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Abnormal 5-methylcytosine lncRNA methylome is involved in human high-grade serous ovarian cancer.

ABSTRACT: Methylcytosine (m5C) is an important posttranscriptional RNA methylation modification. Studies have reported that aberrant RNA methylation can regulate tumorigenesis and development, indicating the importance of exploring the distribution and biological functions of m5C modification in human high-grade serous ovarian cancer (HGSOC) lncRNAs. In the current study, we identified 2,050 dysregulated m5C peaks, 1,767 of which were significantly upregulated, while 283 were significantly downregulated by performing methylated RNA immunoprecipitation sequencing on 3 pairs of human HGSOC tissues and paired normal tissues. GO enrichment analysis showed that genes altered by the m5C peak played a key role in phylogeny, protein metabolism, and gene mismatch repair. KEGG pathway analysis revealed that these genes were enriched in some important pathways in cancer regulation, such as the PI3K-Akt signalling pathway, transcriptional dysregulation in cancer, and mismatch repair pathways. In addition, through joint analysis of MeRIP-seq and RNA-seq data, we identified 1671 differentially methylated m5C peaks and synchronous differentially expressed genes. These genes play a key role in cell growth or maintenance, RNA metabolism and material transport. We analyzed expression of the m5C modification regulatory gene collagen type IV alpha 3 chain (COL4A3) in 80 HGSOC tissue samples by immunohistochemistry and found that high expression of COL4A3 was significantly correlated with CA125 level (P=0.016), lymph node metastasis (P<0.001), degree of interstitial invasion (P<0.001) and FIGO staging (P<0.001) and indicated a poorer prognosis. Our results revealed the critical role of m5C methylation of lncRNAs in HGSOC, and provided a reference for the prognostic stratification and treatment strategy of HGSOC.

SUBMITTER: Meng L

PROVIDER: S-EPMC8748087 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAccumulating evidence has indicated that methylation status is closely related to tumourigenesis and a few aggressive features of diverse cancers. However, as an important methylation regulation modification, the distribution of 5-methylcytosine (m5C) in high-grade serous ovarian cancer (HGSOC) remains unclear.Materials and methodsWe collected three pairs of human HGSOC tissues and adjacent non-tumour tissues to analyse the transcriptome-wide m5C methylation of messenger RNAs (mRNAs) by methylated RNA immunoprecipitation sequencing. Gene ontology (GO) enrichment analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis were performed to eExplore the potential biological functions of these genes and important cancer pathways. We used immunohistochemistry to analyse the expression of the m5C modification regulatory gene MAP2K3 in 80 HGSOC tissue samples, and their associations with clinical parameters were analyzed using the Spearman-rho test. Univariate and multivariate Cox regression analyses were performed to identify potential prognostic factors. Kaplan-Meier analysis was performed to analyze overall survival.ResultsWe identified 2050 dysregulated m5C peaks, 1767 of which were significantly upregulated, while 283 were significantly downregulated. GO enrichment analysis showed that genes altered by the m5C peak played a key role in system development, transporter complex, and transporter activity. KEGG pathway analysis revealed that these genes were enriched in some important pathways in cancer regulation, such as inflammatory mediator regulation of the TRP channels pathway, Wnt signalling pathway, and focal adhesion pathways. In addition, through joint analysis of MeRIP-seq and RNA-seq data, we identified 125 differentially methylated m5C peaks and synchronous differentially expressed genes. These genes play key roles in cell growth, maintenance, plasma membranes, and cell adhesion molecule activity. Immunohistochemical staining results showed that high expression of MAP2K3 was significantly correlated with CA125 level (p < 0.001), tumour size (p = 0.001), lymph node metastasis (p = 0.008), depth of myometrial invasion (p < 0.001), and FIGO stage (p < 0.001), indicating a poor prognosis.ConclusionOur results reveal the different distribution patterns of m5C in HGSOC and adjacent tissues and the possible involvement of m5C in HGSOC cell functions. Our study provides new insights into the epi-transcriptomic dysregulation of m5C in the tumourigenesis of HGSOC.

