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Showing 1 - 200 of 295 Journals sorted alphabetically
Acta Neuropathologica Communications     Open Access   (Followers: 1, SJR: 2.302, h-index: 14)
Acta Veterinaria Scandinavica     Open Access   (Followers: 2, SJR: 0.425, h-index: 37)
Addiction Science & Clinical Practice     Open Access   (Followers: 6, SJR: 0.956, h-index: 22)
Advances in Simulation     Open Access   (Followers: 4)
Agriculture & Food Security     Open Access   (Followers: 14)
AIDS Research and Therapy     Open Access   (Followers: 14, SJR: 0.839, h-index: 28)
Algorithms for Molecular Biology     Open Access   (Followers: 4, SJR: 0.97, h-index: 24)
Allergy, Asthma and Clinical Immunology     Open Access   (Followers: 24, SJR: 0.782, h-index: 17)
Alzheimer's Research & Therapy     Open Access   (Followers: 4, SJR: 2.046, h-index: 25)
Animal Biotelemetry     Open Access   (Followers: 1)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 9, SJR: 0.827, h-index: 36)
Annals of General Psychiatry     Open Access   (Followers: 22, SJR: 0.727, h-index: 32)
Annals of Occupational and Environmental Medicine     Open Access   (Followers: 9)
Annals of Surgical Innovation and Research     Open Access   (Followers: 3, SJR: 0.429, h-index: 10)
Antimicrobial Resistance and Infection Control     Open Access   (Followers: 8, SJR: 1.096, h-index: 12)
Archives of Physiotherapy     Open Access   (Followers: 12)
Archives of Public Health     Open Access   (Followers: 11, SJR: 0.974, h-index: 11)
Arthritis Research & Therapy     Open Access   (Followers: 13, SJR: 1.617, h-index: 111)
Asia Pacific Family Medicine     Open Access   (Followers: 1, SJR: 0.227, h-index: 6)
Asthma Research and Practice     Open Access   (Followers: 1)
Basic and Clinical Andrology     Open Access   (SJR: 0.195, h-index: 7)
Behavioral and Brain Functions     Open Access   (Followers: 3, SJR: 0.989, h-index: 42)
Big Data Analytics     Open Access   (Followers: 25)
BioData Mining     Open Access   (Followers: 4, SJR: 1.331, h-index: 13)
Bioelectronic Medicine     Open Access  
Biological Procedures Online     Open Access   (SJR: 0.664, h-index: 31)
Biological Research     Open Access   (SJR: 0.629, h-index: 41)
Biology Direct     Open Access   (Followers: 7, SJR: 3.341, h-index: 45)
Biology of Mood & Anxiety Disorders     Open Access   (Followers: 5, SJR: 0.974, h-index: 4)
Biology of Sex Differences     Open Access   (Followers: 2, SJR: 2.25, h-index: 18)
Biomarker Research     Open Access   (Followers: 2)
Biomaterials Research     Open Access   (Followers: 4)
BioMedical Engineering OnLine     Open Access   (Followers: 7, SJR: 0.531, h-index: 44)
BioPsychoSocial Medicine     Open Access   (Followers: 7, SJR: 0.638, h-index: 20)
Biotechnology for Biofuels     Open Access   (Followers: 10, SJR: 2.557, h-index: 47)
BMC Anesthesiology     Open Access   (Followers: 17, SJR: 0.655, h-index: 23)
BMC Biochemistry     Open Access   (Followers: 14, SJR: 0.792, h-index: 38)
BMC Bioinformatics     Open Access   (Followers: 137, SJR: 1.722, h-index: 144)
BMC Biology     Open Access   (Followers: 60, SJR: 3.871, h-index: 71)
BMC Biophysics     Open Access   (Followers: 3, SJR: 0.309, h-index: 9)
BMC Biotechnology     Open Access   (Followers: 16, SJR: 0.914, h-index: 54)
BMC Cancer     Open Access   (Followers: 27, SJR: 1.627, h-index: 84)
BMC Cardiovascular Disorders     Open Access   (Followers: 21, SJR: 1.023, h-index: 37)
BMC Cell Biology     Open Access   (Followers: 46, SJR: 1.486, h-index: 48)
BMC Clinical Pathology     Open Access   (Followers: 7, SJR: 0.753, h-index: 24)
BMC Complementary and Alternative Medicine     Open Access   (Followers: 14, SJR: 0.783, h-index: 53)
BMC Dermatology     Open Access   (Followers: 13, SJR: 0.854, h-index: 27)
BMC Developmental Biology     Open Access   (Followers: 13, SJR: 1.38, h-index: 55)
BMC Ear, Nose and Throat Disorders     Open Access   (Followers: 1, SJR: 0.636, h-index: 15)
BMC Ecology     Open Access   (Followers: 20, SJR: 1.433, h-index: 27)
BMC Emergency Medicine     Open Access   (Followers: 18, SJR: 0.679, h-index: 22)
BMC Endocrine Disorders     Open Access   (Followers: 8, SJR: 0.733, h-index: 25)
BMC Evolutionary Biology     Open Access   (Followers: 72, SJR: 2.053, h-index: 83)
BMC Family Practice     Open Access   (Followers: 13, SJR: 0.978, h-index: 42)
BMC Gastroenterology     Open Access   (Followers: 15, SJR: 0.999, h-index: 50)
BMC Genetics     Open Access   (Followers: 25, SJR: 1.185, h-index: 51)
BMC Genomics     Open Access   (Followers: 85, SJR: 2.343, h-index: 108)
BMC Geriatrics     Open Access   (Followers: 14, SJR: 1.025, h-index: 41)
BMC Health Services Research     Open Access   (Followers: 15, SJR: 1.128, h-index: 64)
BMC Hematology     Open Access   (Followers: 3)
BMC Immunology     Open Access   (Followers: 10, SJR: 1.087, h-index: 38)
BMC Infectious Diseases     Open Access   (Followers: 17, SJR: 1.51, h-index: 66)
BMC Intl. Health and Human Rights     Open Access   (Followers: 6, SJR: 0.878, h-index: 26)
BMC Medical Education     Open Access   (Followers: 42, SJR: 0.698, h-index: 38)
BMC Medical Ethics     Open Access   (Followers: 21, SJR: 0.859, h-index: 26)
BMC Medical Genetics     Open Access   (Followers: 7, SJR: 1.062, h-index: 52)
BMC Medical Genomics     Open Access   (Followers: 4, SJR: 1.71, h-index: 37)
BMC Medical Imaging     Open Access   (Followers: 8, SJR: 0.651, h-index: 22)
BMC Medical Informatics and Decision Making     Open Access   (Followers: 23, SJR: 1.1, h-index: 44)
BMC Medical Physics     Open Access   (Followers: 6, SJR: 0.564, h-index: 13)
BMC Medical Research Methodology     Open Access   (Followers: 9, SJR: 1.788, h-index: 67)
BMC Medicine     Open Access   (Followers: 13, SJR: 3.415, h-index: 72)
BMC Microbiology     Open Access   (Followers: 12, SJR: 1.391, h-index: 74)
BMC Molecular Biology     Open Access   (Followers: 142, SJR: 1.224, h-index: 53)
BMC Musculoskeletal Disorders     Open Access   (Followers: 20, SJR: 0.881, h-index: 61)
BMC Nephrology     Open Access   (Followers: 9, SJR: 1.113, h-index: 29)
BMC Neurology     Open Access   (Followers: 22, SJR: 1.07, h-index: 45)
BMC Neuroscience     Open Access   (Followers: 16, SJR: 1.318, h-index: 70)
BMC Nursing     Open Access   (Followers: 22, SJR: 0.561, h-index: 20)
BMC Nutrition     Open Access   (Followers: 8)
BMC Obesity     Open Access   (Followers: 6)
BMC Ophthalmology     Open Access   (Followers: 15, SJR: 0.938, h-index: 29)
BMC Oral Health     Open Access   (Followers: 6, SJR: 0.616, h-index: 28)
BMC Palliative Care     Open Access   (Followers: 26, SJR: 1.003, h-index: 25)
BMC Pediatrics     Open Access   (Followers: 17, SJR: 1.097, h-index: 47)
BMC Pharmacology     Open Access   (Followers: 2, SJR: 0.739, h-index: 30)
BMC Pharmacology & Toxicology     Open Access   (Followers: 6, SJR: 0.792, h-index: 10)
BMC Physiology     Open Access   (Followers: 4, SJR: 0.996, h-index: 30)
BMC Plant Biology     Open Access   (Followers: 13, SJR: 1.945, h-index: 71)
BMC Pregnancy and Childbirth     Open Access   (Followers: 21, SJR: 1.397, h-index: 45)
BMC Proceedings     Full-text available via subscription   (Followers: 1, SJR: 0.445, h-index: 9)
BMC Psychiatry     Open Access   (Followers: 27, SJR: 1.307, h-index: 57)
BMC Psychology     Open Access   (Followers: 17)
BMC Public Health     Open Access   (Followers: 147, SJR: 1.372, h-index: 81)
BMC Pulmonary Medicine     Open Access   (Followers: 4, SJR: 1.011, h-index: 38)
BMC Research Notes     Open Access   (Followers: 4, SJR: 0.702, h-index: 38)
BMC Rheumatology     Open Access  
