   (Followers: 9, SJR: 1.899, CiteScore: 6)
BMC Anesthesiology     Open Access   (Followers: 17, SJR: 0.807, CiteScore: 2)
BMC Biochemistry     Open Access   (Followers: 15, SJR: 0.708, CiteScore: 2)
BMC Bioinformatics     Open Access   (Followers: 141, SJR: 1.479, CiteScore: 2)
BMC Biology     Open Access   (Followers: 64, SJR: 3.842, CiteScore: 5)
BMC Biophysics     Open Access   (Followers: 3, SJR: 0.682, CiteScore: 2)
BMC Biotechnology     Open Access   (Followers: 16, SJR: 1.012, CiteScore: 3)
BMC Cancer     Open Access   (Followers: 30, SJR: 1.464, CiteScore: 3)
BMC Cardiovascular Disorders     Open Access   (Followers: 22, SJR: 0.909, CiteScore: 2)
BMC Cell Biology     Open Access   (Followers: 48, SJR: 1.277, CiteScore: 3)
BMC Clinical Pathology     Open Access   (Followers: 7, SJR: 1.141, CiteScore: 3)
BMC Complementary and Alternative Medicine     Open Access   (Followers: 16, SJR: 0.858, CiteScore: 3)
BMC Dermatology     Open Access   (Followers: 13, SJR: 0.796, CiteScore: 2)
BMC Developmental Biology     Open Access   (Followers: 13, SJR: 1.43, CiteScore: 2)
BMC Ear, Nose and Throat Disorders     Open Access   (Followers: 1, SJR: 0.653, CiteScore: 2)
BMC Ecology     Open Access   (Followers: 21, SJR: 1.076, CiteScore: 2)
BMC Emergency Medicine     Open Access   (Followers: 17, SJR: 0.572, CiteScore: 1)
BMC Endocrine Disorders     Open Access   (Followers: 7, SJR: 0.965, CiteScore: 2)
BMC Evolutionary Biology     Open Access   (Followers: 72, SJR: 1.656, CiteScore: 3)
BMC Family Practice     Open Access   (Followers: 13, SJR: 1.137, CiteScore: 2)
BMC Gastroenterology     Open Access   (Followers: 15, SJR: 1.231, CiteScore: 3)
BMC Genetics     Open Access   (Followers: 30, SJR: 1.16, CiteScore: 3)
BMC Genomics     Open Access   (Followers: 91, SJR: 2.11, CiteScore: 4)
BMC Geriatrics     Open Access   (Followers: 14, SJR: 1.257, CiteScore: 3)
BMC Health Services Research     Open Access   (Followers: 16, SJR: 1.151, CiteScore: 2)
BMC Hematology     Open Access   (Followers: 5, SJR: 0.545, CiteScore: 1)
BMC Immunology     Open Access   (Followers: 10, SJR: 0.993, CiteScore: 3)
BMC Infectious Diseases     Open Access   (Followers: 19, SJR: 1.576, CiteScore: 3)
BMC Intl. Health and Human Rights     Open Access   (Followers: 6, SJR: 1.006, CiteScore: 2)
BMC Medical Education     Open Access   (Followers: 45, SJR: 0.765, CiteScore: 2)
BMC Medical Ethics     Open Access   (Followers: 21, SJR: 1.016, CiteScore: 2)
BMC Medical Genetics     Open Access   (Followers: 8, SJR: 1.109, CiteScore: 2)
BMC Medical Genomics     Open Access   (Followers: 4, SJR: 1.688, CiteScore: 3)
BMC Medical Imaging     Open Access   (Followers: 9, SJR: 0.536, CiteScore: 2)
BMC Medical Informatics and Decision Making     Open Access   (Followers: 23, SJR: 0.812, CiteScore: 2)
BMC Medical Physics     Open Access   (Followers: 6)
BMC Medical Research Methodology     Open Access   (Followers: 9, SJR: 2.221, CiteScore: 3)
BMC Medicine     Open Access   (Followers: 13, SJR: 4.219, CiteScore: 7)
BMC Microbiology     Open Access   (Followers: 13, SJR: 1.242, CiteScore: 3)
BMC Molecular Biology     Open Access   (Followers: 147, SJR: 1.216, CiteScore: 2)
BMC Musculoskeletal Disorders     Open Access   (Followers: 23, SJR: 0.951, CiteScore: 2)
BMC Nephrology     Open Access   (Followers: 8, SJR: 1.098, CiteScore: 3)
BMC Neurology     Open Access   (Followers: 22, SJR: 1.006, CiteScore: 2)
BMC Neuroscience     Open Access   (Followers: 15, SJR: 1.12, CiteScore: 2)
BMC Nursing     Open Access   (Followers: 26, SJR: 0.766, CiteScore: 2)
BMC Nutrition     Open Access   (Followers: 9)
BMC Obesity     Open Access   (Followers: 6)
BMC Ophthalmology     Open Access   (Followers: 16, SJR: 0.921, CiteScore: 2)
BMC Oral Health     Open Access   (Followers: 6, SJR: 0.867, CiteScore: 2)
BMC Palliative Care     Open Access   (Followers: 31, SJR: 1.105, CiteScore: 2)
BMC Pediatrics     Open Access   (Followers: 17, SJR: 1.278, CiteScore: 2)
BMC Pharmacology     Open Access   (Followers: 2)
BMC Pharmacology & Toxicology     Open Access   (Followers: 6, SJR: 0.785, CiteScore: 2)
BMC Physiology     Open Access   (Followers: 4, SJR: 0.936, CiteScore: 2)
BMC Plant Biology     Open Access   (Followers: 15, SJR: 1.887, CiteScore: 4)
BMC Pregnancy and Childbirth     Open Access   (Followers: 22, SJR: 1.427, CiteScore: 3)
BMC Proceedings     Full-text available via subscription   (Followers: 1, SJR: 0.302, CiteScore: 1)
BMC Psychiatry     Open Access   (Followers: 32, SJR: 1.346, CiteScore: 3)
BMC Psychology     Open Access   (Followers: 18, SJR: 0.817, CiteScore: 2)
BMC Public Health     Open Access   (Followers: 172, SJR: 1.337, CiteScore: 3)
BMC Pulmonary Medicine     Open Access   (Followers: 4, SJR: 1.373, CiteScore: 3)
BMC Research Notes     Open Access   (Followers: 4, SJR: 0.691, CiteScore: 2)
BMC Rheumatology     Open Access   (Followers: 1)
BMC Sports Science, Medicine and Rehabilitation     Open Access   (Followers: 29, SJR: 0.926, CiteScore: 2)
BMC Structural Biology     Open Access   (Followers: 7, SJR: 1.024, CiteScore: 2)
BMC Surgery     Open Access   (Followers: 10, SJR: 0.693, CiteScore: 2)
BMC Systems Biology     Open Access   (Followers: 12, SJR: 1.109, CiteScore: 2)
BMC Urology     Open Access   (Followers: 15, SJR: 0.853, CiteScore: 2)
BMC Veterinary Research     Open Access   (Followers: 18, SJR: 0.934, CiteScore: 2)
BMC Women's Health     Open Access   (Followers: 12, SJR: 0.931, CiteScore: 2)
BMC Zoology     Open Access   (Followers: 1)
Borderline Personality Disorder and Emotion Dysregulation     Open Access   (Followers: 10)
Breast Cancer Research     Open Access   (Followers: 15, SJR: 3.026, CiteScore: 6)
Burns & Trauma     Open Access   (Followers: 13)
Cancer & Metabolism     Open Access   (Followers: 6)
Cancer Cell Intl.     Open Access   (Followers: 6, SJR: 1.13, CiteScore: 3)
Cancer Communications     Open Access  
Cancer Convergence     Open Access  
Cancer Imaging     Open Access   (Followers: 3, SJR: 1.012, CiteScore: 3)
Cancer Nanotechnology     Open Access   (Followers: 2, SJR: 1.168, CiteScore: 4)
Cancers of the Head & Neck     Open Access   (Followers: 2)
Canine Genetics and Epidemiology     Open Access   (Followers: 1)
Carbon Balance and Management     Open Access   (Followers: 5, SJR: 0.977, CiteScore: 2)
