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Int. J. Mol. Sci., Volume 18, Issue 2 (February 2017)

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Cover Story (view full-size image) Five missense point mutations occurring near the nucleotide-binding pocket are associated with [...] Read more.
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Open AccessArticle Next-Generation Sequencing Approach in Methylation Analysis of HNF1B and GATA4 Genes: Searching for Biomarkers in Ovarian Cancer
Int. J. Mol. Sci. 2017, 18(2), 474; https://doi.org/10.3390/ijms18020474
Received: 3 February 2017 / Revised: 14 February 2017 / Accepted: 16 February 2017 / Published: 22 February 2017
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Abstract
DNA methylation is well-known to be associated with ovarian cancer (OC) and has great potential to serve as a biomarker in monitoring response to therapy and for disease screening. The purpose of this study was to investigate methylation of HNF1B and GATA4 and
[...] Read more.
DNA methylation is well-known to be associated with ovarian cancer (OC) and has great potential to serve as a biomarker in monitoring response to therapy and for disease screening. The purpose of this study was to investigate methylation of HNF1B and GATA4 and correlate detected methylation with clinicopathological characteristic of OC patients. The study group consisted of 64 patients with OC and 35 control patients. To determine the most important sites of HNF1B and GATA4, we used next-generation sequencing. For further confirmation of detected methylation of selected regions, we used high-resolution melting analysis and methylation-specific real-time polymerase chain reaction (PCR). Selected regions of HNF1B and GATA4 were completely methylation free in all control samples, whereas methylation-positive pattern was observed in 32.8% (HNF1B) and 45.3% (GATA4) of OC samples. Evaluating both genes together, we were able to detect methylation in 65.6% of OC patients. We observed a statistically significant difference in HNF1B methylation between samples with different stages of OC. We also detected subtype specific methylation in GATA4 and a decrease of methylation in late stages of OC. The combination of unmethylated HNF1B and methylated GATA4 was associated with longer overall survival. In our study, we employed innovative approach of methylation analysis of HNF1B and GATA4 to search for possible epigenetic biomarkers. We confirmed the significance of the HNF1B and GATA4 hypermethylation with emphasis on the need of selecting the most relevant sites for analysis. We suggest selected CpGs to be further examined as a potential positive prognostic factor. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Open AccessReview Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer
Int. J. Mol. Sci. 2017, 18(2), 473; https://doi.org/10.3390/ijms18020473
Received: 16 January 2017 / Revised: 9 February 2017 / Accepted: 16 February 2017 / Published: 22 February 2017
Cited by 8 | PDF Full-text (496 KB) | HTML Full-text | XML Full-text
Abstract
The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs
[...] Read more.
The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread. Full article
(This article belongs to the collection Regulation by Non-Coding RNAs)
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Open AccessReview The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype
Int. J. Mol. Sci. 2017, 18(2), 472; https://doi.org/10.3390/ijms18020472
Received: 24 October 2016 / Revised: 2 February 2017 / Accepted: 13 February 2017 / Published: 22 February 2017
Cited by 4 | PDF Full-text (1064 KB) | HTML Full-text | XML Full-text
Abstract
With the exception of a few Mendelian traits, almost all phenotypes (traits) in livestock science are quantitative or complex traits regulated by the expression of many genes. For most of the complex traits, differential expression of genes, rather than genomic variation in the
