Copper oxide nanoparticles induce anticancer activity in A549 lung cancer cells by inhibition of histone deacetylase

Objectives

Copper oxide nanoparticles (CuO NPs) promoting anticancer activity may be due to the regulation of various classes of histone deacetylases (HDACs).

Results

Green-synthesized CuO NPs significantly arrested total HDAC level and also suppressed class I, II and IV HDACs mRNA expression in A549 cells. A549 cells treated with CuO NPs downregulated oncogenes and upregulated tumor suppressor protein expression. CuO NPs positively regulated both mitochondrial and death receptor-mediated apoptosis caspase cascade pathway in A549 cells.

Conclusion

Green-synthesized CuO NPs inhibited HDAC and therefore shown apoptosis mediated anticancer activity in A549 lung cancer cell line.

     

Metastatic tumor cells – genotypes and phenotypes

Background

Metastasis is the primary cause of mortality in cancer patients. Therefore, elucidating the genetics and epigenetics of metastatic tumor cells and the mechanisms by which tumor cells acquire metastatic properties constitute significant challenges in cancer research.

Objective

To summarize the current understandings of the specific genotype and phenotype of the metastatic tumor cells.

Method and Result

In-depth genetic analysis of tumor cells, especially with advances in the next-generation sequencing, have revealed insights of the genotypes of metastatic tumor cells. Also, studies have shown that the cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) phenotypes are associated with the metastatic cascade.

Conclusion

In this review, we will discuss recent advances in the field by focusing on the genomic instability and phenotypic dynamics of metastatic tumor cells.

     

A systems biology approach to invasive behavior: comparing cancer metastasis and suburban sprawl development

Background

Despite constant progress, cancer remains the second leading cause of death in the United States. The ability of tumors to metastasize is central to this dilemma, as many studies demonstrate successful treatment correlating to diagnosis prior to cancer spread. Hence a better understanding of cancer invasiveness and metastasis could provide critical insight.

Presentation of the hypothesis

We hypothesize that a systems biology-based comparison of cancer invasiveness and suburban sprawl will reveal similarities that are instructive.

Testing the hypothesis

We compare the structure and behavior of invasive cancer to suburban sprawl development. While these two systems differ vastly in dimension, they appear to adhere to scale-invariant laws consistent with invasive behavior in general. We demonstrate that cancer and sprawl have striking similarities in their natural history, initiating factors, patterns of invasion, vessel distribution and even methods of causing death.

Implications of the hypothesis

We propose that metastatic cancer and suburban sprawl provide striking analogs in invasive behavior, to the extent that conclusions from one system could be predictive of behavior in the other. We suggest ways in which this model could be used to advance our understanding of cancer biology and treatment.

     

Upregulation of the solute carrier family 7 genes is indicative of poor prognosis in papillary thyroid carcinoma

Background

The solute carrier (SLC) 7 family genes comprise 14 members and function as cationic amino acid/glycoprotein transporters in many cells, they are essential for the maintenance of amino acid nutrition and survival of tumor cells. This study was conducted to analyze the associations of SLC7 family gene expression with mortality in papillary thyroid carcinoma (PTC).

Methods

Clinical features, somatic mutations, and SLC7 family gene expression data were downloaded from The Cancer Genome Atlas database. Linear regression model analysis was performed to analyze the correlations between SLC7 family gene expression and clinicopathologic features. Kaplan-Meier survival and logistic regression analyses were performed to characterize the associations between gene expression and patients’ overall survival.

Results

Patient mortality was negatively associated with age and tumor size but positively increased cancer stage and absence of thyroiditis in PTC patients. Kaplan-Meier survival analysis indicated that patients with high SLC7A3, SLC7A5, and SLC7A11 expression levels exhibited poorer survival than those with low SLC7A3, SLC7A5, and SLC7A11 expression levels (P?<?0.05 for all cases). Logistic regression analysis showed that SLC7A3, SLC7A5, and SLC7A11 were associated with increased mortality (odds ratio [OR] 8.61, 95% confidence interval [CI] 2.3–55.91; OR 3.87, 95% CI 1.18–17.31; and OR 3.87, 95% CI 1.18–17.31, respectively.

Conclusion

Upregulation of SLC7A3, SLC7A5, and SLC7A11 expression was associated with poor prognosis in PTC patients, and SLC7 gene expression levels are potentially useful prognostic biomarkers.