Cardio-Oncology     Open Access  
Cardiovascular Diabetology     Open Access   (Followers: 10, SJR: 2.157, CiteScore: 5)
Cardiovascular Ultrasound     Open Access   (Followers: 4, SJR: 0.812, CiteScore: 2)
Cell Communication and Signaling     Open Access   (Followers: 2, SJR: 2.211, CiteScore: 4)
Cell Division     Open Access   (Followers: 1, SJR: 2.445, CiteScore: 4)
Cellular & Molecular Biology Letters     Hybrid Journal   (Followers: 3)
Cerebellum & Ataxias     Open Access   (Followers: 1)
Child and Adolescent Psychiatry and Mental Health     Open Access   (Followers: 24, SJR: 0.901, CiteScore: 2)
Chinese Medicine     Open Access   (Followers: 2, SJR: 0.57, CiteScore: 2)
Chinese Neurosurgical J.     Open Access  
Chiropractic & Manual Therapies     Open Access   (Followers: 5, SJR: 0.599, CiteScore: 2)
Cilia     Open Access   (SJR: 0.732, CiteScore: 1)
Clinical and Molecular Allergy     Open Access   (Followers: 5, SJR: 0.933, CiteScore: 3)
Clinical and Translational Allergy     Open Access   (Followers: 2, SJR: 1.425, CiteScore: 4)
Clinical Diabetes and Endocrinology     Open Access   (Followers: 22)
Clinical Epigenetics     Open Access   (Followers: 11, SJR: 2.435, CiteScore: 5)
Clinical Sarcoma Research     Open Access  
Conflict and Health     Open Access   (Followers: 7, SJR: 1.851, CiteScore: 3)
Contraception and Reproductive Medicine     Open Access   (Followers: 1)
COPD Research and Practice     Open Access   (SJR: 0.755, CiteScore: 2)
Cost Effectiveness and Resource Allocation     Open Access   (Followers: 4, SJR: 0.888, CiteScore: 2)
Critical Care     Open Access   (Followers: 58, SJR: 2.48, CiteScore: 5)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Diabetology & Metabolic Syndrome     Open Access   (Followers: 7, SJR: 0.943, CiteScore: 2)
Diagnostic and Prognostic Research     Open Access  
Diagnostic Pathology     Open Access   (Followers: 10, SJR: 0.818, CiteScore: 2)
Disaster and Military Medicine     Open Access   (Followers: 4)
Emerging Themes in Epidemiology     Open Access   (Followers: 13, SJR: 1.003, CiteScore: 2)
Energy, Sustainability and Society     Open Access   (Followers: 16, SJR: 0.607, CiteScore: 2)
Environmental Health     Open Access   (Followers: 11, SJR: 1.662, CiteScore: 4)
Environmental Health and Preventive Medicine     Open Access   (Followers: 3, SJR: 0.5, CiteScore: 1)
Epigenetics & Chromatin     Open Access   (Followers: 8, SJR: 3.767, CiteScore: 5)
European J. of Medical Research     Open Access   (Followers: 1, SJR: 0.55, CiteScore: 1)
European Review of Aging and Physical Activity     Open Access   (Followers: 10, SJR: 1.308, CiteScore: 4)
Experimental & Translational Stroke Medicine     Open Access   (Followers: 8, SJR: 0.98, CiteScore: 3)
Experimental Hematology & Oncology     Open Access   (Followers: 3, SJR: 0.842, CiteScore: 2)
Eye and Vision     Open Access   (Followers: 1)
Fertility Research and Practice     Open Access   (Followers: 2)
Fibrogenesis & Tissue Repair     Open Access   (SJR: 1.531, CiteScore: 4)
Fisheries and Aquatic Sciences     Open Access   (Followers: 2, SJR: 0.199, CiteScore: 0)
Flavour     Open Access   (Followers: 3)
Fluids and Barriers of the CNS     Open Access   (Followers: 2, SJR: 2.054, CiteScore: 5)
Frontiers in Zoology     Open Access   (Followers: 7, SJR: 1.597, CiteScore: 3)
Genes and Environment     Open Access   (Followers: 1, SJR: 0.516, CiteScore: 1)
Genetics Selection Evolution     Open Access   (Followers: 8, SJR: 1.745, CiteScore: 4)
Genome Biology     Open Access   (Followers: 32)
Genome Medicine     Open Access   (Followers: 6, SJR: 4.537, CiteScore: 7)
Global Health Research and Policy     Open Access   (Followers: 4)
Globalization and Health     Open Access   (Followers: 5, SJR: 1.262, CiteScore: 2)
Gut Pathogens     Full-text available via subscription   (Followers: 5, SJR: 1.066, CiteScore: 3)
Gynecologic Oncology Research and Practice     Open Access   (Followers: 1)
Harm Reduction J.     Open Access   (SJR: 1.445, CiteScore: 3)
Head & Face Medicine     Open Access   (Followers: 1, SJR: 0.62, CiteScore: 2)
Health and Quality of Life Outcomes     Open Access   (Followers: 14, SJR: 1.069, CiteScore: 3)
Health Research Policy and Systems     Open Access   (Followers: 14, SJR: 1.11, CiteScore: 2)
Hereditary Cancer in Clinical Practice     Open Access   (SJR: 0.848, CiteScore: 2)
Hereditas     Open Access   (Followers: 1, SJR: 0.278, CiteScore: 1)
Human Genomics     Open Access   (Followers: 3, SJR: 1.501, CiteScore: 3)
Human Resources for Health     Open Access   (Followers: 9, SJR: 1.301, CiteScore: 2)
Immunity & Ageing     Open Access   (Followers: 10, SJR: 1.218, CiteScore: 3)
Implementation Science     Open Access   (Followers: 18, SJR: 2.443, CiteScore: 4)
Infectious Agents and Cancer     Open Access   (SJR: 0.855, CiteScore: 2)
Infectious Diseases of Poverty     Open Access   (Followers: 1, SJR: 1.212, CiteScore: 3)
Inflammation and Regeneration     Open Access   (Followers: 2)
Intl. Breastfeeding J.     Open Access   (Followers: 23, SJR: 0.913, CiteScore: 3)
Intl. J. for Equity in Health     Open Access   (Followers: 6, SJR: 1.04, CiteScore: 2)
Intl. J. of Behavioral Nutrition and Physical Activity     Open Access   (Followers: 25, SJR: 2.626, CiteScore: 6)
Intl. J. of Health Geographics     Open Access   (Followers: 8, SJR: 1.385, CiteScore: 3)
Intl. J. of Mental Health Systems     Open Access   (Followers: 7, SJR: 0.721, CiteScore: 2)
Intl. J. of Pediatric Endocrinology     Open Access   (Followers: 10)
Intl. J. of Retina and Vitreous     Open Access   (Followers: 2)
Investigative Genetics     Open Access   (Followers: 1, SJR: 1.809, CiteScore: 3)
Irish Veterinary J.     Open Access   (Followers: 4, SJR: 0.657, CiteScore: 1)
Israel J. of Health Policy Research     Open Access   (SJR: 0.488, CiteScore: 1)
Italian J. of Pediatrics     Open Access   (Followers: 1, SJR: 0.685, CiteScore: 2)
J. for ImmunoTherapy of Cancer     Open Access   (Followers: 5, SJR: 2.798, CiteScore: 6)
J. of Angiogenesis Research     Open Access   (Followers: 2)
J. of Animal Science and Biotechnology     Open Access   (Followers: 4, SJR: 1.228, CiteScore: 3)
J. of Animal Science and Technology     Open Access   (Followers: 2)
J. of Biological Engineering     Open Access   (Followers: 3, SJR: 1.34, CiteScore: 4)