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With the exception of a few Mendelian traits, almost all phenotypes (traits) in livestock science are quantitative or complex traits regulated by the expression of many genes. For most of the complex traits, differential expression of genes, rather than genomic variation in the gene coding sequences, is associated with the genotype of a trait. The expression profiles of the animal’s transcriptome, proteome and metabolome represent endophenotypes that influence/regulate the externally-observed phenotype. These expression profiles are generated by interactions between the animal’s genome and its environment that range from the cellular, up to the husbandry environment. Thus, understanding complex traits requires knowledge about not only genomic variation, but also environmental effects that affect genome expression. Gene products act together in physiological pathways and interaction networks (of pathways). Due to the lack of annotation of the functional genome and ontologies of genes, our knowledge about the various biological systems that contribute to the development of external phenotypes is sparse. Furthermore, interaction with the animals’ microbiome, especially in the gut, greatly influences the external phenotype. We conclude that a detailed understanding of complex traits requires not only understanding of variation in the genome, but also its expression at all functional levels. Full article
(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map to Explain Complex Traits)
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Open AccessArticle Gomisin N Inhibits Melanogenesis through Regulating the PI3K/Akt and MAPK/ERK Signaling Pathways in Melanocytes
Int. J. Mol. Sci. 2017, 18(2), 471; https://doi.org/10.3390/ijms18020471
Received: 20 December 2016 / Revised: 9 February 2017 / Accepted: 13 February 2017 / Published: 22 February 2017
Cited by 3 | PDF Full-text (3145 KB) | HTML Full-text | XML Full-text
Abstract
Gomisin N, one of the lignan compounds found in Schisandra chinensis has been shown to possess anti-oxidative, anti-tumorigenic, and anti-inflammatory activities in various studies. Here we report, for the first time, the anti-melenogenic efficacy of Gomisin N in mammalian cells as well as
[...] Read more.
Gomisin N, one of the lignan compounds found in Schisandra chinensis has been shown to possess anti-oxidative, anti-tumorigenic, and anti-inflammatory activities in various studies. Here we report, for the first time, the anti-melenogenic efficacy of Gomisin N in mammalian cells as well as in zebrafish embryos. Gomisin N significantly reduced the melanin content without cellular toxicity. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, Gomisin N downregulated the expression levels of key proteins that function in melanogenesis. Gomisin N downregulated melanocortin 1 receptor (MC1R), adenylyl cyclase 2, microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). In addition, Gomisin N-treated Melan-A cells exhibited increased p-Akt and p-ERK levels, which implies that the activation of the PI3K/Akt and MAPK/ERK pathways may function to inhibit melanogenesis. We also validated that Gomisin N reduced melanin production by repressing the expression of MITF, tyrosinase, TRP-1, and TRP-2 in mouse and human cells as well as in developing zebrafish embryos. Collectively, we conclude that Gomisin N inhibits melanin synthesis by repressing the expression of MITF and melanogenic enzymes, probably through modulating the PI3K/Akt and MAPK/ERK pathways. Full article
(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)
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Open AccessArticle An Automated Micro-Total Immunoassay System for Measuring Cancer-Associated α2,3-linked Sialyl N-Glycan-Carrying Prostate-Specific Antigen May Improve the Accuracy of Prostate Cancer Diagnosis
Int. J. Mol. Sci. 2017, 18(2), 470; https://doi.org/10.3390/ijms18020470
Received: 1 February 2017 / Revised: 17 February 2017 / Accepted: 18 February 2017 / Published: 22 February 2017
Cited by 2 | PDF Full-text (3652 KB) | HTML Full-text | XML Full-text
Abstract
The low specificity of the prostate-specific antigen (PSA) for early detection of prostate cancer (PCa) is a major issue worldwide. The aim of this study to examine whether the serum PCa-associated α2,3-linked sialyl N-glycan-carrying PSA (S2,3PSA) ratio measured by automated micro-total immunoassay
[...] Read more.