BMC Sports Science, Medicine and Rehabilitation     Open Access   (Followers: 27, SJR: 0.471, h-index: 7)
BMC Structural Biology     Open Access   (Followers: 8, SJR: 1.118, h-index: 42)
BMC Surgery     Open Access   (Followers: 9, SJR: 0.675, h-index: 31)
BMC Systems Biology     Open Access   (Followers: 12, SJR: 1.493, h-index: 52)
BMC Urology     Open Access   (Followers: 13, SJR: 0.719, h-index: 27)
BMC Veterinary Research     Open Access   (Followers: 16, SJR: 0.952, h-index: 31)
BMC Women's Health     Open Access   (Followers: 11, SJR: 0.746, h-index: 30)
BMC Zoology     Open Access  
Borderline Personality Disorder and Emotion Dysregulation     Open Access   (Followers: 10)
Breast Cancer Research     Open Access   (Followers: 17, SJR: 3.133, h-index: 107)
Burns & Trauma     Open Access   (Followers: 2)
Burns & Trauma     Open Access   (Followers: 10)
Cancer & Metabolism     Open Access   (Followers: 6)
Cancer Cell Intl.     Open Access   (Followers: 6, SJR: 1.05, h-index: 33)
Cancer Imaging     Open Access   (Followers: 2, SJR: 0.67, h-index: 30)
Cancers of the Head & Neck     Open Access   (Followers: 1)
Canine Genetics and Epidemiology     Open Access   (Followers: 1)
Cardio-Oncology     Open Access  
Cardiovascular Diabetology     Open Access   (Followers: 9, SJR: 1.757, h-index: 47)
Cardiovascular Ultrasound     Open Access   (Followers: 4, SJR: 0.65, h-index: 31)
Cell Communication and Signaling     Open Access   (Followers: 2, SJR: 1.86, h-index: 37)
Cell Division     Open Access   (Followers: 1, SJR: 2.011, h-index: 32)
Cellular & Molecular Biology Letters     Hybrid Journal   (Followers: 3)
Cerebellum & Ataxias     Open Access   (Followers: 1)
Child and Adolescent Psychiatry and Mental Health     Open Access   (Followers: 21, SJR: 1.25, h-index: 25)
Chinese Medicine     Open Access   (Followers: 2, SJR: 0.655, h-index: 24)
Chinese Neurosurgical J.     Open Access  
Chiropractic & Manual Therapies     Open Access   (Followers: 5, SJR: 0.575, h-index: 19)
Cilia     Open Access   (SJR: 3.69, h-index: 12)
Clinical and Molecular Allergy     Open Access   (Followers: 5, SJR: 0.871, h-index: 24)
Clinical and Translational Allergy     Open Access   (Followers: 2, SJR: 0.119, h-index: 2)
Clinical Diabetes and Endocrinology     Open Access   (Followers: 18)
Clinical Hypertension     Open Access   (Followers: 4)
Clinical Sarcoma Research     Open Access  
Conflict and Health     Open Access   (Followers: 7, SJR: 0.831, h-index: 12)
Contraception and Reproductive Medicine     Open Access  
COPD Research and Practice     Open Access  
Cost Effectiveness and Resource Allocation     Open Access   (Followers: 4, SJR: 0.767, h-index: 26)
Critical Care     Open Access   (Followers: 56, SJR: 2.002, h-index: 112)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Diabetology & Metabolic Syndrome     Open Access   (Followers: 7, SJR: 0.834, h-index: 23)
Diagnostic and Prognostic Research     Open Access  
Diagnostic Pathology     Open Access   (Followers: 7, SJR: 0.775, h-index: 29)
Disaster and Military Medicine     Open Access   (Followers: 4)
Emerging Themes in Epidemiology     Open Access   (Followers: 13, SJR: 1.172, h-index: 24)
Environmental Health     Open Access   (Followers: 11, SJR: 1.898, h-index: 51)
Environmental Health and Preventive Medicine     Open Access   (Followers: 3, SJR: 0.608, h-index: 24)
Epigenetics & Chromatin     Open Access   (Followers: 8, SJR: 4.614, h-index: 26)
European J. of Medical Research     Open Access   (Followers: 1, SJR: 0.592, h-index: 46)
European Review of Aging and Physical Activity     Open Access   (Followers: 8, SJR: 0.597, h-index: 14)
Experimental & Translational Stroke Medicine     Open Access   (Followers: 8, SJR: 0.644, h-index: 13)
Experimental Hematology & Oncology     Open Access   (Followers: 3)
Eye and Vision     Open Access   (Followers: 1)
Fertility Research and Practice     Open Access   (Followers: 2)
Fibrogenesis & Tissue Repair     Open Access   (SJR: 2.496, h-index: 27)
Fisheries and Aquatic Sciences     Open Access   (Followers: 2, SJR: 0.223, h-index: 8)
Flavour     Open Access   (Followers: 3)
Fluids and Barriers of the CNS     Open Access   (Followers: 2, SJR: 2.034, h-index: 29)
Frontiers in Zoology     Open Access   (Followers: 5, SJR: 1.866, h-index: 37)
Genes and Environment     Open Access   (Followers: 1, SJR: 0.161, h-index: 5)
Genetics Selection Evolution     Open Access   (Followers: 7, SJR: 1.341, h-index: 55)
Genome Biology     Open Access   (Followers: 31, SJR: 9.86, h-index: 168)
Genome Medicine     Open Access   (Followers: 5, SJR: 2.915, h-index: 40)
Global Health Research and Policy     Open Access   (Followers: 4)
Globalization and Health     Open Access   (Followers: 5, SJR: 1.261, h-index: 29)
Gut Pathogens     Full-text available via subscription   (Followers: 5, SJR: 1.136, h-index: 18)
Gynecologic Oncology Research and Practice     Open Access   (Followers: 1)
Harm Reduction J.     Open Access   (SJR: 1.239, h-index: 31)
Head & Face Medicine     Open Access   (Followers: 1, SJR: 0.416, h-index: 22)
Health and Quality of Life Outcomes     Open Access   (Followers: 14, SJR: 1.02, h-index: 75)
Health Research Policy and Systems     Open Access   (Followers: 13, SJR: 1.032, h-index: 28)
Hereditary Cancer in Clinical Practice     Open Access   (SJR: 0.678, h-index: 14)
Hereditas     Open Access   (Followers: 1, SJR: 0.423, h-index: 40)
Human Genomics     Open Access   (Followers: 2, SJR: 1.632, h-index: 35)
Human Resources for Health     Open Access   (Followers: 9, SJR: 1.193, h-index: 38)
Immunity & Ageing     Open Access   (Followers: 10, SJR: 1.178, h-index: 28)
Implementation Science     Open Access   (Followers: 17, SJR: 2.259, h-index: 53)
Infectious Agents and Cancer     Open Access   (SJR: 1.085, h-index: 21)
Infectious Diseases of Poverty     Open Access   (Followers: 1, SJR: 0.977, h-index: 12)
Inflammation and Regeneration     Open Access   (Followers: 1)
Intl. Breastfeeding J.     Open Access   (Followers: 22, SJR: 0.934, h-index: 23)
Intl. J. for Equity in Health     Open Access   (Followers: 6, SJR: 1.316, h-index: 31)
Intl. J. of Behavioral Nutrition and Physical Activity     Open Access   (Followers: 24, SJR: 2.216, h-index: 64)
Intl. J. of Health Geographics     Open Access   (Followers: 6, SJR: 1.216, h-index: 48)
Intl. J. of Mental Health Systems     Open Access   (Followers: 7, SJR: 0.484, h-index: 18)
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: 0.98, h-index: 13)
Irish Veterinary J.     Open Access   (Followers: 5, SJR: 0.477, h-index: 17)
Israel J. of Health Policy Research     Open Access   (SJR: 0.379, h-index: 7)
Italian J. of Pediatrics     Open Access   (Followers: 1, SJR: 0.685, h-index: 20)
J. for ImmunoTherapy of Cancer     Open Access   (Followers: 5)
J. of Angiogenesis Research     Open Access   (Followers: 2)
J. of Animal Science and Biotechnology     Open Access   (Followers: 4, SJR: 0.87, h-index: 10)
J. of Animal Science and Technology     Open Access   (Followers: 2)
J. of Biological Engineering     Open Access   (Followers: 3, SJR: 1.104, h-index: 22)
J. of Biological Research - Thessaloniki     Open Access   (SJR: 0.273, h-index: 10)
J. of Biomedical Semantics     Open Access   (Followers: 2, SJR: 0.903, h-index: 18)
J. of Cardiothoracic Surgery     Open Access   (Followers: 4, SJR: 0.622, h-index: 26)
J. of Cardiovascular Magnetic Resonance     Open Access   (Followers: 1, SJR: 3.238, h-index: 58)
J. of Clinical Movement Disorders     Open Access   (Followers: 3)
J. of Congenital Cardiology     Open Access   (Followers: 4)
J. of Diabetes and Metabolic Disorders     Open Access   (Followers: 8, SJR: 0.693, h-index: 9)