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Journal Cover
Journal of Experimental & Clinical Cancer Research
Journal Prestige (SJR): 2
Citation Impact (citeScore): 6
Number of Followers: 3  

  This is an Open Access Journal Open Access journal
ISSN (Print) 0392-9078 - ISSN (Online) 1756-9966
Published by Biomed Central Ltd. Homepage  [302 journals]
  • CCDC6 and USP7 expression levels suggest novel treatment options in
           high-grade urothelial bladder cancer

    • Abstract: Background The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing. Deficiency of the tumor suppressor CCDC6 determines PARP-inhibitor sensitivity. The CCDC6 levels are modulated by the deubiquitinase USP7. In this work we scored CCDC6 and USP7 expression levels in primary UBC and we evaluated the expression levels of CCDC6 in correlation with the effects of the PARP-inhibitors combined with the USP7 inhibitor, P5091, in vitro. Since PARP-inhibitors could be enhanced by conventional chemotherapy or DNA damage inducers, we tested the new agent RRx-001, able to induce DNA damage, to prove the benefit of combined treatments in bladder cancer cells. Methods The J82, T24, 5637 and KU-19-19 bladder cancer cells were exposed to USP7 inhibitor P5091 in presence of cycloheximide to analyse the CCDC6 stability. Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays. The ability of the DNA damage inducer RRx-001 to modulate CCDC6 protein levels and H2AX phosphorylation was detected at immunoblot. The combination of USP7 inhibitor plus RRx-001 enhanced the PARP-inhibitor sensitivity, as evaluated by cell viability assays. The results of the scores and correlation of CCDC6 and USP7 expression levels obtained by UBC primary biopsies staining were used to cluster patients by a K-mean cluster analysis. Results P5091 determining CCDC6 degradation promoted bladder cancer cells sensitivity to PARP-inhibitor drugs. RRx-001, by inducing DNA damage, enhanced the effects of the combined treatment. The immunohistochemical staining of both CCDC6 and USP7 proteins allowed to cluster the high grade (G3) UBC patients, on the basis of CCDC6 expression levels. Conclusions In high grade UBC the identification of two clusters of patients based on CCDC6 and USP7 expession can possibly indicate the use of PARP-inhibitor drugs, in combination with USP7 inhibitor in addition to the DNA damage inducer RRx-001, that also acts as an immunomodulatory agent, offering novel therapeutic strategy for personalized medicine in bladder cancer patients.
      PubDate: 2019-02-20
  • Lnc-PDZD7 contributes to stemness properties and chemosensitivity in
           hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional

    • Abstract: Background Hepatocellular carcinoma (HCC) with stemness features are pivotal for tumorigenesis, chemoresistance, and progression. Long non-coding RNAs have been implicated in the regulation of HCC stemness features; however, their mechanisms remain largely unknown. Here, we found that Lnc-PDZD7 is a potential oncogene. We systematically analyzed the clinical significance and mechanism of Lnc-PDZD7 in stemness and chemosensitivity regulation. Methods We analyzed the Lnc-PDZD7 expression levels in liver cancer tissues and cell line by qRT-PCR and In situ hybridization. Gain- and loss-of-function experiments were conducted to investigate the biological functions of Lnc-PDZD7 in stemness and chemosensitivity regulation. Bioinformatics analysis, dual-luciferase reporter assays were performed to validate that Lnc-PDZD7 competitively regulates EZH2, Moreover, chromatin immunoprecipitation assays, bisulfite genomic sequencing and Western blot were performed to evaluate the mechanisms of EZH2 repressing ATOH8. Results Lnc-PDZD7 is frequently upregulated in HCC tissues. Patients with high Lnc-PDZD7 expression had poorer prognoses and a poor response to adjuvant TACE therapy. Lnc-PDZD7 could promote stemness features and suppress the sensitivity of HCC cells to anticancer drugs in vitro and in vivo. Mechanistically, Lnc-PDZD7 functioned as a molecular sponge for miR-101, antagonizing its ability to repress EZH2 expression. Subsequently, EZH2 can further inhibit the expression of the stemness regulator ATOH8 via elevating its H3K27 trimethylation and DNA methylation. Conclusion Lnc-PDZD7 promotes stemness properties and suppresses chemosensitivity though the miR-101/EZH2/ATOH8 pathway, providing new biomarkers for diagnosis and potential drug targets for HCC.
      PubDate: 2019-02-20
  • A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell
           carcinoma metastasis, cancer stemness and drug resistance via enhancing
           β5-integrin/c-met signaling pathway

