FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism

Zhang, Chunyu; Liao, Yuandong; Liu, Pan; Du, Qiqiao; Liang, Y. Daniel; Ooi, Shiyin; Qin, Shengmei; He, Shanyang; Yao, Shuzhong; Wang, Wei

doi:10.7150/thno.44868

Cited by 113 publications

(100 citation statements)

References 58 publications

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“…For example, the association between

and cervical cancer were documented in Wen et al [ 32 ], whereas

was connected with the respective cervical cancer in Luo et al [ 33 ]. In addition,

and cervical cancer are reported in Liang et al [ 34 ], while

was found to be linked to cervical cancer in Zhang et al [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

A Linear Regression and Deep Learning Approach for Detecting Reliable Genetic Alterations in Cancer Using DNA Methylation and Gene Expression Data

Mallik

Seth

Bhadra

et al. 2020

Genes

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DNA methylation change has been useful for cancer biomarker discovery, classification, and potential treatment development. So far, existing methods use either differentially methylated CpG sites or combined CpG sites, namely differentially methylated regions, that can be mapped to genes. However, such methylation signal mapping has limitations. To address these limitations, in this study, we introduced a combinatorial framework using linear regression, differential expression, deep learning method for accurate biological interpretation of DNA methylation through integrating DNA methylation data and corresponding TCGA gene expression data. We demonstrated it for uterine cervical cancer. First, we pre-filtered outliers from the data set and then determined the predicted gene expression value from the pre-filtered methylation data through linear regression. We identified differentially expressed genes (DEGs) by Empirical Bayes test using Limma. Then we applied a deep learning method, “nnet” to classify the cervical cancer label of those DEGs to determine all classification metrics including accuracy and area under curve (AUC) through 10-fold cross validation. We applied our approach to uterine cervical cancer DNA methylation dataset (NCBI accession ID: GSE30760, 27,578 features covering 63 tumor and 152 matched normal samples). After linear regression and differential expression analysis, we obtained 6287 DEGs with false discovery rate (FDR) <0.001. After performing deep learning analysis, we obtained average classification accuracy 90.69% (±1.97%) of the uterine cervical cancerous labels. This performance is better than that of other peer methods. We performed in-degree and out-degree hub gene network analysis using Cytoscape. We reported five top in-degree genes (PAIP2, GRWD1, VPS4B, CRADD and LLPH) and five top out-degree genes (MRPL35, FAM177A1, STAT4, ASPSCR1 and FABP7). After that, we performed KEGG pathway and Gene Ontology enrichment analysis of DEGs using tool WebGestalt(WEB-based Gene SeT AnaLysis Toolkit). In summary, our proposed framework that integrated linear regression, differential expression, deep learning provides a robust approach to better interpret DNA methylation analysis and gene expression data in disease study.

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“…For example, the association between

and cervical cancer were documented in Wen et al [ 32 ], whereas

was connected with the respective cervical cancer in Luo et al [ 33 ]. In addition,

and cervical cancer are reported in Liang et al [ 34 ], while

was found to be linked to cervical cancer in Zhang et al [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

A Linear Regression and Deep Learning Approach for Detecting Reliable Genetic Alterations in Cancer Using DNA Methylation and Gene Expression Data

Mallik

Seth

Bhadra

et al. 2020

Genes

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“…In addition, sulfasalazine induces ferroptosis in breast cancer cells, and the mechanism may be associated with the increased expression of DMT1 Mrna (71). Furthermore, a number of studies have shown that fatty acid metabolism is essential for maintaining the microenvironment of malignant tumors and participating in the occurrence and development of tumors (72,73). ACSL4 serves a key role in fatty acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Dihydrotanshinone I inhibits human glioma cell proliferation via the activation of ferroptosis