The low specificity of the prostate-specific antigen (PSA) for early detection of prostate cancer (PCa) is a major issue worldwide. The aim of this study to examine whether the serum PCa-associated α2,3-linked sialyl N-glycan-carrying PSA (S2,3PSA) ratio measured by automated micro-total immunoassay systems (μTAS system) can be applied as a diagnostic marker of PCa. The μTAS system can utilize affinity-based separation involving noncovalent interaction between the immunocomplex of S2,3PSA and Maackia amurensis lectin to simultaneously determine concentrations of free PSA and S2,3PSA. To validate quantitative performance, both recombinant S2,3PSA and benign-associated α2,6-linked sialyl N-glycan-carrying PSA (S2,6PSA) purified from culture supernatant of PSA cDNA transiently-transfected Chinese hamster ovary (CHO)-K1 cells were used as standard protein. Between 2007 and 2016, fifty patients with biopsy-proven PCa were pair-matched for age and PSA levels, with the same number of benign prostatic hyperplasia (BPH) patients used to validate the diagnostic performance of serum S2,3PSA ratio. A recombinant S2,3PSA- and S2,6PSA-spiked sample was clearly discriminated by μTAS system. Limit of detection of S2,3PSA was 0.05 ng/mL and coefficient variation was less than 3.1%. The area under the curve (AUC) for detection of PCa for the S2,3PSA ratio (%S2,3PSA) with cutoff value 43.85% (AUC; 0.8340) was much superior to total PSA (AUC; 0.5062) using validation sample set. Although the present results are preliminary, the newly developed μTAS platform for measuring %S2,3PSA can achieve the required assay performance specifications for use in the practical and clinical setting and may improve the accuracy of PCa diagnosis. Additional validation studies are warranted. Full article
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Open AccessReview Potential Modes of Intercellular α-Synuclein Transmission
Int. J. Mol. Sci. 2017, 18(2), 469; https://doi.org/10.3390/ijms18020469
Received: 19 December 2016 / Revised: 1 February 2017 / Accepted: 6 February 2017 / Published: 22 February 2017
Cited by 12 | PDF Full-text (750 KB) | HTML Full-text | XML Full-text
Abstract
Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson’s disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different
[...] Read more.
Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson’s disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of α-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which α-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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Open AccessArticle Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties
Int. J. Mol. Sci. 2017, 18(2), 468; https://doi.org/10.3390/ijms18020468
Received: 24 December 2016 / Revised: 15 February 2017 / Accepted: 17 February 2017 / Published: 22 February 2017
Cited by 4 | PDF Full-text (3970 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS,
[...] Read more.
Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS, although it is still unclear whether this interaction is critical in the regulation of glioblastoma stem cells (GSCs). In this study, we examined whether small interfering RNA-mediated BIS knockdown decreased protein levels of HSF1 and subsequent nuclear localization under GSC-like sphere (SP)-forming conditions. Consistent with BIS depletion, HSF1 knockdown also reduced sex determining region Y (SRY)-box 2 (SOX2) expression, a marker of stemness, accompanying the decrease in SP-forming ability and matrix metalloprotease 2 (MMP2) activity. When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased. Taken together, our findings suggest that targeting BIS or HSF1 could be a viable therapeutic strategy for GSCs resistant to conventional TMZ treatment. Full article
(This article belongs to the Special Issue Cancer Stem Cells)
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Open AccessArticle Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway
Int. J. Mol. Sci. 2017, 18(2), 467; https://doi.org/10.3390/ijms18020467
Received: 2 January 2017 / Revised: 31 January 2017 / Accepted: 10 February 2017 / Published: 22 February 2017
Cited by 1 | PDF Full-text (2660 KB) | HTML Full-text | XML Full-text
Abstract
Panel-based next generation sequencing (NGS) is currently preferred over whole exome sequencing (WES) for diagnosis of familial breast cancer, due to interpretation challenges caused by variants of uncertain clinical significance (VUS). There is also no consensus on the selection criteria for WES. In
[...] Read more.
