Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway

Zhang, Wenyi; Pan, Rulu; Lu, Mei; Zhang, Qian; Lin, Ziqi; Qin, Yuan; Wang, Zhanyu; Gong, Siqing; Lin, Huan; Chong, Shuyi; Lu, Lijuan; Liao, Wanqin; Lu, Xincheng

doi:10.1038/s41388-021-02029-4

Cited by 14 publications

(8 citation statements)

References 52 publications

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“…Previous review displays that expression of LCN2 in CAC is variable (34). Some in vitro and in vivo studies in the literature support the role of LCN2 as a tumor promoter (35), but the difference is that in most of the current studies, LCN2 is generally considered to be a protective factor in CRC (36)(37)(38). LCN2 expression was significantly lower in metastatic or advancedstage CRC than that in non-metastatic or early-stage CRC (39).…”

Section: Discussionmentioning

confidence: 94%

LCN2 as a Potential Diagnostic Biomarker for Ulcerative Colitis-Associated Carcinogenesis Related to Disease Duration

et al. 2022

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BackgroundPatients with long-duration ulcerative colitis (UC) had a higher risk of developing ulcerative colitis-associated carcinogenesis (UCAC) when compared to those with short-duration UC. This study aimed to discover the biomarker for cancer surveillance related to disease duration.MethodsThe microarrays were divided into short-duration (<10 years) UC, long-duration (≥10 years) UC, UCAC, and normal groups in the Gene Expression Omnibus (GEO) datasets. Differentially expressed genes (DEGs) of GEO and the hub genes of the selected weighted gene co-expression network analysis (WGCNA) were intersected to obtain the overlapping genes. Among these genes, the key gene was identified by using the protein–protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the cytoHubba of Cytoscape, and the expression levels. Also, immunofluorescence of human colonic mucosa and animal experiment were used to validate the expression trend of the key gene in the progress of UC developing into UCAC.ResultsLipocalin-2 (LCN2) was more relevant with disease duration of UC and significantly negatively correlated with the risk of UCAC. The expression level of LCN2 in short-duration UC was higher than that of long-duration UC (P < 0.01), long-duration UC was higher than that of UCAC (P = 0.001), and UC and UCAC were all higher than that of the normal (P < 0.001). We then discovered that the expression trend of LCN2 in blood and stool samples was consistent with that in colorectal mucosa.ConclusionThe research indicates that LCN2 could be a novel biomarker to evaluate cancer surveillance related to disease duration of developing UC into UCAC. Compared with that of blood samples, stool detection of LCN2 may have more advantages for diagnosis value of early stage of UCAC as a complement to colonoscopy surveillance.

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Section: Discussionmentioning

confidence: 94%

LCN2 as a Potential Diagnostic Biomarker for Ulcerative Colitis-Associated Carcinogenesis Related to Disease Duration

et al. 2022

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“…For the CCL-138-R cells, a total of four genes/proteins were upregulated, and three were downregulated, compared with parental cells ( Figure 2 B). Following a review of the literature, a reduced number of genes with a potential involvement in HNSCC tumours were finally selected for study through the TCGA database [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. The number of genes was reduced to the following: prostate stem cell antigen ( PSCA ), member of the RAS oncogene family ( RAB7A ), TNF alpha induced protein 2 ( TNFAIP2 ), glycoprotein nmb ( GPNMB ), niban apoptosis regulator 2 ( NIBAN2 ), structure specific recognition protein 1 ( SSRP1 ), aldo-keto reductase family 1 member C3 ( AKR1C3 ), lipocalin 2 ( LCN2 ), sperm associated antigen 9 ( SPAG9 ), galectin 3 binding protein ( LGALS3BP ) and eukaryotic translation elongation factor 1 alpha 2 ( EEF1A2 ) ( Figure 2 C).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma

García-Mayea

Benítez-Álvarez

Sánchez-García

et al. 2022

Cancers

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To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 downregulated genes for CCL-138-R cells. Moreover, we crossed-checked the RNA-seq results with the proteomic profiles of HTB-43-R (versus HTB-43) and CCL-138-R (versus CCL-138) cell lines. For the HTB-43-R cells, 21 upregulated and 72 downregulated targets overlapped between the proteomic and transcriptomic data; whereas in CCL-138-R cells, four upregulated and three downregulated targets matched. Following an extensive literature search, six genes from the RNA-seq (CLDN1, MAGEB2, CD24, CEACAM6, IL1B and ISG15) and six genes from the RNA-seq and proteomics crossover (AKR1C3, TNFAIP2, RAB7A, LGALS3BP, PSCA and SSRP1) were selected to be studied by qRT-PCR in 11 HNSCC patients: six resistant and five sensitive to conventional therapy. Interestingly, the high MAGEB2 expression was associated with resistant tumours and is revealed as a novel target to sensitise resistant cells to therapy in HNSCC patients.

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“…In this context, DNA methylation represents the main regulation mechanism able to reprogram the expression pattern of key genes involved in carcinogenic processes. Several studies have demonstrated that DNA methylation is involved in aberrant expression of the LCN2 , SLC22A17 , and MMP9 genes in various tumors ( Cui et al, 2008 ; Falzone et al, 2016a ; Zhang et al, 2021 ). However, the DNA methylation regulation of LCN2 and SLC22A17 has not been sufficiently investigated in cancer.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment

Candido

Tomasello

Lavoro

et al. 2022

Front. Cell Dev. Biol.

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Several features of cancer cells such as proliferation, invasion, metastatic spreading, and drug resistance are affected by their interaction with several tumor microenvironment (TME) components, including neutrophil gelatinase-associated lipocalin (NGAL), solute carrier family 22 member 17 (SLC22A17), and matrix metallopeptidase 9 (MMP9). These molecules play a key role in tumor growth, invasion, and iron-dependent metabolism of cancer cells. However, the precise epigenetic mechanisms underlying the gene regulation of Lipocalin 2 (LCN2), SLC22A17, and MMP9 in cancer still remain unclear. To this purpose, computational analysis was performed on TCGA and GTEx datasets to evaluate the expression and DNA methylation status of LCN2, SLC22A17, and MMP9 genes in different tumor types. Correlation analysis between gene/isoforms expression and DNA methylation levels of LCN2, SLC22A17, and MMP9 was performed to investigate the role of DNA methylation in the modulation of these genes. Protein network analysis was carried out using reverse phase protein arrays (RPPA) data to identify protein–protein interactions of the LCN2–SLC22A17–MMP9 network. Furthermore, survival analysis was performed according to gene expression and DNA methylation levels. Our results demonstrated that LCN2 and MMP9 were mainly upregulated in most tumor types, whereas SLC22A17 was largely downregulated, representing a specific hallmark signature for all gastrointestinal tumors. Notably, the expression of LCN2, SLC22A17, and MMP9 genes was negatively affected by promoter methylation. Conversely, intragenic hypermethylation was associated with the overexpression of SLC22A17 and MMP9 genes. Protein network analysis highlighted the role of the LCN2–SLC22A17–MMP9 network in TME by the interaction with fibronectin 1 and claudin 7, especially in rectal tumors. Moreover, the impact of expression and methylation status of LCN2, SLC22A17, and MMP9 on overall survival and progression free interval was tumor type–dependent. Overall, our analyses provide a detailed overview of the expression and methylation status of LCN2, SLC22A17, and MMP9 in all TCGA tumors, indicating that the LCN2–SLC22A17–MMP9 network was strictly regulated by DNA methylation within TME. Our findings pave the way for the identification of novel DNA methylation hotspots with diagnostic and prognostic values and suitable for epi-drug targeting.

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Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway

Cited by 14 publications

References 52 publications

LCN2 as a Potential Diagnostic Biomarker for Ulcerative Colitis-Associated Carcinogenesis Related to Disease Duration

LCN2 as a Potential Diagnostic Biomarker for Ulcerative Colitis-Associated Carcinogenesis Related to Disease Duration

Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma

Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment

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