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Journal Cover Journal of Experimental & Clinical Cancer Research
  [SJR: 1.702]   [H-I: 51]   [2 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Print) 0392-9078 - ISSN (Online) 1756-9966
   Published by Biomed Central Ltd. Homepage  [295 journals]
  • MiR-760 suppresses human colorectal cancer growth by targeting
           BATF3/AP-1/cyclinD1 signaling

    • Abstract: Background Recent studies have reported that microRNAs (miRNAs) often function as negative post-transcriptional regulators with altered expression levels found in colorectal cancer (CRC). There have been few studies on miRNAs that regulate the oncogenic alterations in CRC. Here, we aim to explore the anti-cancer miRNA and the potential mechanisms by which miRNAs modulate CRC progression. Methods We performed an integrated analysis of CRC miRNA expression datasets in The Cancer Genome Atlas (TCGA). The miRNA with the lowest expression, miR-760, was validated in an independent validation sample cohort of 76 CRC tissues. Functional assays, such as CCK-8 assay, colony formation assay, and CFSE staining, were used to determine the oncogenic role of miR-760 in human CRC progression. Furthermore, western blotting and dual-luciferase reporter assay were used to determine the mechanism by which miR-760 promotes proliferation of CRC cells. Xenograft nude mouse models were used to determine the role of miR-760 in CRC tumorigenicity in vivo. Immunohistochemical assays were conducted to study the relationship between miR-760 expression and basic leucine zipper transcriptional factor ATF-like 3 (BATF3) expression in human CRC samples. Results miR-760 was markedly downregulated in CRC tissues, and low miR-760 expression was associated with poor prognosis among CRC patients. Upregulation of miR-760 suppressed CRC cell proliferation, whereas downregulation of miR-760 promoted CRC proliferation in vitro. Additionally, we identified BATF3 as a direct target of miR-760, and that the essential biological function of miR-760 during CRC progression both in vitro and in vivo is to suppress the expression of BATF3 and downstream cyclinD1 via AP-1 transcription factor. Finally, we showed a significant correlation between miR-760 and BATF3 expression in CRC tissues. Conclusions miR-760 inhibited CRC growth by downregulating BATF3/AP-1/ cyclinD1 signaling.
      PubDate: 2018-04-16
  • The phospholipase DDHD1 as a new target in colorectal cancer therapy