Panel-based next generation sequencing (NGS) is currently preferred over whole exome sequencing (WES) for diagnosis of familial breast cancer, due to interpretation challenges caused by variants of uncertain clinical significance (VUS). There is also no consensus on the selection criteria for WES. In this study, a pathology-supported genetic testing (PSGT) approach was used to select two BRCA1/2 mutation-negative breast cancer patients from the same family for WES. Homozygosity for the MTHFR 677 C>T mutation detected during this PSGT pre-screen step was considered insufficient to cause bilateral breast cancer in the index case and her daughter diagnosed with early-onset breast cancer (<30 years). Extended genetic testing using WES identified the RAD50 R385C missense mutation in both cases. This rare variant with a minor allele frequency (MAF) of <0.001 was classified as a VUS after exclusion in an affected cousin and extended genotyping in 164 unrelated breast cancer patients and 160 controls. Detection of functional polymorphisms (MAF > 5%) in the folate pathway in all three affected family members is consistent with inheritance of the luminal-type breast cancer in the family. PSGT assisted with the decision to pursue extended genetic testing and facilitated clinical interpretation of WES aimed at reduction of recurrence risk. Full article
(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)
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Open AccessReview The Temporal Pattern, Flux, and Function of Autophagy in Spinal Cord Injury
Int. J. Mol. Sci. 2017, 18(2), 466; https://doi.org/10.3390/ijms18020466
Received: 25 December 2016 / Revised: 16 February 2017 / Accepted: 17 February 2017 / Published: 21 February 2017
Cited by 4 | PDF Full-text (2107 KB) | HTML Full-text | XML Full-text
Abstract
Previous studies have indicated that autophagy plays a critical role in spinal cord injury (SCI), including traumatic spinal cord injury (TSCI) and ischemia-reperfusion spinal cord injury (IRSCI). However, while the understanding of mechanisms underlying autophagy in SCI has progressed, there remain several controversial
[...] Read more.
Previous studies have indicated that autophagy plays a critical role in spinal cord injury (SCI), including traumatic spinal cord injury (TSCI) and ischemia-reperfusion spinal cord injury (IRSCI). However, while the understanding of mechanisms underlying autophagy in SCI has progressed, there remain several controversial points: (1) temporal pattern results of autophagic activation after SCI are not consistent across studies; (2) effect of accumulation of autophagosomes due to the blockade or enhancement of autophagic flux is uncertain; (3) overall effect of enhanced autophagy remains undefined, with both beneficial and detrimental outcomes reported in SCI literature. In this review, the temporal pattern of autophagic activation, autophagic flux, autophagic cell death, relationship between autophagy and apoptosis, and pharmacological intervention of autophagy in TSCI (contusion injury, compression injury and hemisection injury) and IRSCI are discussed. Types of SCI and severity appear to contribute to differences in outcomes regarding temporal pattern, flux, and function of autophagy. With future development of specific strategies on autophagy intervention, autophagy may play an important role in improving functional recovery in patients with SCI. Full article
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment 2016)
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Open AccessArticle The Adverse Effects of Triptolide on the Reproductive System of Caenorhabditis elegans: Oogenesis Impairment and Decreased Oocyte Quality
Int. J. Mol. Sci. 2017, 18(2), 464; https://doi.org/10.3390/ijms18020464
Received: 30 October 2016 / Revised: 1 February 2017 / Accepted: 14 February 2017 / Published: 21 February 2017
Cited by 1 | PDF Full-text (6466 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Previous studies have revealed that Triptolide damages female reproductive capacity, but the mechanism is unclear. In this study, we used Caenorhabditis elegans to investigate the effects of Triptolide on the germline and explore its possible mechanisms. Our data show that exposure for 4
[...] Read more.