Project description:BackgroundPrimary or acquired chemoresistance is a key link in the high mortality rate of ovarian cancer. There is no reliable method to predict chemoresistance in ovarian cancer. We hypothesized that specific methylation characteristics could distinguish chemoresistant and chemosensitive ovarian cancer patients.MethodsIn this study, we used 450 K Infinium Methylation BeadChip to detect the different methylation CpGs between ovarian cancer patients. The differential methylation genes were analyzed by GO and KEGG Pathway bioinformatics analysis. The candidate CpGs were confirmed by pyrosequencing. The expression of abnormal methylation gene was identified by QRT-PCR and IHC. ROC analysis confirmed the ability to predict chemotherapy outcomes. Prognosis was evaluated using Kaplan-Meier.ResultsIn advanced high-grade serous ovarian cancer, 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) remained hypermethylated in chemoresistant patients. The sensitivity, specificity and AUC of 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) methylation to predict chemotherapy sensitivity were 63.60-97.00%, 46.40-89.30% and 0.774-0.846. PFS of 6 candidate genes (ITGB6:cg21105318, cg07896068; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934) hypermethylation patients was significantly shorter. The expression of NCALD and LAMA3 in chemoresistant patients was lower than that of chemosensitive patients. Spearman analysis showed that NCALD and LAMA3 methylations were negatively correlated with their expression.ConclusionsAs a new biomarker of chemotherapy sensitivity, hypermethylation of NCALD and LAMA3 is associated with poor PFS in advanced high-grade serous ovarian cancer. In the future, further research on NCALD and LAMA3 will be needed to provide guidance for clinical stratification of demethylation therapy.

Project description:BackgroundDespite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients.MethodsGenome-wide next-generation sequencing was performed on methylation-enriched tumor DNA of two HGSOC patient groups with residual disease, extreme responders (≥18 months progression-free survival (PFS), n = 8) and non-responders (≤6 months PFS, n = 10) to platinum-based chemotherapy. DNA methylation and expression data of the same patients were integrated to create a gene list. Genes were validated on an independent cohort of extreme responders (n = 21) and non-responders (n = 31) using pyrosequencing and qRT-PCR. In silico validation was performed using publicly available DNA methylation (n = 91) and expression (n = 208) datasets of unselected advanced stage HGSOC patients. Functional validation of FZD10 on chemosensitivity was carried out in ovarian cancer cell lines using siRNA-mediated silencing.ResultsIntegrated genome-wide methylome and expression analysis identified 45 significantly differentially methylated and expressed genes between two chemoresponse groups. Four genes FZD10, FAM83A, MYO18B, and MKX were successfully validated in an external set of extreme chemoresponsive HGSOC patients. High FZD10 and MKX methylation were related with extreme responders and high FAM83A and MYO18B methylation with non-responders. In publicly available advanced stage HGSOC datasets, FZD10 and MKX methylation levels were associated with PFS. High FZD10 methylation was strongly associated with improved PFS in univariate analysis (hazard ratio (HR) = 0.43; 95% CI, 0.27-0.71; P = 0.001) and multivariate analysis (HR = 0.39; 95% CI, 0.23-0.65; P = 0.003). Consistently, low FZD10 expression was associated with improved PFS (HR = 1.36; 95% CI, 0.99-1.88; P = 0.058). FZD10 silencing caused significant sensitization towards cisplatin treatment in survival assays and apoptosis assays.ConclusionsBy applying genome-wide integrated methylome analysis on extreme chemoresponsive HGSOC patients, we identified novel clinically relevant, epigenetically-regulated markers of platinum-sensitivity in HGSOC patients. The clinical potential of these markers in predictive and therapeutic approaches has to be further validated in prospective studies.

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Abnormal 5-methylcytosine lncRNA methylome is involved in human high-grade serous ovarian cancer.

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