2020

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The aim of the present study was to investigate the effect of dihydrotanshinone I (DHI) on the survival of human glioma cells and the expression levels of ferroptosis-associated proteins. Human U251 and U87 glioma cells were cultured in vitro and treated with different concentrations of DHI and/or the ferroptosis inhibitor ferrostatin-1. A Cell Counting Kit-8 assay was used to determine the cell survival rate. The cells were further analyzed to determine their 5-, 12-and 15-hydroxyeicosatetraenoic acid (HETE), lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, and reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios. Western blotting was used to detect ferroptosis-associated glutathione peroxidase 4 (GPX4) and long-chain acyl-CoA synthetase 4 (ACSL-4). Changes in the mitochondrial membrane potential (MMP) were also observed using tetramethylrhodamine methyl ester staining and confocal fluorescence microscopy. The results revealed that DHI inhibited the proliferation of human glioma cells. Following treatment of the U251 and U87 cells with DHI, changes in the expression levels of ferroptosis-associated proteins were observed; the expression level of GPX4 decreased and that of ACSL-4 increased. DHI also increased the levels of LDH and MDA in the human glioma cells and reduced the GSH/GSSG ratio. The DHI-treated cells also exhibited a marked reduction in MMP. Furthermore, ferrostatin-1 blocked the DHI-induced effects in human glioma cells. From these results, it may be concluded that DHI inhibits the proliferation of human glioma cells via the induction of ferroptosis.

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“…FABPs are key intracellular molecules involved in the uptake, transportation and storage of fatty acids and in the mediation of signal transduction and gene transcription [33]. FABP5 promotes various cancer progression and could be correlated to poor prognosis in a wide range of malignant cancers including cervical cancer, breast cancer, prostate cancer and colorectal cancer, et al [34][35][36][37]. Zhao et al [38] indicates that speci c FABP5 silencing reduces the invasiveness and arrest cell cycle in G0/G1 phase, resulting in a signi cant increase in apoptosis of gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

FABP5 enhances malignancies of lower-grade gliomas via canonical activation of NF-κB signaling

Wang

Alafate

Wang

et al. 2020

Preprint

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Abstract Background Lower-grade gliomas (LGGs) are grade II/III gliomas based on the WHO classification with significant genetic heterogeneity and clinical properties. Traditional histological classification of gliomas has been challenged by the improvement of molecular stratification, however, the reproducibility and diagnostic accuracy of LGGs classification remain poor. Methods In this study, we derived all relevant data of LGGs including TCGA and CGGA databases from official websites. Bioinformatic analyses unveiled the clinical significance of FABP5 and its potential downstream targets. IHC, qRT-PCR and western blot assays were further conducted to validate those bioinformatic findings. Moreover, lentiviral transduction assays were performed to evaluate the function of FABP5 in patient-derived cell lines. Results We identified fatty acid binding protein 5 (FABP5) as one of the most enriched genes in malignant LGGs and elevated FABP5 revealed severe outcomes in LGGs. Functionally, lentiviral suppression of FABP5 reduced malignant characters including proliferation, cloning formation, migration, invasion and TMZ resistance, contrarily, the malignancies of LGGs were enhanced by exogenous overexpression of FABP5. Mechanistically, epithelial-mesenchymal transition (EMT) was correlated to FABP5 expression in LGGs and tumor necrosis factor α (TNFα)-dependent NF-κB signaling was involved in this process. Furthermore, FABP5 induced phosphorylation of inhibitor of nuclear factor kappa-B kinase α (IKKα) thus activated nuclear factor kappa-B (NF-κB) signaling. Conclusion Taken together, our study indicated that FABP5 enhances malignancies of LGGs through canonical activation of NF-κB signaling, which could be used as individualized prognostic biomarker and potential therapeutic target of LGGs.

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FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism

Cited by 113 publications

References 58 publications

A Linear Regression and Deep Learning Approach for Detecting Reliable Genetic Alterations in Cancer Using DNA Methylation and Gene Expression Data

A Linear Regression and Deep Learning Approach for Detecting Reliable Genetic Alterations in Cancer Using DNA Methylation and Gene Expression Data

Dihydrotanshinone I inhibits human glioma cell proliferation via the activation of ferroptosis

FABP5 enhances malignancies of lower-grade gliomas via canonical activation of NF-κB signaling

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