    • Abstract: Background Targeting the c-Met signaling pathway has become a therapeutic strategy in multiple types of cancer. We unveiled a novel c-Met regulating mechanism that could be applied as a modality for oral squamous cell carcinoma (OSCC) therapy. Methods Upregulation of keratin 16 (KRT16) was found by comparing isogenic pairs of low and high invasive human OSCC lines via microarray analysis. OSCC cells with ectopic expression or silencing of KRT16 were used to scrutinize functional roles and associated molecular mechanisms. Results We observed that high KRT16 expression significantly correlated with poorer pathological differentiation, advanced stages, increased lymph nodes metastasis, and decreased survival rate from several Taiwanese OSCC patient cohorts. We further revealed that miR-365-3p could target ETS homologous factor (EHF), a KRT16 transcription factor, to decrease migration, invasion, metastasis and chemoresistance in OSCC cells via inhibition of KRT16. Under confocal microscopic examination, c-Met was found possibly partially associates with KRT16 through β5-integrin. Colocalization of these three proteins may facilitate c-Met and β5-integrin–mediated signaling in OSCC cells. Depletion of KRT16 led to increased protein degradation of β5-integrin and c-Met through a lysosomal pathway leading to inhibition of their downstream Src/STAT3/FAK/ERK signaling in OSCC cells. Knockdown of KRT16 enhanced chemosensitivity of OSCC towards 5-fluorouracil (5-FU). Various combination of c-Met inhibitor (foretinib), protein tyrosine kinase inhibitor (genistein), β5-integrin antibody, and 5-FU markedly augmented cytotoxic effects in OSCC cells as well as tumor killing effects in vitro and in vivo. Conclusions Our data indicate that targeting a novel miR-365-3p/EHF/KRT16/β5-integrin/c-Met signaling pathway could improve treatment efficacy in OSCC.
      PubDate: 2019-02-19
  • Blockade of PDGFRβ circumvents resistance to MEK-JAK inhibition via

    • Abstract: Background Despite the increasing progress in targeted and immune based-directed therapies for other solid organ malignancies, currently there is no targeted therapy available for TNBCs. A number of mechanisms have been reported both in pre-clinical and clinical settings that involve inherent, acquired and adaptive resistance to small molecule inhibitors. Here, we demonstrated a novel resistance mechanism in TNBC cells mediated by PDGFRβ in response to JAK2 inhibition. Methods Multiple in vitro (subG1, western blotting, immunofluorescence, RT-PCR, Immunoprecipitation), in vivo and publically available datasets were used. Results We showed that TNBC cells exposed to MEK1/2-JAK2 inhibitors exhibit resistant colonies in anchorage-independent growth assays. Moreover, cells treated with various small molecule inhibitors including JAK2 promote PDGFRβ upregulation. Using publically available databases, we showed that patients expressing high PDGFRβ or its ligand PDGFB exhibit poor relapse-free survival upon chemotherapeutic treatment. Mechanistically we found that JAK2 expression controls steady state levels of PDGFRβ. Thus, co-blockade of PDGFRβ with JAK2 and MEK1/2 inhibitors completely eradicated resistant colonies in vitro. We found that triple-combined treatment had a significant impact on CD44+/CD24− stem-cell-like cells. Likewise, we found a significant tumor growth inhibition in vivo through intratumoral CD8+ T cells infiltration in a manner that is reversed by anti-CD8 antibody treatment. Conclusion These findings reveal a novel regulatory role of JAK2-mediated PDGFRβ proteolysis and provide an example of a PDGFRβ-mediated resistance mechanism upon specific target inhibition in TNBC.
      PubDate: 2019-02-18
  • Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy
           for glioblastoma

    • Abstract: PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.
      PubDate: 2019-02-18
  • Histone deacetylase inhibitors suppress aggressiveness of head and neck
           squamous cell carcinoma via histone acetylation-independent blockade of
           the EGFR-Arf1 axis

    • Abstract: Background A promising arsenal of histone deacetylase (HDAC)-targeted treatment has emerged in the past decade, as the abnormal targeting or retention of HDACs to DNA regulatory regions often occurs in many cancers. Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies worldwide associated with poor overall survival in late-stage patients. HDAC inhibitors have great potential to treat this devastating disease; however, few has been studied regarding the beneficial role of HDAC inhibition in anti-HNSCC therapy and the underlying molecular mechanisms remain elusive. Methods Cell migration and invasion were examined by wound closure and Transwell assays. Protein levels and interactions were assessed by Western blotting and immunoprecipitation. HDAC activity was measured with the fluorometric HDAC Activity Assay. Phospho-receptor tyrosine kinase (RTK) profiling was determined by the Proteome Profiler Human Phospho-RTK Array. Results ADP-ribosylation factor 1 (Arf1), a small GTPase coordinating vesicle-mediated intracellular trafficking, can be inactivated by HDAC inhibitors through histone acetylation-independent degradation of epidermal growth factor receptor (EGFR) in HNSCC cells. Mechanistically, high levels of Arf1 activity are maintained by binding to phosphorylated EGFR which is localized on HNSCC cell plasma membrane. Decreased EGFR phosphorylation is associated with reduced EGFR protein levels in the presence of TSA, which inactivates Arf1 and eventually inhibits invasion in HNSCC cells. Conclusions Our insights explore the critical role of EGFR-Arf1 complex in driving HNSCC progression, and demonstrate the selective action of HDAC inhibitors on this specific axis for suppressing HNSCC invasion. This novel finding represents the first example of modulating the EGFR-Arf1 complex in HNSCC by small molecule agents.
      PubDate: 2019-02-18
  • Combination of Enzastaurin and Ibrutinib synergistically induces
           anti-tumor effects in diffuse large B cell lymphoma