    • Abstract: Background Our previous study demonstrates that Citrus-limon derived nanovesicles are able to decrease colon cancer cell viability, and that this effect is associated with the downregulation of the intracellular phospholipase DDHD domain-containing protein 1 (DDHD1). While few studies are currently available on the contribution of DDHD1 in neurological disorders, there is no information on its role in cancer. This study investigates the role of DDHD1 in colon cancer. Methods DDHD1 siRNAs and an overexpression vector were transfected into colorectal cancer and normal cells to downregulate or upregulate DDHD1 expression. In vitro and in vivo assays were performed to investigate the functional role of DDHD1 in colorectal cancer cell growth. Quantitative proteomics using SWATH-MS was performed to determinate the molecular effects induced by DDHD1 silencing in colorectal cancer cells. Results The results indicate that DDHD1 supports colon cancer cell proliferation and survival, since its downregulation reduces in vitro colon cancer cell viability and increases apoptosis rate, without affecting normal cells. On the contrary, in vivo studies demonstrate that the xenograft tumors, derived from DDHD1-overexpressing cells, have a higher proliferation rate compared to control animals. Additionally, we found that functional categories, significantly affected by DDHD1 silencing, were specifically related to cancer phenotype and for the first time associated to DDHD1 activity. Conclusions In conclusion, this study provides the first evidence confirming the role of DDHD1 in cancer, providing a possibility to define a new target to design more effective therapies for colon cancer patients.
      PubDate: 2018-04-13
  • SP1-induced upregulation of lncRNA SPRY4-IT1 exerts oncogenic properties
           by scaffolding EZH2/LSD1/DNMT1 and sponging miR-101-3p in

    • Abstract: Background Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) behave as a novel class of transcription products during multiple cancer processes. However, the mechanisms responsible for their alteration in cholangiocarcinoma (CCA) are not fully understood. Methods The expression of SPRY4-IT1 in CCA tissues and cell lines was determined by RT-qPCR, and the association between SPRY4-IT1 transcription and clinicopathologic features was analyzed. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to explore whether SP1 could bind to the promoter region of SPRY4-IT1 and activate its transcription. The biological function of SPRY4-IT1 in CCA cells was evaluated both in vitro and in vivo. ChIP, RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were performed to determine the molecular mechanism of SPRY4-IT1 in cell proliferation, apoptosis and invasion. Results SPRY4-IT1 was abnormally upregulated in CCA tissues and cells, and this upregulation was correlated with tumor stage and tumor node metastasis (TNM) stage in CCA patients. SPRY4-IT1 overexpression was also an unfavorable prognostic factor for patients with CCA. Additionally, SP1 could bind directly to the SPRY4-IT1 promoter region and activate its transcription. Furthermore, SPRY4-IT1 silencing caused tumor suppressive effects via reducing cell proliferation, migration and invasion; inducing cell apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) process in CCA cells. Mechanistically, enhancer of zeste homolog 2 (EZH2) along with the lysine specific demethylase 1 (LSD1) or DNA methyltransferase 1 (DNMT1) were recruited by SPRY4-IT1, which functioned as a scaffold. Importantly, SPRY4-IT1 positively regulated the expression of EZH2 through sponging miR-101-3p. Conclusions Our data illustrate how SPRY4-IT1 plays an oncogenic role in CCA and may offer a potential therapeutic target for treating CCA.
      PubDate: 2018-04-11
  • Iron-dependent cell death as executioner of cancer stem cells

    • Abstract: This commentary highlights the findings by Mai, et al. that ironomycin, derivatives of salinomycin, exhibited more potent and selective therapeutic activity against breast cancer stem cells by accumulating and sequestering iron in lysosome, followed by an iron-mediated lysosomal production of reactive oxygen species and an iron-dependent cell death. These unprecedented findings identified iron homeostasis and iron-mediated processes as potentially druggable in the context of cancer stem cells.
      PubDate: 2018-04-10
  • GDF15 promotes the proliferation of cervical cancer cells by
           phosphorylating AKT1 and Erk1/2 through the receptor ErbB2

    • Abstract: Background Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. However, the function of GDF15 in cervical cancer has not yet been reported. Methods Immunohistochemistry was used to detect GDF15 expression in normal cervix and in different cervical cancer lesions. Cell growth curves, MTT, tumor formation assays and flow cytometry were utilized to observe the effects of ectopic GDF15 expression on the proliferation and cell cycle of cervical cancer cells. Real-time PCR, western blotting and immunoprecipitation assays were conducted to measure the expression of genes related to the cell cycle and the PI3K/AKT and MAPK/ERK signaling pathways. A chromatin immunoprecipitation assay was performed to confirm whether C-myc bound to a specific region of the GDF15 promoter. Inhibitor treatment and immunoprecipitation assays were employed to identify the association between GDF15 and ErbB2. Results GDF15 expression gradually increased during the progression of cervical carcinogenesis. GDF15 promoted cervical cancer cell proliferation via exogenous rhGDF15 treatment or the use of gene editing technology in vitro and in vivo and significantly accelerated the cell cycle transition from G0/G1 to S phase. The expression of p-ErbB2, p-AKT1, p-Erk1/2, CyclinD1 and CyclinE1 was up-regulated and the expression of p21 was down-regulated in GDF15-overexpressing and rhGDF15-treated cervical cancer cells. C-myc trans-activated GDF15 expression by binding to the E-box motifs in the promoter of GDF15 and contributed to the positive feedback of GDF15/C-myc/GDF15. Furthermore, GDF15 bound to ErbB2 in a protein complex in cervical cancer cells. Conclusions Our data demonstrated that GDF15 promoted the proliferation of cervical cancer cells via the up-regulation of CyclinD1 and CyclinE1 and the down-regulation of p21 through both the PI3K/AKT and MAPK/ERK signaling pathways in a complex with ErbB2.
      PubDate: 2018-04-10
  • Alternative splicing of human telomerase reverse transcriptase in gliomas
           and its modulation mediated by CX-5461