     

RNA-binding protein Dnd1 inhibits epithelial–mesenchymal transition and cancer stem cell-related traits on hepatocellular carcinoma cells

Objectives

To investigate the roles of Dead end 1 (Dnd1) in modulating cancer stem cell-related traits of hepatocellular carcinoma (HCC).

Results

Dead end (Dnd1) inhibited spheroid formation, suppressed the expression of stemness-related genes, and increased sensitivity to sorafenib in HCC cells. Mechanistically, Dnd1 could bind to 3′-UTR of LATS2, the key kinase of Hippo pathway, thus elevating LATS2 mRNA stability and its expression, subsequently leading to phosphorylation of YAP and its cytoplasmic retention. As a result, epithelial–mesenchymal transition (EMT) was weakened and therefore the generation of HCC stem cell properties was suppressed.

Conclusions

Dnd1 functions as a tumor suppressor by prohibiting CSC-like characteristics via activating Hippo pathway in HCC cells. Dnd1 could thus be a novel therapeutic target for HCC patients.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it

Introduction

Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.

Objectives

(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.

Methods

A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.

Results

Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.

Conclusion

Further efforts are required to improve data sharing in metabolomics.

     

Pseudo current density maps of electrophysiological heart,nerve or brain function and their physical basis

Background

In recent years the visualization of biomagnetic measurement data by so-called pseudo current density maps or Hosaka-Cohen (HC) transformations became popular.

Methods

The physical basis of these intuitive maps is clarified by means of analytically solvable problems.

Results

Examples in magnetocardiography, magnetoencephalography and magnetoneurography demonstrate the usefulness of this method.

Conclusion

Hardware realizations of the HC-transformation and some similar transformations are discussed which could advantageously support cross-platform comparability of biomagnetic measurements.

     

Untargeted metabolomics suffers from incomplete raw data processing

Introduction

Untargeted metabolomics is a powerful tool for biological discoveries. To analyze the complex raw data, significant advances in computational approaches have been made, yet it is not clear how exhaustive and reliable the data analysis results are.

Objectives

Assessment of the quality of raw data processing in untargeted metabolomics.

Methods

Five published untargeted metabolomics studies, were reanalyzed.

Results

Omissions of at least 50 relevant compounds from the original results as well as examples of representative mistakes were reported for each study.

Conclusion

Incomplete raw data processing shows unexplored potential of current and legacy data.

     

Blockade of ARHGAP11A reverses malignant progress via inactivating Rac1B in hepatocellular carcinoma

Background

The molecular signaling events involving in high malignancy and poor prognosis of hepatocellular carcinoma (HCC) are extremely complicated. Blockade of currently known targets has not yet led to successful clinical outcome. More understanding about the regulatory mechanisms in HCC is necessary for developing new effective therapeutic strategies for HCC patients.

Methods

The expression of Rho GTPase-activating protein 11A (ARHGAP11A) was examined in human normal liver and HCC tissues. The correlations between ARHGAP11A expression and clinicopathological stage or prognosis in HCC patients were analyzed. ARHGAP11A was downregulated to determine its role in the proliferation, invasion, migration, epithelial-to-mesenchymal transition (EMT) development, and regulatory signaling of HCC cells in vitro and in vivo.

Results

ARHGAP11A exhibited high expression in HCC, and was significantly correlated with clinicopathological stage and prognosis in HCC patients. Moreover, ARHGAP11A facilitated Hep3B and MHCC97-H cell proliferation, invasion, migration and EMT development in vitro. ARHGAP11A knockdown significantly inhibited the in vivo growth and metastasis of HCC cells. Furthermore, ARHGAP11A directly interacted with Rac1B independent of Rho GTPase- activating activity. Rac1B blockade effectively interrupted ARHGAP11A-elicited HCC malignant phenotype. Meanwhile, upregulation of Rac1B reversed ARHGAP11A knockdown mediated mesenchymal-to-epithelial transition (MET) development in HCC cells.

Conclusion

ARHGAP11A facilitates malignant progression in HCC patients via ARHGAP11A-Rac1B interaction. The ARHGAP11A/Rac1B signaling could be a potential therapeutic target in the clinical treatment of HCC.

     

Chemogeography of the red macroalgae <Emphasis Type="Italic">Asparagopsis</Emphasis>: metabolomics,bioactivity, and relation to invasiveness

Introduction

The Latitudinal Gradient Hypothesis (LGH) foresees that specialized metabolites are overexpressed under low latitudes, where organisms are subjected to higher herbivory pressure. The widespread macroalga Asparagopsis taxiformis is composed of six distinct genetic lineages, some of them being introduced in many regions.