    • Abstract: Background Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma. Although durable remissions can be achieved in more than half of these patients, DLBCL remains a significant clinical challenge, with approximately 30% of patients not being cured. BCR-associated kinases (SYK, BTK, and PI3K) inhibitors have exhibited encouraging pre-clinical and clinical effects, as reported by many researchers. Early studies demonstrated that protein kinase C-β (PKCβ) inhibitors alter phosphorylation level the Bruton’s tyrosine kinase (BTK), which leads to enhanced BTK signaling. Here, for the first time, we investigate whether the combination of PKCβ inhibitor enzastaurin and BTK inhibitor ibrutinib has synergistic anti-tumor effects in DLBCL. Methods In vitro cell proliferation was analyzed using Cell Titer-Glo Luminescent Cell Viability Assay. Induction of apoptosis and cell cycle arrest were measured by flow cytometry. Western Blotting analysis was used to detect the essential regulatory enzymes in related signaling pathways. RNA-seq was conducted to evaluate the whole transcriptome changes brought by co-treatment with low doses of enzastaurin and ibrutinib. The synergistic anti-tumor effects of enzastaurin and ibrutinib were also evaluated in vivo. Results Combination of enzastaurin and ibrutinib produced a lasting synergistic effect on the survival and proliferation of DLBCL cells, including reduction of proliferation, promoting apoptosis, inducting G1 phase arrest, preventing cell invasion and migration, and down-regulating activation of downstream signaling. More importantly, whole-transcriptome changes results showed that combination therapy worked synergistically to regulate whole-transcriptome expression compared with enzastaurin and ibrutinib alone. Co-treatment with low doses of enzastaurin and ibrutinib could effectively downregulate BCR, NF-κB, JAK and MAPK related signaling pathway. Furthermore, the mRNA expression analysis further indicated that co-treatment significantly decreased the mRNA levels of NOTCH1. The combination effect in inhibiting proliferation of DLBCL cells probably was realized through suppression of NOTCH1 expression. Finally, the anti-tumor activity of co-treatment also was demonstrated in vivo. Conclusions Combination of enzastaurin and ibrutinib had synergistic anti-tumor effects in DLBCL, independent of molecular subtype. These results provided a sound foundation for an attractive therapeutic treatment, and the simultaneous suppression of BTK and PKCβ might be a new treatment strategy for DLBCL.
      PubDate: 2019-02-18
  • H 2 S suppresses indoleamine 2, 3-dioxygenase 1 and exhibits
           immunotherapeutic efficacy in murine hepatocellular carcinoma

    • Abstract: Background Over-expression and over-activation of immunosuppressive enzyme indoleamine 2, 3 -dioxygenase 1 (IDO1) is a key mechanism of cancer immune escape. However, the regulation of IDO1 has not been fully studied. The relation between hydrogen sulfide (H2S) and IDO1 is unclear. Methods The influences of endogenous and exogenous H2S on the expression of IDO1, iNOS and NF-κB and STAT3 signaling proteins were investigated using qPCR or western blot, and the production of nitric oxide (NO) was analyzed by nitrate/nitrite assay in Cse−/− mice and MCF-7 and SGC-7901 cells. The effect of H2S on IDO1 activity was investigated by HPLC and in-vitro enzymatic assay. The effect of H2S on tryptophan metabolism was tested by luciferase reporter assay in MCF-7 and SGC-7901 cells. The correlation between H2S-generating enzyme CSE and IDO1 was investigated by immunostaining and heatmaps analysis in clinical specimens and tissue arrays of hepatocellular carcinoma (HCC) patients. The immunotherapeutic effects of H2S on H22 HCC-bearing mice were investigated. Results Using Cse−/− mice, we found that H2S deficiency increased IDO1 expression and activity, stimulated NF-κB and STAT3 pathways and decreased the expression of NO-generating enzyme Inos. Using IDO1-expressing MCF-7 and SGC-7901 cells, we found that exogenous H2S inhibited IDO1 expression by blocking STAT3 and NF-κB pathways, and decreased IDO1 activity via H2S/NO crosstalk, and combinedly decreased the tryptophan metabolism. The negative correlation between H2S-generating enzyme CSE and IDO1 was further validated in clinical specimens and tissue arrays of HCC patients. Additionally, H2S donors effectively restricted the tumor development in H22 HCC-bearing mice via downregulating IDO1 expression, inducing T-effector cells and inhibiting MDSCs. Conclusions Thus, H2S, as a novel negative regulator of IDO1, shows encouraging antitumor immunotherapeutic effects and represents a novel therapeutic target in cancer therapy.
      PubDate: 2019-02-18
  • EVI1 promotes epithelial-to-mesenchymal transition, cancer stem cell
           features and chemo−/radioresistance in nasopharyngeal carcinoma

    • Abstract: Background Aberrant EVI1 expression is frequently reported in cancer studies; however, its role in nasopharyngeal carcinoma (NPC) has not been examined in detail. The aim of the present study is to investigate the involvement of EVI1 in progression and prognosis of NPC. Methods RT-PCR, immunohistochemistry and western blot assays were used to examine the expression of EVI1 in NPC tissues and cell lines. Fluorescence in situ hybridization assay was used to examine the amplification of EVI1 in NPC tissues. The biological effect of EVI1 was determined by both in vitro and in vivo studies. The dual-luciferase reporter assay was performed to confirm that EVI1 bind at E-cadherin andβ-catenin promoters. The ChIP, EMSA, and coimmunoprecipitation combined with mass spectrometry assays were used to analyze the EVI1 regulated proteins. Results EVI1 expression level was up-regulated in NPC tissues and cell lines. EVI1 was amplificated in NPC tissues. We observed that EVI1 down-regulation decreased the cell proliferation and invasive capacity of NPC cells in vitro and in vivo. EVI1, snail, and HDAC1 formed a co-repressor complex to repress E-cadherin expression and ultimately contributed to epithelial mesenchymal transition (EMT) phenotype in NPC cells. In another way, EVI1 directly bound at β-catenin promoter and activated its expression. β-catenin mediated EVI1’s function on cancer stem cells (CSCs) properties. EVI1 up-regulation predicted unfavorable prognosis and contributed to chemo/radio-resistance in NPC cells. Finally, we constructed arsenic trioxide-loaded nanoparticles (ALNPs) and revealed that ALNPs exerted anti-tumor effect in NPC cells. Conclusions Our data indicated that EVI1 played an oncogenic role in NPC growth and metastasis and that EVI1 might serve as a novel molecular target for the treatment of NPC.
      PubDate: 2019-02-15
  • EGFR signaling confers resistance to BET inhibition in hepatocellular
           carcinoma through stabilizing oncogenic MYC