    • Abstract: Background Glioma is a heterogeneous, invasive primary brain tumor with a wide range of patient survival and a lack of reliable prognostic biomarkers. Human telomerase reverse transcriptase (hTERT) has been reported in the presence of multiple transcripts in various tumor systems. The biological function and precise regulatory mechanisms of hTERT transcripts remain uncertain. Methods Alternative splicing of hTERT and telomerase activity were examined in 96 glioma specimens, including 38 glioblastomas (GBMs), 23 oligodendrogliomas (ODMs), and 35 oligoastrocytomas (OAMs). The correlation between telomerase activity or hTERT transcripts and patient clinical characteristics was investigated. We examined the regulation of alternative splicing of hTERT and telomerase activity by G-quadruplex stabilizer CX-5461 in GBM cells. The biological effects of CX-5461 on GBM cell lines, including inhibition of cell proliferation, effects on cell cycle/apoptosis, and telomere DNA damage were further explored. Results The β splicing was verified in human gliomas and hTERT+β was significantly correlated with higher telomerase activity, higher KPS, larger tumor size, and higher tumor grades. Meanwhile, glioma patients lacking hTERT+β expression or telomerase activity showed a significant survival benefit. Notably, CX-5461 altered hTERT splicing patterns, leading to an increase of hTERT-β transcript and a decrease of hTERT+β transcript expression, which inhibits telomerase activity. In addition, CX-5461 had cytotoxic effects on GBM cells and caused telomere DNA damage response, induced G2/M arrest and apoptosis. Conclusions The hTERT+β is verified to be correlated with clinical parameters in gliomas, and could serve as a prognostic marker or possibly therapeutic target for gliomas. CX-5461 can regulate the splicing pattern of hTERT, inhibit telomerase activity, and kill GBM cells.
      PubDate: 2018-04-10
  • Lipid accumulation in human breast cancer cells injured by iron depletors

    • Abstract: Background Current insights into the effects of iron deficiency in tumour cells are not commensurate with the importance of iron in cell metabolism. Studies have predominantly focused on the effects of oxygen or glucose scarcity in tumour cells, while attributing insufficient emphasis to the inadequate supply of iron in hypoxic regions. Cellular responses to iron deficiency and hypoxia are interlinked and may strongly affect tumour metabolism. Methods We examined the morphological, proteomic, and metabolic effects induced by two iron chelators—deferoxamine (DFO) and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT)—on MDA-MB-231 and MDA-MB-157 breast cancer cells. Results These chelators induced a cytoplasmic massive vacuolation and accumulation of lipid droplets (LDs), eventually followed by implosive, non-autophagic, and non-apoptotic death similar to methuosis. Vacuoles and LDs are generated by expansion of the endoplasmic reticulum (ER) based on extracellular fluid import, which includes unsaturated fatty acids that accumulate in LDs. Typical physiological phenomena associated with hypoxia are observed, such as inhibition of translation, mitochondrial dysfunction, and metabolic remodelling. These survival-oriented changes are associated with a greater expression of epithelial/mesenchymal transcription markers. Conclusions Iron starvation induces a hypoxia-like program able to scavenge nutrients from the extracellular environment, and cells assume a hypertrophic phenotype. Such survival strategy is accompanied by the ER-dependent massive cytoplasmic vacuolization, mitochondrial dysfunctions, and LD accumulation and then evolves into cell death. LDs containing a greater proportion of unsaturated lipids are released as a consequence of cell death. The consequence of the disruption of iron metabolism in tumour tissue and the effects of LDs on intercellular communication, cancer–inflammation axis, and immunity remain to be explored. Considering the potential benefits, these are crucial subjects for future mechanistic and clinical studies.
      PubDate: 2018-04-03
  • Mature and progenitor endothelial cells perform angiogenesis also under
           protease inhibition: the amoeboid angiogenesis

    • Abstract: Background Controlling vascular growth is a challenging aim for the inhibition of tumor growth and metastasis. The amoeboid and mesenchymal types of invasiveness are two modes of migration interchangeable in cancer cells: the Rac-dependent mesenchymal migration requires the activity of proteases; the Rho-ROCK-dependent amoeboid motility is protease-independent and has never been described in endothelial cells. Methods A cocktail of physiologic inhibitors (Ph-C) of serine-proteases, metallo-proteases and cysteine-proteases, mimicking the physiological environment that cells encounter during their migration within the angiogenesis sites was used to induce amoeboid style migration of Endothelial colony forming cells (ECFCs) and mature endothelial cells (ECs). To evaluate the mesenchymal-ameboid transition RhoA and Rac1 activation assays were performed along with immunofluorescence analysis of proteins involved in cytoskeleton organization. Cell invasion was studied in Boyden chambers and Matrigel plug assay for the in vivo angiogenesis. Results In the present study we showed in both ECFCs and ECs, a decrease of activated Rac1 and an increase of activated RhoA upon shifting of cells to the amoeboid conditions. In presence of Ph-C inhibitors both cell lines acquired a round morphology and Matrigel invasion was greatly enhanced with respect to that observed in the absence of protease inhibition. We also observed that the urokinase-plasminogen-activator (uPAR) receptor silencing and uPAR-integrin uncoupling with the M25 peptide abolished both mesenchymal and amoeboid angiogenesis of ECFCs and ECs in vitro and in vivo, indicating a role of the uPAR-integrin-actin axis in the regulation of amoeboid angiogenesis. Furthermore, under amoeboid conditions endothelial cells seem to be indifferent to VEGF stimulation, which induces an amoeboid signaling pattern also in mesenchymal conditions. Conclusion Here we first provide a data set disclosing that endothelial cells can move and differentiate into vascular structures in vitro and in vivo also in the absence of proteases activity, performing a new type of neovascularization: the “amoeboid angiogenesis”. uPAR is indispensable for ECs and ECFCs to perform an efficient amoeboid angiogenesis. Therefore, uPAR silencing or the block of its integrin-interaction, together with standard treatment against VEGF, could be a possible solution for angiogenesis inhibition.
      PubDate: 2018-04-03
  • Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling
           and accelerates pancreatic carcinoma metastasis