Objectives

To study (i) metabolic fingerprints of the macroalga and (ii) its bioactivity in space and time, both as proxies of its investment in defensive traits, in order to assess links between bioactivities and metabotypes with macroalgal invasiveness.

Methods

289 macroalgal individuals, from four tropical and three temperate regions, were analyzed using untargeted metabolomics and the standardized Microtox® assay.

Results

Metabotypes showed a low divergence between tropical and temperate populations, while bioactivities were higher in temperate populations. However, these phenotypes varied significantly in time, with a higher variability in tropical regions. Bioactivities were high and stable in temperate regions, whereas they were low and much variable in tropical regions. Although the introduced lineage two exhibited the highest bioactivities, this lineage could also present variable proliferation fates.

Conclusion

The metabolomic approach partly discriminates macroalgal populations from various geographic origins. The production of chemical defenses assessed by the bioactivity assay does not match the macroalgal genetic lineage and seems more driven by the environment. The higher content of chemical defenses in temperate versus tropical populations is not in accordance with the LGH and cannot be related to the invasiveness of the macroalgae.

     

PTEN at the interface of immune tolerance and tumor suppression

Background

PTEN is well known to function as a tumor suppressor that antagonizes oncogenic signaling and maintains genomic stability. The PTEN gene is frequently deleted or mutated in human cancers and the wide cancer spectrum associated with PTEN deficiency has been recapitulated in a variety of mouse models of Pten deletion or mutation. Pten mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality.

Objective

To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator.

Methods

This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted.

Results

Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape.

Conclusion

Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells.

     

Untargeted and stable isotope-assisted metabolomic analysis of MDA-MB-231 cells under hypoxia

Introduction

Hypoxia commonly occurs in cancers and is highly related with the occurrence, development and metastasis of cancer. Treatment of triple negative breast cancer remains challenge. Knowledge about the metabolic status of triple negative breast cancer cell lines in hypoxia is valuable for the understanding of molecular mechanisms of this tumor subtype to develop effective therapeutics.

Objectives

Comprehensively characterize the metabolic profiles of triple negative breast cancer cell line MDA-MB-231 in normoxia and hypoxia and the pathways involved in metabolic changes in hypoxia.

Methods

Differences in metabolic profiles affected pathways of MDA-MB-231 cells in normoxia and hypoxia were characterized using GC–MS based untargeted and stable isotope assisted metabolomic techniques.

Results

Thirty-three metabolites were significantly changed in hypoxia and nine pathways were involved. Hypoxia increased glycolysis, inhibited TCA cycle, pentose phosphate pathway and pyruvate carboxylation, while increased glutaminolysis in MDA-MB-231 cells.

Conclusion

The current results provide metabolic differences of MDA-MB-231 cells in normoxia and hypoxia conditions as well as the involved metabolic pathways, demonstrating the power of combined use of untargeted and stable isotope-assisted metabolomic methods in comprehensive metabolomic analysis.

     

Metabolomic profiling of maternal hair suggests rapid development of intrahepatic cholestasis of pregnancy

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a common maternal liver disease; development can result in devastating consequences, including sudden fetal death and stillbirth. Currently, recognition of ICP only occurs following onset of clinical symptoms.

Objective

Investigate the maternal hair metabolome for predictive biomarkers of ICP.

Methods

The maternal hair metabolome (gestational age of sampling between 17 and 41 weeks) of 38 Chinese women with ICP and 46 pregnant controls was analysed using gas chromatography–mass spectrometry.

Results

Of 105 metabolites detected in hair, none were significantly associated with ICP.

Conclusion

Hair samples represent accumulative environmental exposure over time. Samples collected at the onset of ICP did not reveal any metabolic shifts, suggesting rapid development of the disease.

     

Effect of everolimus on the glucose metabolic pathway in mouse skeletal muscle cells (C2C12)

Introduction

Everolimus selectively inhibits mammalian target of rapamycin complex 1 (mTORC1) and exerts an antineoplastic effect. Metabolic disturbance has emerged as a common and unique side effect of everolimus.

Objectives

We used targeted metabolomic analysis to investigate the effects of everolimus on the intracellular glycometabolic pathway.