Previous studies have revealed that Triptolide damages female reproductive capacity, but the mechanism is unclear. In this study, we used Caenorhabditis elegans to investigate the effects of Triptolide on the germline and explore its possible mechanisms. Our data show that exposure for 4 h to 50 and 100 mg/L Triptolide reduced C. elegans fertility, led to depletion and inactivation of spermatids with the changes in the expression levels of related genes, and increased the number of unfertilized oocytes through damaging chromosomes and DNA damage repair mechanisms. After 24 and 48 h of the 4 h exposure to 50 and 100 mg/L Triptolide, we observed shrink in distal tip cells, an increase in the number of apoptotic cells, a decrease in the number of mitotic germ cells and oocytes in diakinesis stage, and chromatin aggregates in −1 oocytes. Moreover, expression patterns of the genes associated with mitotic germ cell proliferation, apoptosis, and oocyte quality were altered after Triptolide exposure. Therefore, Triptolide may damage fertility of nematodes by hampering the development of oocytes at different developmental stages. Alterations in the expression patterns of genes involved in oocyte development may explain the corresponding changes in oocyte development in nematodes exposed to Triptolide. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Open AccessArticle Cryptomphalus aspersa Mollusc Egg Extract Promotes Regenerative Effects in Human Dermal Papilla Stem Cells
Int. J. Mol. Sci. 2017, 18(2), 463; https://doi.org/10.3390/ijms18020463
Received: 7 December 2016 / Revised: 13 February 2017 / Accepted: 15 February 2017 / Published: 21 February 2017
Cited by 2 | PDF Full-text (7601 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The aim of this study was to test, by an in vitro approach, whether a natural extract derived from eggs of the mollusc Cryptomphalus aspersa (e-CAF) that seems to present regenerative properties, can enhance the mobilization of human hair dermal papilla cells (HHDPCs)
[...] Read more.
The aim of this study was to test, by an in vitro approach, whether a natural extract derived from eggs of the mollusc Cryptomphalus aspersa (e-CAF) that seems to present regenerative properties, can enhance the mobilization of human hair dermal papilla cells (HHDPCs) and play a role on tissue repair and regeneration. We have tested HHDPCs proliferation by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium-bromide (MTT) assay; cell migration by using a wound healing assay, as well as the modulation of the expression of cytoskeletal (F-actin and vimentin) and cell adhesion to the extracellular matrix (ECM) (vinculin and P-FAK) proteins. We also explored whether e-CAF could lead HHDPCs to keratinocytes and/or fibroblasts by evaluating the expression of specific markers. We have compared these e-CAF effects with those induced by TGFβ1, implicated in regulation of cell proliferation and migration. e-CAF promotes proliferation and migration of HDDPCs cells in a time- and dose-dependent manner; it also increases the migratory behavior and the expression of adhesion molecules. These results support the fact that e-CAF could play a role on skin regeneration and be used for the prevention or repair of damaged tissue, either due to external causes or as a result of cutaneous aging. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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Open AccessArticle Caffeic Acid Expands Anti-Tumor Effect of Metformin in Human Metastatic Cervical Carcinoma HTB-34 Cells: Implications of AMPK Activation and Impairment of Fatty Acids De Novo Biosynthesis
Int. J. Mol. Sci. 2017, 18(2), 462; https://doi.org/10.3390/ijms18020462
Received: 23 December 2016 / Revised: 14 February 2017 / Accepted: 16 February 2017 / Published: 21 February 2017
Cited by 7 | PDF Full-text (3404 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The efficacy of cancer treatments is often limited and associated with substantial toxicity. Appropriate combination of drug targeting specific mechanisms may regulate metabolism of tumor cells to reduce cancer cell growth and to improve survival. Therefore, we investigated the effects of anti-diabetic drug
[...] Read more.