    • Abstract: Background The bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and related mechanisms of drug resistance are poorly understood in hepatocellular carcinomas (HCC). Here, we investigated the anti-tumor effects of BET inhibitor on HCC and the molecular mechanisms involved in its associated drug resistance. Methods We assessed the cytotoxicity of BET inhibitor on HCC cells compared with sorafenib by cell viability assay, metastasis assay and reproduced the anti-tumor effect in xenograft mouse model. In addition, the molecular mechanisms involved in drug resistance on JQ1-resistant HCC cells were revealed by western blotting, qRT-PCR, whole exome-sequencing and gene-editing technology. Finally, with specific inhibition of EGFR or ERK activity by interference RNAs or inhibitors, the efficacy of the synergistic treatment was investigated using cell viability assay, colony formation, apoptosis and xenograft mouse model. Results We found that JQ1, a commonly used BET bromo-domain inhibitor, offered a better anti-tumor response than sorafenib in MYC-positive HCC cells by inducing apoptosis in vitro and in vivo. Unlike sorafenib, JQ1 treatment significantly impaired mitochondrial respiration and glycolysis in HCC cells. Importantly, we revealed that MAPK activation by a previously undescribed activating mutation of EGFR-I645L, was critical for JQ1 sensitivity through stabilizing oncogenic MYC protein in JQ1-resistant HCC cells. Inhibition of either EGFR or ERK activity overcame the JQ1 resistance and significantly decreased MYC protein level in vitro and in vivo. Conclusion Since MYC amplification is frequently identified in HCC, co-occurring with EGFR amplification, our findings suggest that targeting EGFR signaling might be essential for JQ1 therapy in advanced HCC.
      PubDate: 2019-02-15
  • Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer
           cells to elicit a chemoresistant phenotype

    • Abstract: Background How exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of drug resistance in the context of the hypoxic tumor microenvironment in epithelial ovarian cancer (EOC) remains poorly understood. Methods The miRNA levels were detected by qRT-PCR. Protein levels of HIF-1α, CD163 and PTEN-PI3K/AKT pathway were assessed by Western blot (WB) and Immunohistochemistry (IHC). Exosomes were isolated, and then confirmed by Transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA) and WB. Internalization of macrophages-secreted exosomes in EOC cells was detected by Confocal microscope. Subsequently, Dual-luciferase reporter assay verified PTEN was the target of miR-223. Gain- and loss-of-function experiments, rescue experiments, and SKOV3 xenograft models were performed to uncover the underlying mechanisms of miR-223 and PTEN-PI3K/AKT pathway, as well as the exosomal miR-223 in inducing multidrug resistance in vitro and in vivo. Results Here, we showed hypoxic EOC cells triggered macrophages recruitment and induced macrophages into a tumor-associated macrophage (TAM)-like phenotype; exosomes derived from hypoxic macrophages enhanced the malignant phenotype of EOC cells, miR-223 was enriched in exosomes released from macrophages under hypoxia, which could be transferred to the co-cultivated EOC cells, accompanied by enhanced drug resistant of EOC cells. Besides, results from a functional assay revealed that exosomal miR-223 derived from macrophages promoted the drug resistance of EOC cells via the PTEN-PI3K/AKT pathway both in vivo and in vitro. Furthermore, patients with high HIF-1a expression had statistically higher CD163+ cell infiltration and intertumoral levels of miR-223. Finally, circulating exosomal miR-223 levels were closely related to the recurrence of EOC. Conclusions These data indicate a unique role of exosomal miR-223 in the cross-talk between macrophages and EOC cells in chemotherapy resistance, through a novel exosomal miR-223/PTEN-PI3K/AKT signaling pathway.
      PubDate: 2019-02-15
  • Landscape of tumor suppressor long noncoding RNAs in breast cancer

    • Abstract: Background The landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown. Methods Data from whole transcriptome sequencing of 33 breast specimens in the Harbin Medical University Cancer Center cohort and The Cancer Genome Atlas was applied to identify and validate the landscape of tumor suppressor long noncoding RNAs, which was further validated by The Cancer Genome Atlas pancancer data including 33 cancer types and 12,839 patients. Next, the expression model, prognostic roles, potential biological functions and epigenetic regulation of tumor suppressor long noncoding RNAs were investigated and validated in the breast cancer and pancancer cohorts. Finally, EPB41L4A-AS2 was selected to validate our novel finding, and the tumor suppressive roles of EPB41L4A-AS2 in breast cancer were examined. Results We identified and validated the landscape of tumor suppressor long noncoding RNAs in breast cancer. The expression of the identified long noncoding RNAs was downregulated in cancer tissue samples compared with normal tissue samples, and these long noncoding RNAs correlated with a favorable prognosis in breast cancer patients and the patients in the pancancer cohort. Multiple carcinogenesis-associated biological functions were predicted to be regulated negatively by these long noncoding RNAs. Moreover, these long noncoding RNAs were transcriptionally regulated by epigenetic modification, including DNA methylation and histone methylation modification. Finally, EPB41L4A-AS2 inhibited breast cancer cell proliferation, migration and invasion and induced cell apoptosis in vitro. Mechanistically, EPB41L4A-AS2, acting at least in part as a tumor suppressor, upregulated tumor suppressor gene expression. Moreover, ZNF217 recruited EZH2 to the EPB41L4A-AS2 locus and suppressed the expression of EPB41L4A-AS2 by epigenetically increasing H3K27me3 enrichment. Conclusions This work enlarges the functional landscape of known long noncoding RNAs in human cancer and provides novel insights into the suppressive roles of these long noncoding RNAs.
      PubDate: 2019-02-14
  • Poly-specific neoantigen-targeted cancer vaccines delay patient derived
           tumor growth

    • Abstract: Background Personalized cancer vaccines based on neoantigens have reached the clinical trial stage in melanoma. Different vaccination protocols showed efficacy in preclinical models without a clear indication of the quality and the number of neoantigens required for an effective cancer vaccine. Methods In an effort to develop potent and efficacious neoantigen-based vaccines, we have developed different neoantigen minigene (NAM) vaccine vectors to determine the rules for a successful neoantigen cancer vaccine (NCV) delivered by plasmid DNA and electroporation. Immune responses were analyzed at the level of single neoantigen by flow cytometry and correlated with tumor growth. Adoptive T cell transfer, from HLA-2.1.1 mice, was used to demonstrate the efficacy of the NCV pipeline against human-derived tumors. Results In agreement with previous bodies of evidence, immunogenicity was driven by predicted affinity. A strong poly-functional and poly-specific immune response was observed with high affinity neoantigens. However, only a high poly-specific vaccine vector was able to completely protect mice from subsequent tumor challenge. More importantly, this pipeline - from the selection of neoantigens to vaccine design - applied to a new model of patient derived tumor xenograft resulted in therapeutic treatment. Conclusions These results suggest a feasible strategy for a neoantigen cancer vaccine that is simple and applicable for clinical developments.
      PubDate: 2019-02-14
  • SHP1 and SHP2 inhibition enhances the pro-differentiative effect of
           phorbol esters: an alternative approach against acute myeloid leukemia