Methods

Mouse skeletal muscle cells (C2C12) were exposed to everolimus for 48 h, and changes in intracellular metabolites were determined by capillary electrophoresis time-of-flight mass spectrometry. mRNA abundance, protein expression and activity were measured for enzymes involved in glycometabolism and related pathways.

Results

Both extracellular and intracellular glucose levels increased with exposure to everolimus. Most intracellular glycometabolites were decreased by everolimus, including those involved in glycolysis and the pentose phosphate pathway, whereas no changes were observed in the tricarboxylic acid cycle. Everolimus suppressed mRNA expression of enzymes related to glycolysis, downstream of mTOR signaling enzymes and adenosine 5′-monophosphate protein kinases. The activity of key enzymes involved in glycolysis and the pentose phosphate pathway were decreased by everolimus. These results show that everolimus impairs glucose utilization in intracellular metabolism.

Conclusions

The present metabolomic analysis indicates that everolimus impairs glucose metabolism in muscle cells by lowering the activities of glycolysis and the pentose phosphate pathway.

     

Quantitative analysis of tetrahydrofolate metabolites from <Emphasis Type="Italic">clostridium autoethanogenum</Emphasis>

Introduction

Quantification of tetrahydrofolates (THFs), important metabolites in the Wood–Ljungdahl pathway (WLP) of acetogens, is challenging given their sensitivity to oxygen.

Objective

To develop a simple anaerobic protocol to enable reliable THFs quantification from bioreactors.

Methods

Anaerobic cultures were mixed with anaerobic acetonitrile for extraction. Targeted LC–MS/MS was used for quantification.

Results

Tetrahydrofolates can only be quantified if sampled anaerobically. THF levels showed a strong correlation to acetyl-CoA, the end product of the WLP.

Conclusion

Our method is useful for relative quantification of THFs across different growth conditions. Absolute quantification of THFs requires the use of labelled standards.

     

KniMet: a pipeline for the processing of chromatography–mass spectrometry metabolomics data

Introduction

Data processing is one of the biggest problems in metabolomics, given the high number of samples analyzed and the need of multiple software packages for each step of the processing workflow.

Objectives

Merge in the same platform the steps required for metabolomics data processing.

Methods

KniMet is a workflow for the processing of mass spectrometry-metabolomics data based on the KNIME Analytics platform.

Results

The approach includes key steps to follow in metabolomics data processing: feature filtering, missing value imputation, normalization, batch correction and annotation.

Conclusion

KniMet provides the user with a local, modular and customizable workflow for the processing of both GC–MS and LC–MS open profiling data.

     

A methodology for elucidating regulatory mechanisms leading to changes in lipid profiles

Introduction

It is difficult to elucidate the metabolic and regulatory factors causing lipidome perturbations.

Objectives

This work simplifies this process.

Methods

A method has been developed to query an online holistic lipid metabolic network (of 7923 metabolites) to extract the pathways that connect the input list of lipids.

Results

The output enables pathway visualisation and the querying of other databases to identify potential regulators. When used to a study a plasma lipidome dataset of polycystic ovary syndrome, 14 enzymes were identified, of which 3 are linked to ELAVL1—an mRNA stabiliser.

Conclusion

This method provides a simplified approach to identifying potential regulators causing lipid-profile perturbations.

     

Circ_0027599/PHDLA1 suppresses gastric cancer progression by sponging miR-101-3p.1

Background

Pleckstrin homology-like domain family A member 1 (PHLDA1) is a tumor suppressor gene in gastric cancer, but its role regulated by circular RNAs (circRNAs) is not known. CircRNAs are important regulators in cancer growth and progression, however, the molecular roles of circRNAs in gastric cancer are rarely known. The study was aimed to investigate the role of circRNAs in regulating PHLDA1 expression in gastric cancer.

Results

The circRNA expression profile in the gastric cancer tissues by circRNA microarray showed that hsa_circ_0027599 (circ_0027599) was significantly down-regulated in gastric cancer patients and cells when comparing with the controls. Circ_0027599 overexpression suppressed gastric cancer cell proliferation and metastasis. By using bioinformatics tools and luciferase reporter assays, circ_0027599 was verified as a sponge of miR-101-3p.1 (miR-101) and suppressed cancer cell survival and metastasis. It was also verified that PHLDA1 was regulated by circ_0027599 in gastric cancer cells.

Conclusions

The study uncovered that PHLDA1 was regulated by circ_0027599/miR-101, which suppressed gastric cancer survival and metastasis in gastric cancer.