m6A Regulator-Mediated Tumour Infiltration and Methylation Modification in Cervical Cancer Microenvironment

Zhang, Wenyi; Xiao, Pei; Tang, Jian; Wang, Rui; Wang, Xiangdong; Wang, Fengxu; Ruan, Junpu; Yu, Shali; Tang, Juan; Huang, Rongrong; Zhao, Xinyuan

doi:10.3389/fimmu.2022.888650

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…Tumor microenvironment (TME) plays a vital role in the growth and development of tumors, including immune cells, stromal cells, blood vessels, and extracellular matrix (ECM) (43). Immune cells and stromal cells dominate the tumor microenvironment in cervical cancer, and T cells and mast cells have been suggested to be significantly associated with the survival rate of patients with cervical cancer (44). In the current study, by conducting comprehensive analyses of large-scale miRNA expression data and CESC clinical data from TCGA database, we successfully identified miR-95-3p as a candidate prognostic marker for cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

MiR-95-3p acts as a prognostic marker and promotes cervical cancer progression by targeting VCAM1

Feng¹,

Lu²,

Sun³

et al. 2022

Ann Transl Med

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Background: Cervical cancer patients have a high risk of metastasis and a poor prognosis with shorter disease-free survival. Thus, novel biomarkers and feasible therapies urgently need to be discovered. Previous studies have shown that miR-95-3p plays crucial roles in several cancer types. However, the roles of miR-95-3p in cervical cancer remain unknown. Methods: The micro ribonucleic acid (miRNA) expression data and clinical characteristics of cervical cancer samples were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses were conducted to identify the prognostic-related miRNAs. The potential target genes of miR-95-3p were predicted by the TargetScan database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to explore the target gene of miR-95-3p. The effects of miR-95-3p inhibition and overexpression on cell proliferation were inspected by cell counting kit-8 (CCK-8) assays and cell colony formation assays. Woundhealing assays and transwell assays were also used to examine cell migration ability in HeLa and SiHa cells. Results: MiR-95-3p was the only miRNA significantly associated with the poor prognosis of cervical squamous cell carcinoma. A further analysis suggested that vascular cell adhesion molecule 1 (VCAM1) is a target gene of miR-95-3p in cervical cancer, and miR-95-3p promotes the malignant behavior of cervical cancer cells by inhibiting the expression of VCAM1. The CCK-8 and cell colony assays showed that miR-95-3p downregulation significantly suppressed cell proliferation in the HeLa and SiHa cells. The transwell and wound-healing assays showed that miR-95-3p inhibition suppressed cell migration in the HeLa and SiHa cells. Further the Western blot analysis and the quantitative real-time-polymerase chain reaction (qRT-PCR) showed that the knockdown of miR-95-3p in HeLa cells resulted in increased VCAM1 expression. And VCAM1 was highly expressed in the paired adjacent normal cervical epithelium tissue samples, but lowly expressed in the cervical tumor tissue samples. Conclusions: Our study was the first to show that miR-95-3p could serve as a prognostic biomarker of cervical cancer. Mechanistically, we discovered that miR-95-3p inhibited the expression of the cell adhesion molecule VCAM1 and thus promoted further tumor progression.

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Section: Discussionmentioning

confidence: 99%

MiR-95-3p acts as a prognostic marker and promotes cervical cancer progression by targeting VCAM1

Feng¹,

Lu²,

Sun³

et al. 2022

Ann Transl Med

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“…In addition, complex mechanisms between RNAs and proteins may also lead to different outcomes. Zhang’s research 16 explored the expression patterns of m 6 A molecules in CC and comprehensively analyzed the connection with immune-related processes. Although expression patterns were explored for both, we ultimately constructed m 6 AScore based on m 6 A regulator expression values rather than differential genes.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, we extracted the expression levels of regulators from the TCGA and cervical tissue transcription data, deleting the regulators in which expression levels were unavailable. Finally, 33 m 6 A modification regulators were selected as candidate molecules for this study 16 , 20 (Table S1 ).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, the abnormal expression of methyltransferase complex components in m 6 A modification affects both gastric cancer and liver cancer, including adjusted by FTO and WTAP instead of METTL3 and METTL14, which were considered as principal roles in m 6 A modification 13 , 14 . Collectively, although the mechanism of m 6 A modification in cancer including CC has been well studied in recent years 15 , 16 , the evidence for the importance of m 6 A modification importance in CC recurrence and diagnostic analysis is still lacking.…”