    • Abstract: Background The differentiation-based therapy for acute promyelocytic leukemia (APL) is an inspiring example for the search of novel strategies aimed at treatment of other subtypes of acute myeloid leukemia (AML). Thus, the discovery of new molecular players in cell differentiation becomes a paramount research area to achieve this goal. Here, the involvement of the protein tyrosine phosphatases SHP1 and SHP2 on leukemic cells differentiation is shown, along with the therapeutic possibilities of their targeting to enhance the differentiation induction effect of phorbol esters. Methods The oxidation status and enzymatic activity of SHP1 and SHP2 during PMA-induced differentiation of HEL cells was evaluated. Additionally, the effects of RNAi-mediated downregulation of these phosphatases on cell differentiation was studied. Afterwards, the impact of chemical inhibition of SHP1 and SHP2 on differentiation both in the presence and absence of phorbol esters was tested. Finally, the anti-leukemic potential of phorbol esters and chemical inhibitors of SHP1 and SHP2 was addressed in several AML model cell lines, a xenograft mouse model and AML primary cells in vitro. Results An increase of oxidation with a concomitant decrease of activity was observed for both phosphatases at the onset of PMA-induced differentiation. Consistently, silencing of these proteins favored the process, with an enhanced effect upon their simultaneous downregulation. Moreover, the proteins SRC and β-catenin were identified as downstream targets of SHP1 and SHP2 in this context. In agreement with these findings, chemical inhibition of the phosphatases promoted cell differentiation itself and enhanced the effect of phorbol esters. Interestingly, treatment with the phorbol ester prostratin and the dual inhibitor of SHP1 and SHP2 NSC87877 synergistically hampered the proliferation of AML cell lines, prolonged the survival of xenografted mice and reduced the clonogenic potential of AML primary cells. Conclusions SHP1 and SHP2 are relevant mediators of differentiation in AML cells and their inhibition either alone or in combination with prostratin seems a promising differentiation-based therapeutic strategy against different subtypes of AML beyond APL.
      PubDate: 2019-02-14
  • SKP2 promotes breast cancer tumorigenesis and radiation tolerance through
           PDCD4 ubiquitination

    • Abstract: Background S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear. Methods To validate the interaction between SKP2 and PDCD4, mass spectrometric analysis and reciprocal co-immunoprecipitation (Co-IP) experiments were performed. SKP2 stably overexpressed or knockdown breast cancer cell lines were established and western blot was used to detect proteins changes before and after radiation. In vitro and in vivo experiments were performed to verify whether SKP2 inhibits cell apoptosis and promotes DNA-damage response via PDCD4 suppression. SMIP004 was used to test the effect of radiotherapy combined with SKP2 inhibitor. Results We found that SKP2 remarkably promoted PDCD4 phosphorylation, ubiquitination and degradation. SKP2 promoted cell proliferation, inhibited cell apoptosis and enhanced the response to DNA-damage via PDCD4 suppression in breast cancer. SKP2 and PDCD4 showed negative correlation in human breast cancer tissues. Radiotherapy combine with SKP2 inhibitor SMIP004 showed significant inhibitory effects on breast cancer cells in vitro and in vivo. Conclusions We identify PDCD4 as an important ubiquitination substrate of SKP2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance via PDCD4 degradation. Radiotherapy combine with SKP2-targeted adjuvant therapy may improve breast cancer patient survival in clinical medicine.
      PubDate: 2019-02-13
  • LRG-1 promotes pancreatic cancer growth and metastasis via modulation of
           the EGFR/p38 signaling

    • Abstract: Background The abnormal expression of leucine-rich-alpha-2-glycoprotein 1 (LRG-1) is reported to be associated with multiple malignancies, but its role in the progression of pancreatic ductal adenocarcinoma (PDAC) remains to be determined. Methods The expression of LRG-1 was assessed in PDAC tissues by RT-PCR, Western blot and immunohistochemistry. LRG-1-silenced or overexpressed cell lines were constructed using shRNA or LRG-1-overexpressing plasmids. EdU incorporation assay, Transwell invasion and wound-healing assays were performed to evaluate the proliferation, invasion and migration of PDAC cells. In addition, protein expression of the mitogen-activated protein kinase (MAPK) pathway was detected using Western blot. Finally, Co-immunoprecipitation assay was conducted in search of the potential interaction between LRG-1 and epidermal growth factor receptor (EGFR). Results The expression of LRG-1 in PDAC tissue was significantly higher than that in adjacent normal tissue, and high LRG-1 expression predicted poor survival and a late tumor stage. In addition, LRG-1 markedly promoted the viability, proliferation, migration and invasion of PDAC cells in vitro and facilitated tumor growth in vivo. More importantly, we revealed that these bioactivities of LRG-1 might result from its selective interaction with EGFR, which might further activate the p38/MAPK signaling pathways. Conclusion LRG-1 may prove to be a promising biomarker for predicting prognosis of PDAC patients. Inhibition of LRG-1 or its downstream pathway could be a potential therapeutic target for the treatment of PDAC.
      PubDate: 2019-02-13
  • Low glucose and metformin-induced apoptosis of human ovarian cancer cells
           is connected to ASK1 via mitochondrial and endoplasmic reticulum
           stress-associated pathways