    • Abstract: Background Dying cells after irradiation could promote the repopulation of surviving cancer cells leading to tumor recurrence. We aim to define the role of dying cells in promoting pancreatic cancer cells metastasis following radiotherapy. Methods Using the transwell system as the in vitro co-culture model, a small number of untreated pancreatic cancer cells were seeded in the upper chamber, while a larger number of lethally treated pancreatic cancer cells were seeded in the lower chamber. A series of experiments were conducted to investigate the role of dying-cell-derived HMGB1 on the invasion of pancreatic cancer in vitro and cancer metastasis in vivo. We then designed shRNA knockdown and Western blot assays to detect signaling activity. Results We found that dying pancreatic cancer cells significantly promote the invasion of pancreatic cancer cells in vitro and cancer metastasis in vivo. HMGB1 gene knockdown attenuated the migration-stimulating effect of irradiated, dying cells on living pancreatic cancer cells. Finally, we showed that dying-cell-derived HMGB1 functions in a paracrine manner to affect cancer-cell migration dependent on acquiring an epithelial-mesenchymal transition (EMT) phenotype and PI3K/pAkt activation. This process is mediated by the receptor for TLR2. Conclusion Our study indicates that, during radiotherapy, dying pancreatic cancer cells activate paracrine signaling events that promote the mobility of surviving tumor cells. We suggest a strategy to inhibit HMGB1 for preventing pancreatic carcinoma relapse and metastasis.
      PubDate: 2018-04-03
  • MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic
           ductal adenocarcinoma

    • Abstract: Background By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear. Methods The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated. Results We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC. Conclusion Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.
      PubDate: 2018-04-03
  • SGK1 inhibition-induced autophagy impairs prostate cancer metastasis by
           reversing EMT

    • Abstract: Background Despite SGK1 has been identified and characterized as a tumor-promoting gene, the functions and underlying mechanisms of SGK1 involved in metastasis regulation have not yet been investigated in cancer. Methods We investigated the cellular responses to GSK650394 treatment and SGK1 silencing (or overexpression) in human prostate cancer (PCa) cell lines and PC3 xenografts by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry. Results In the present study, we found that SGK1 expression positively correlates with human prostate cancer (PCa) progression and metastasis. We show that SGK1 inhibition significantly attenuates EMT and metastasis both in vitro and in vivo, whereas overexpression of SGK1 dramaticlly promoted the invasion and migration of PCa cells. Our further results suggest that SGK1 inhibition induced antimetastatic effects, at least partially via autophagy-mediated repression of EMT through the downregulation of Snail. Moreover, ectopic expression of SGK1 obviously attenuated the GSK650394-induced autophagy and antimetastatic effects. What’s more, dual inhibition of mTOR and SGK1 enhances autophagy and leads to synergistic antimetastatic effects on PCa cells. Conclusions Taken together, this study unveils a novel mechanism in which SGK1 functions as a tumor metastasis-promoting gene and highlights how co-targeting SGK1 and autophagy restrains cancer progression due to the amplified antimetastatic effects.
      PubDate: 2018-04-02
  • 5′/ 3′ imbalance strategy to detect ALK fusion genes in circulating
           tumor RNA from patients with non-small cell lung cancer

    • Abstract: Background Detecting an ALK fusion gene in patients with non-small cell lung cancer (NSCLC) could provide evidence to guide individualized therapy. Methods The 5′/3′ imbalance strategy for quantitative reverse transcription-PCR (RT-qPCR) was developed to detect ALK fusion genes in circulating tumor RNA (ctRNA) of NSCLC patients. Results This method was validated in patients with the ALK fusion gene confirmed by next generation sequencing (NGS). The amount of the ALK fusion gene detected by the new method ranged from 33.2 to 987.4, (mean 315.2), in the patients confirmed to have the ALK fusion gene (+). This is much higher than the amount of fusion gene detected in the patients who are negative for the ALK fusion gene (−). The amount detected in the ALK fusion gene (−) samples ranged from 0.36 to 13.04, (mean 4.58). In 188 NSCLC patients, the specificity and sensitivity of the method was compared to that of the FISH method. About 10.64% of the patients showed higher ALK fusion gene expression, and were classified as ALK fusion gene (+). This is identical to the percentage of patients detected by the FISH method to be ALK fusion gene (+). The cutoff value for diagnosis of ALK fusion (+) is 32.9 as determined by this method. Conclusions A new RT-PCR method using a 5′/3′ imbalance strategy was developed, with high specificity and sensitivity, for detection of the ALK fusion gene in ctRNA of NSCLC patients. This method can rapidly detect ALK fusion genes in patients, which will be helpful for guiding targeted therapy, particularly the individualized usage of TKIs in these patients.
      PubDate: 2018-03-27
  • The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the
           combination with PI3K/AKT/mTOR inhibitors through impairment of glucose
           metabolism in TNBC cells

    • Abstract: Background Cell cycle regulators have gain attention as potential targets for anticancer therapy. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which coordinate the G1-S transition. Palbociclib is currently approved for the treatment of hormone receptor positive, HER2-negative advanced breast cancer (BC) in association with letrozole or fulvestrant. In contrast, its efficacy in triple negative BC (TNBC), either alone or in combined therapies, has not been fully investigated to date. Methods Here we evaluated the potential of combining palbociclib with PI3K/mTOR inhibitors in Rb-proficient TNBC cells comparing different schedules of treatment: simultaneous, sequential, or sequential combined treatment (pre-incubation with palbociclib followed by exposure to both palbociclib and PI3K/mTOR inhibitors). We assessed the effects on cell proliferation, cell death, and cell cycle distribution, and looked at the impact of such treatments on glucose metabolism. Results Palbociclib exerted cytostatic effects in Rb-positive TNBC cells, inducing a reversible blockade in G0/G1 cell cycle phase associated with down-regulation of CDK6, Rb, and c-myc expression and/or activity. Palbociclib treatment induced AKT signaling, providing a rationale for its combination with PI3K/mTOR inhibitors. The simultaneous or sequential treatment resulted in an additive inhibition of cell proliferation. On the other hand, the sequential combined treatment in which palbociclib was maintained also during exposure to PI3K/mTOR inhibitors gave rise to synergistic anti-proliferative and pro-apoptotic effects, by inhibiting both CDK4/6/Rb/myc and PI3K/mTOR signaling. Interestingly, the inhibition of the Rb/E2F/myc axis mediated by palbociclib resulted in a significant down-regulation of glucose metabolism; most importantly, these inhibitory effects were enhanced by the combination of palbociclib with BYL719 (specific inhibitor of the p110α PI3K-subunit), which promoted a stronger inhibition of GLUT-1 glucose transporter expression, glucose uptake and consumption in comparison with individual treatments, under both normoxic and hypoxic conditions. Conclusions Combination of palbociclib with PI3K/mTOR inhibitors may represent a promising therapeutic option for the treatment of Rb-proficient TNBC, with the sequential combined schedule showing a superior efficacy over the other schedules. In addition our results demonstrate that the impairment of glucose metabolism may contribute to the anti-tumor activity of such drug combinations.
      PubDate: 2018-03-27
  • Inflammatory interferon activates HIF-1α-mediated
           epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway

    • Abstract: Background Tumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pathways of individual TME are extensively studied, evidence showing interaction and crosstalk between hypoxia and inflammation remain unclear. Thus, we examined whether interferon (IFN) could modulate both inflammatory and hypoxic responses under normoxia and its relation with cancer development. Methods IFN was used to induce inflammation response and HIF-1α expression in various cancer cell lines. Corresponding signaling pathways were then analyzed by a combination of pharmacological inhibitors, immunoblotting, GST-Raf pull-down assays, dominant-negative and short-hairpin RNA-mediated knockdown approaches. Specifically, roles of functional HIF-1α in the IFN-induced epithelial-mesenchymal transition (EMT) and other tumorigenic propensities were examined by knockdown, pharmacological inhibition, luciferase reporter, clonogenic, anchorage-independent growth, wound-healing, vasculogenic mimicry, invasion and sphere-formation assays as well as cellular morphology observation. Results We showed for the first time that IFN induced functional HIF-1α expression in a time- and dose- dependent manner in various cancer cell lines under both hypoxic and normoxic conditions, and then leading to an activated HIF-1α pathway in an IFN-mediated pro-inflammatory TME. IFN regulates anti-apoptosis activity, cellular metastasis, EMT and vasculogenic mimicry by a novel mechanism through mainly the activation of PI3K/AKT/mTOR axis. Subsequently, pharmacological and genetic modulations of HIF-1α, JAK, PI3K/AKT/mTOR or p38 pathways efficiently abrogate above IFN-induced tumorigenic propensities. Moreover, HIF-1α is required for the IFN-induced invasiveness, tumorigenesis and vasculogenic mimicry. Further supports for the HIF-1α-dependent tumorigenesis were obtained from results of xenograft mouse model and sphere-formation assay. Conclusions Our mechanistic study showed an induction of HIF-1α and EMT ability in an IFN-mediated inflammatory TME and thus demonstrating a novel interaction between inflammatory and hypoxic TMEs. Moreover, targeting HIF-1α may be a potential target for inhibiting tumor tumorigenesis and EMT by decreasing cancer cells wound healing and anchorage-independent colony growth. Our results also lead to rationale guidance for developing new therapeutic strategies to prevent relapse via targeting TME-providing IFN signaling and HIF-1α programming.
      PubDate: 2018-03-27
  • Treatment of B-cell precursor acute lymphoblastic leukemia with the
           Galectin-1 inhibitor PTX008

    • Abstract: Background Drug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studies showed that Galectin-3, a lectin that clusters galactose-modified glycoproteins and that has both an intracellular and extracellular location, protects different subtypes of BP-ALL cells against chemotherapy. Galectin-1 is related to Galectin-3 and its expression was previously reported to be restricted to the MLL subtype of BP-ALL. Methods and results Here, we report that Galectin-1 is expressed at different levels in and on different subclasses of BP-ALLs. Bone marrow plasma also contains high levels of Galectin-1. PTX008 is an allosteric inhibitor which inhibits Galectin-1 but not Galectin-3-mediated agglutination. The compound reduces migration of BP-ALL cells to CXCL12 and OP9 stromal cells and inhibits fibronectin-mediated adhesion. It also affects cell cycle progression of BCP-ALL cells. PTX008 is cytostatic for BP-ALL cells even when these are co-cultured with protective stroma, and can sensitize ALL cells to vincristine chemotherapy in vitro and in mice. Conclusions PTX008 inhibits multiple functions that contribute to BP-ALL survival. The effects of Galectin-1 inhibition on both BP-ALL cell proliferation and migration suggest both the leukemia cells as well as the microenvironment that protects these cells may be targeted.
      PubDate: 2018-03-27
  • Inhibiting YAP expression suppresses pancreatic cancer progression by
           disrupting tumor-stromal interactions

    • Abstract: Background Hippo/YAP pathway is known to be important for development, growth and organogenesis, and dysregulation of this pathway leads to tumor progression. We and others find that YAP is up-regulated in pancreatic ductal adenocarcinoma (PDAC) and associated with worse prognosis of patients. Activated pancreatic stellate cells (PSCs) forming the components of microenvironment that enhance pancreatic cancer cells (PCs) invasiveness and malignance. However, the role and mechanism of YAP in PDAC tumor-stromal interaction is largely unknown. Methods The expression of YAP in Pancreatic cancer cell lines and PDAC samples was examined by Western blot and IHC. The biological role of YAP on cancer cell proliferation, epithelial-mesenchymal transition (EMT) and invasion were evaluated by MTT, Quantitative real-time PCR analysis, Western blot analysis and invasion assay. The effect of YAP on PSC activation was evaluated by PC-PSC co-culture conditions and xenograft PDAC mouse model. Results Firstly, knockdown of YAP inhibits PDAC cell proliferation and invasion in vitro. In addition, YAP modulates the PC and PSC interaction via reducing the production of connective tissue growth factor (CTGF) from PCs, inhibits paracrine-mediated PSC activation under PC-PSC co-culture conditions and in turn disrupts TGF-β1-mediated tumor-stromal interactions. Lastly, inhibiting YAP expression prevents tumor growth and suppresses desmoplastic reaction in vivo. Conclusions These results demonstrate that YAP contributes to the proliferation and invasion of PC and the activation of PSC via tumor-stromal interactions and that targeting YAP may be a promising therapeutic strategy for PDAC treatment.
      PubDate: 2018-03-27
  • miR-148b-3p inhibits gastric cancer metastasis by inhibiting the
           Dock6/Rac1/Cdc42 axis