The efficacy of cancer treatments is often limited and associated with substantial toxicity. Appropriate combination of drug targeting specific mechanisms may regulate metabolism of tumor cells to reduce cancer cell growth and to improve survival. Therefore, we investigated the effects of anti-diabetic drug Metformin (Met) and a natural compound caffeic acid (trans-3,4-dihydroxycinnamic acid, CA) alone and in combination to treat an aggressive metastatic human cervical HTB-34 (ATCC CRL­1550) cancer cell line. CA at concentration of 100 µM, unlike Met at 10 mM, activated 5'-adenosine monophosphate-activated protein kinase (AMPK). What is more, CA contributed to the fueling of mitochondrial tricarboxylic acids (TCA) cycle with pyruvate by increasing Pyruvate Dehydrogenase Complex (PDH) activity, while Met promoted glucose catabolism to lactate. Met downregulated expression of enzymes of fatty acid de novo synthesis, such as ATP Citrate Lyase (ACLY), Fatty Acid Synthase (FAS), Fatty Acyl-CoA Elongase 6 (ELOVL6), and Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells. In conclusion, CA mediated reprogramming of glucose processing through TCA cycle via oxidative decarboxylation. The increased oxidative stress, as a result of CA treatment, sensitized cancer cells and, acting on cell biosynthesis and bioenergetics, made HTB-34 cells more susceptible to Met and successfully inhibited neoplastic cells. The combination of Metformin and caffeic acid to suppress cervical carcinoma cells by two independent mechanisms may provide a promising approach to cancer treatment. Full article
(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies)
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Open AccessReview Effects and Side Effects of Using Sorafenib and Sunitinib in the Treatment of Metastatic Renal Cell Carcinoma
Int. J. Mol. Sci. 2017, 18(2), 461; https://doi.org/10.3390/ijms18020461
Received: 31 January 2017 / Revised: 13 February 2017 / Accepted: 17 February 2017 / Published: 21 February 2017
Cited by 9 | PDF Full-text (563 KB) | HTML Full-text | XML Full-text
Abstract
In recent years, targeted therapies have proven beneficial in terms of progression-free survival (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC). The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are included in international clinical guidelines as first-line
[...] Read more.
In recent years, targeted therapies have proven beneficial in terms of progression-free survival (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC). The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are included in international clinical guidelines as first-line and second-line therapy in mRCC. Hypertension is an adverse effect of these drugs and the degree of hypertension associates with the anti-tumour effect. Studies have compared newer targeted drugs to sorafenib and sunitinib in terms of PFS, OS, quality of life and safety profiles. Phase III studies presented promising response rates and acceptable safety profiles of axitinib and tivozanib compared to sorafenib, and a phase II study reported greater efficacy using a combination of bevacizumab and IFN-α compared to sunitinib. Treatment with nintedanib exhibited a notably low prevalence of hypertension compared to sunitinib. The use of sorafenib and sunitinib are challenged by new drugs, but do not appear likely to be substituted in the near future. To clarify whether newer targeted drugs should replace sorafenib and sunitinib, more research is needed. This manuscript reviews the current utility and adverse effects of sorafenib and sunitinib and newer targeted therapies in the treatment of mRCC. Full article
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Open AccessArticle Inhibition of CCAR1, a Coactivator of β-Catenin, Suppresses the Proliferation and Migration of Gastric Cancer Cells
Int. J. Mol. Sci. 2017, 18(2), 460; https://doi.org/10.3390/ijms18020460
Received: 27 October 2016 / Revised: 30 January 2017 / Accepted: 15 February 2017 / Published: 21 February 2017
Cited by 4 | PDF Full-text (4006 KB) | HTML Full-text | XML Full-text
Abstract
The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a
[...] Read more.
The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/β-catenin signaling, and which plays an important role in transcriptional regulation by β-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target. Full article
(This article belongs to the collection Programmed Cell Death and Apoptosis)
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Open AccessCommunication Programmed Death Ligand 1 (PD-L1) Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients
Int. J. Mol. Sci. 2017, 18(2), 459; https://doi.org/10.3390/ijms18020459
Received: 28 December 2016 / Revised: 6 February 2017 / Accepted: 15 February 2017 / Published: 21 February 2017
Cited by 13 | PDF Full-text (1603 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Triple Negative Breast Cancers (TNBC) subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1) is a trans-membrane protein expressed on a wide variety of cells including immune cells,
[...] Read more.
Triple Negative Breast Cancers (TNBC) subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1) is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes) PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs), to define its real prognostic value, optimizing immunohistochemistry method with an “approved for diagnostic assay” antibody. PD-L1 expression directly correlated with proliferation index (Ki-67), glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan–Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS) but not correlated with overall survival (OS). Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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