    • Abstract: Background Metformin, a first-line drug for type 2 diabetes, could induce apoptosis in cancer cells. However, the concentration of glucose affects the effect of metformin, especially low glucose in the culture medium can enhance the cytotoxicity of metformin on cancer cells. Since mitochondria and endoplasmic reticulum is vital for maintaining cell homeostasis, we speculate that low glucose and metformin-induced cell apoptosis may be associated with mitochondria and endoplasmic reticulum. ASK1, as apoptosis signaling regulating kinase 1, is associated with cell apoptosis and mitochondrial damage. This study was designed to investigate the functional significance of ASK1, mitochondria and endoplasmic reticulum and underlying mechanism in low glucose and metformin-induced cell apoptosis. Methods An MTT assay was used to evaluate cell viability in SKOV3, OVCAR3 and HO8910 human ovarian cancer cells. Cell apoptosis was analyzed by flow cytometry. The expression of ASK1 was inhibited using a specific pharmacological inhibitor or ASK1-siRNA. Immunofluorescence was used to detect mitochondrial damage and ER stress. Nude mouse xenograft models were given metformin or/and NQDI-1, and ASK1 expression was detected using immunoblotting. In addition, subcellular fractionation of mitochondria was performed to assay the internal connection between ASK1 and mitochondria. Results The present study found that low glucose in culture medium enhanced the anticancer effect of metformin in human ovarian cancer cells. Utilization of a specific pharmacological inhibitor or ASK1-siRNA identified a potential role for ASK1 as an apoptotic protein in the regulation of low glucose and metformin-induced cell apoptosis via ASK1-mediated mitochondrial damage through the ASK1/Noxa pathway and via ER stress through the ROS/ASK1/JNK pathway. Moreover, ASK1 inhibition weakened the antitumor activity of metformin in vivo. Thus, mitochondrial damage and ER stress play a crucial role in low glucose–enhanced metformin cytotoxicity in human ovarian cancer cells. Conclusions These data suggested that low glucose and metformin induce cell apoptosis via ASK1-mediated mitochondrial damage and ER stress. These findings indicated that the effect of metformin in anticancer treatment may be related to cell culture conditions.
      PubDate: 2019-02-13
  • DRAM2 acts as an oncogene in non-small cell lung cancer and suppresses the
           expression of p53

    • Abstract: Background Damage-regulated autophagy modulator 2(DRAM2) is associated with autophagy processes. However, the role of DRAM2 in the progression of human neoplasms is still unknown. Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Methods Tumor specimens from 259 NSCLC patients were collected and analyzed. Transwell migration, cell cycle analysis, MTT and colony formation assays were performed to determine the effect of DRAM2 overexpression and knockdown on NSCLC-cell migration and proliferation. Western blotting confirmed the expression of DRAM2, p53, and the other involved proteins. Results DRAM2 was preferentially upregulated in NSCLC tissues and higher expression of DRAM2 in NSCLC correlated with tumor node metastases stage and lymph node metastasis. Additionally, DRAM2 overexpression promoted cell metastasis and proliferation in vitro, while knockdown of DRAM2 expression yielded opposite result. Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. DRAM2 overexpression also increased proteins CDK4, CyclinD3, and decreased p27 expression, all of which are cell cycle-related factors. Consistently knocked down DRAM2 had the opposite effect. We also found that DRAM2 expression was negatively correlated to p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. Finally, absence of p53 did not influence the function of DRAM2 in NSCLC, but overexpression of p53 repressed its function. Conclusions DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Therefore, DRAM2 may act as an oncogene in NSCLC and could serve as a prognostic factor and potential target for NSCLC treatment.
      PubDate: 2019-02-12
  • PRIMA-1 MET -induced neuroblastoma cell death is modulated by p53 and mycn
           through glutathione level

    • Abstract: Background Neuroblastoma is the most common extracranial solid tumor in children. This cancer has a low frequency of TP53 mutations and its downstream pathway is usually intact. This study assessed the efficacy of the p53 activator, PRIMA-1MET, in inducing neuroblastoma cell death. Methods CellTiter 2.0 was used to study susceptibility and specificity of NB cell lines to PRIMA-1MET. Real-time PCR and western blot were used to assess the most common p53 transactivation targets. Induction of p53 and Noxa, and inhibition of Cas3/7, were used to assess impact on cell death after PRIMA-1MET treatment. Flow cytometry was used to analyze cell cycle phase and induction of apoptosis, reactive oxygen species, and the collapse of mitochondrial membrane potential. Results Neuroblastoma cell lines were at least four times more susceptible to PRIMA-1MET than were primary fibroblasts and keratinocyte cell lines. PRIMA-1MET induced cell death rapidly and in all cell cycle phases. Although PRIMA-1MET activated p53 transactivation activity, p53’s role is likely limited because its main targets remained unaffected, whereas pan-caspase inhibitor demonstrated no ability to prevent cell death. PRIMA-1MET induced oxidative stress and modulated the methionine/cysteine/glutathione axis. Variations of MYCN and p53 modulated intracellular levels of GSH and resulted in increased/decreased sensitivity of PRIMA-1MET. PRIMA-1MET inhibited thioredoxin reductase, but the effect of PRIMA-1MET was not altered by thioredoxin inhibition. Conclusions PRIMA-1MET could be a promising new agent to treat neuroblastoma because it demonstrated good anti-tumor action. Although p53 is involved in PRIMA-1MET-mediated cell death, our results suggest that direct interaction with p53 has a limited role in neuroblastoma but rather acts through modulation of GSH levels.
      PubDate: 2019-02-12
  • MiR-223-3p functions as a tumor suppressor in lung squamous cell carcinoma
           by miR-223-3p-mutant p53 regulatory feedback loop

    • Abstract: Background MicroRNAs have an important role in diverse biological processes including tumorigenesis. MiR-223 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in lung squamous cell carcinoma (LSCC). The following study investigates the role of miR-223-3p in LSCC growth and metastasis and its underlying mechanism. Methods MicroRNA profiling analyses were conducted to determine differential miRNAs expression levels in LSCC tumor tissues that successfully formed xenografts in immunocompromised mice (XG) and failed tumor tissues (no-XG). RT-PCR and in situ hybridization (ISH) was performed to evaluate the expression of miR-223-3p in 12 paired adjacent normal tissues and LSCC specimens. Cell proliferation and migration were assessed by CCK-8, colony formation and Transwell assay, respectively. The role of miR-223-3p in LSCC tumorigenesis was examined using xenograft nude models. Bioinformatics analysis, Dual-luciferase reporter assays, Chromatin immunoprecipitation (ChIP) assay and Western blot analysis were used to identify the direct target of miR-223-3p and its interactions. Results MiR-223-3p was downregulated in LSCC tissues that successfully formed xenografts (XG) compared with tumor tissues that failed (no-XG), which was also significantly reduced in LSCC tissues compared with the adjacent normal tissues. Gain- and loss-of function experiments showed that miR-223-3p inhibited proliferation and migration in vitro. More importantly, miR-223-3p overexpression greatly suppressed tumor growth in vivo. Mechanistically, we found that mutant p53 bound to the promoter region of miR-223 and reduced its transcription. Meanwhile, p53 is a direct target of miR-223-3p. Thus, miR-223-3p regulated mutant p53 expression in a feedback loop that inhibited cell proliferation and migration. Conclusions Our study identified miR-223-3p, as a tumor suppressor gene, markedly inhibited cell proliferation and migration via miR-223-3p-mutant p53 feedback loop, which suggested miR-223-3p might be a new therapeutic target in LSCC bearing p53 mutations.
      PubDate: 2019-02-12
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Heriot-Watt University
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