    • Abstract: Background Our previous work showed that some Rho GTPases, including Rho, Rac1 and Cdc42, play critical roles in gastric cancer (GC); however, how they are regulated in GC remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of Dock6, an atypical Rho guanine nucleotide exchange factor (GEF), in GC metastasis. Methods The expression levels of Dock6 and miR-148b-3p in GC tissues and paired nontumor tissues were determined by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. The correlation between Dock6/miR-148b-3p expression and the overall survival of GC patients was calculated by the Kaplan-Meier method and log-rank test. The roles of Dock6 and miR-148b-3p in GC were investigated by in vitro and in vivo functional studies. Rac1 and Cdc42 activation was investigated by GST pull-down assays. The inhibition of Dock6 transcription by miR-148b-3p was determined by luciferase reporter assays. Results A significant increase in Dock6 expression was found in GC tissues compared with nontumor tissues, and its positive expression was associated with lymph node metastasis and a higher TNM stage. Patients with positive Dock6 expression exhibited shorter overall survival periods than patients with negative Dock6 expression. Dock6 promoted GC migration and invasion by increasing the activation of Rac1 and Cdc42. miR-148b-3p expression was negatively correlated with Dock6 expression in GC, and it decreased the motility of GC cells by inhibiting the Dock6/Rac1/Cdc42 axis. Conclusions Dock6 was over-expressed in GC tissues, and its positive expression was associated with GC metastasis and indicated poor prognosis of GC patients. Targeting of Dock6 by miR-148b-3p could activate Rac1 and Cdc42, directly affecting the motility of GC cells. Targeting the Dock6-Rac1/Cdc42 axis could serve as a new therapeutic strategy for GC treatment.
      PubDate: 2018-03-27
  • Growth differentiation factor 15 contributes to marrow adipocyte
           remodeling in response to the growth of leukemic cells

    • Abstract: Background The adipocyte remodeling, including of the morphological change, might indicate special pathological function. Our previous study found that the morphological remodeling of larger marrow adipocytes into small marrow adipocytes correlates with a poor prognosis for acute myeloid leukemia (AML) patients. However, the mechanisms contributed to the marrow adipocyte remodeling are still poorly understood. Methods GDF15 expression was analyzed by RT-qPCR and western blotting assays in the leukemic cells. The enhancing and antibody neutralization tests in vitro were employed to evaluate the effect of GDF15 on the morphology of mature adipocytes. CCK8 test was used to detect the proliferation of leukemic cells after co-cultivation with small marrow adipocytes. Flow cytometry was used to analysis the proportion of cell cycle of leukemic cells. Immunofluorescence staining and linear analysis were applied to verify the GDF15 expression and the relationship between GDF15 and small marrow adipocytes in AML patients. Results In this study, we found that leukemic cell lines not only expressed significantly higher growth differentiation factor 15 (GDF15) than the other three cytokines associated with adipocyte differentiation in RNA level but also secreted GDF15 factor. Furthermore, the in vitro experiments demonstrated that GDF15 was involved in the conversion of small marrow adipocytes from larger marrow adipocytes. Correspondingly, the leukemic cells proliferated more rapidly through regulating the cell cycle when co-cultured with GDF15-induced small marrow adipocytes. The immunofluorescence staining on the bone marrow sections of AML patients further exhibited that GDF15 was partly produced by leukemic cells. The positive correlation between the concentration of GDF15 in the marrow aspirates and the number and the volume of small marrow adipocytes might suggest the contribution of GDF15 in AML patients (r = 0.72, r = 0.67). Conclusions GDF15 secreted by leukemic cells was involved in the morphological remodeling of marrow adipocytes, which can in turn promote leukemic cell growth, indicating that GDF15 may be a promising treatment target for AML patients.
      PubDate: 2018-03-22
  • PHD-finger domain protein 5A functions as a novel oncoprotein in lung

    • Abstract: Background PHD-finger domain protein 5A (PHF5A) is a highly conserved small transcriptional regulator also involved in pre-mRNA splicing; however, its biological functions and molecular mechanisms in non-small cell lung cancer (NSCLC) have not yet been investigated. The purpose of this study was to determine the functional relevance and therapeutic potential of PHF5A in lung adenocarcinoma (LAC). Methods The expression of PHF5A in LAC tissues and adjacent non-tumor (ANT) tissues was investigated using immunohistochemistry of a tissue microarray, qRT-PCR, western blot and bioinformatics. The function of PHF5A was determined using several in vitro assays and also in vivo assay by lentiviral vector-mediated PHF5A depletion in LAC cell lines. Results PHF5A was highly upregulated in LAC tissues compared with the ANT counterparts, and closely associated with tumor progression and poor patient prognosis. These results were further confirmed by findings of the TCGA database. Moreover, functional studies demonstrated that PHF5A knockdown not only resulted in reduced cell proliferation, increased cell apoptosis, and cell cycle arrest, but also suppressed migration and invasion in LAC cells. PHF5A silencing was also found to inhibit LAC tumor growth in nude mice. Microarray and bioinformatics analyses revealed that PHF5A depletion led to dysregulation of multiple tumor signaling pathways; selected factors in key signaling pathways were verified in vitro. Conclusions The data suggest for the first time that PHF5A is an oncoprotein that contributes to LAC progression by regulating multiple signaling pathways, and may constitute a prognostic factor and potential new therapeutic target in NSCLC.
      PubDate: 2018-03-22
  • Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma
           by targeting the AMPK/mTORC1 and mTORC2 pathways

    • Abstract: Background Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-tumor effects in many cancers, including multiple myeloma (MM); however, the underlying molecular mechanisms have not been clearly elucidated. Methods The anti-myeloma effects of metformin were evaluated using human MM cell lines (RPMI8226 and U266) in vitro and in vivo NOD-SCID murine xenograft MM model. Cell viability was assessed with CCK8 and cell proliferation was measured by EdU incorporation assay. Cell cycle distribution and apoptosis were examined by flow cytometry. Transmission electron microscopy was used to visualized autophagosomes. Activation of AMPK and inhibition of mTORC1/C2 pathways was assessed by Western blot analysis. RPMI8226 cells and U266 cell lines with AMPK knockdown were generated by transfection with small interfering RNA targeting the AMPK-α1 and α2 subunits using Lipofectamine 2000 reagent. Results Metformin effectively inhibited the proliferation of MM cell lines, an effect that was associated with the induction of autophagy and G0/G1 cell cycle arrest, but not apoptosis. Metformin activated AMPK and repressed both mTORC1 and mTORC2 signaling pathways in myeloma cells as well as downstream molecular signaling pathways, such as p-4EBP1 and p-AKT. AMPK activation resulted in direct phosphorylation and activation of tuberous sclerosis complex 2 (TSC2), leading to inhibition of the mammalian target of rapamycin (mTOR). In addition, metformin inhibited myeloma cell growth in an AMPK-dependent manner. The xenograft mouse model further confirmed that metformin inhibited tumor growth by upregulation of AMPK and downregulation of mTOR. Conclusions Metformin inhibits the proliferation of myeloma cells by inducing autophagy and cell-cycle arrest. Our results suggest that the molecular mechanism involves dual repression of mTORC1 and mTORC2 pathways via AMPK activation. Our study provides a theoretical basis for the development of novel strategies for the treatment of MM using metformin as an already approved and safe drug.
      PubDate: 2018-03-20
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