Section: Introductionmentioning

confidence: 99%

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Gene signature of m6A RNA regulators in diagnosis, prognosis, treatment, and immune microenvironment for cervical cancer

Wang

Ding

Wang

et al. 2022

Sci Rep

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Continuing studies imply that m6A RNA modification is involved in the development of cervical cancer (CC), but lack strong support on recurrence and diagnosis prediction. In this research, a comprehensive analysis of 33 m6A regulators was performed to fulfill them. Here, we performed diagnostic and prognosis models and identified key regulators, respectively. Then the CC patients were separated into two clusters in accordance with 33 regulators, and participants in the cluster 1 had a worse prognosis. Subsequently, the m6AScore was calculated to quantify the m6A modification pattern based on regulators and we found that patients in cluster 1 had higher m6AScore. Afterwards, immune microenvironment, cell infiltration, escape analyses and tumor burden mutation analyses were executed, and results showed that m6AScore was correlated with them, but to a limited extent. Interestingly, HLAs and immune checkpoint expression, and immunophenoscore in patients with high-m6AScores were significantly lower than those in the low-m6AScore group. These suggested the m6AScores might be used to predict the feasibility of immunotherapy in patients. Results provided a distinctive perspective on m6A modification and theoretical basis for CC diagnosis, prognosis, clinical treatment strategies, and potential mechanism exploration.

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“…The inclusion criteria for the samples are as follows: 1) primary HCC; 2) gene expression profiles and related clinical information were available; 3) preoperative radiotherapy and chemotherapy were not performed. A total of 35 m6A methylation-related regulator genes (MRGs) were collected from previous studies ( Zaccara et al, 2019 ; Chen et al, 2021b ; Zhang et al, 2022 ). Genes were annotated and extracted using the Genome Reference Consortium Human Build 38 (GRCh38).…”

Section: Methodsmentioning

confidence: 99%

M6A regulator-mediated immune infiltration and methylation modification in hepatocellular carcinoma microenvironment and immunotherapy

et al. 2022

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Introduction: Tremendous evidence indicates that N6-methyladenosine (m6A) epigenetic modification and m6A-related enzymes constitute a complex network, which jointly regulates prevailing pathological processes and various signaling pathways in humankind. Currently, the role of the m6A-mediated molecular regulatory network in hepatocellular carcinoma (HCC) remains elusive.Methods: We recruited expression and pathological files of 368 HCC patients from The Cancer Genome Atlas cohort. Four public datasets serve as external authentication sets for nearest template prediction (NTP) validation. The correlation between 35 regulators and their prognostic value was compared. Gene set variation analysis (GSVA) was used to explore the latent mechanism. Four independent algorithms (ssGSEA, xCell, MCP-counter, and TIMER) were used to calculate the ratio of tumor cells and non-tumor cells to evaluate the tumor immune microenvironment. The m6Ascore model was established by principal component analysis (PCA). Prediction of immunotherapy and potential drugs was performed using TIDE and SubMap.Results: A total of 35 m6A regulators were widely associated, most of which were risk factors for HCC patients. The m6A phenotypic-cluster revealed differences in regulator transcriptional level, gene mutation frequency, functional pathways, and immune cell infiltration abundance under distinct m6A patterns. As expected, the m6A gene cluster confirmed the aforementioned results. The m6Ascore model further found that patients in the high-m6Ascore group were associated with lower tumor purity, higher enrichment of immune and stromal cells, upregulation of metabolic pathways, lower expression of m6A regulators, and favorable outcomes. Low-m6Ascore patients were associated with adverse outcomes. Notably, low-m6Ascore patients might be more sensitive to anti-PD-L1 therapy.Conclusion: This study found that a classification model based on the m6A manner could predict HCC prognosis and response to immunotherapy for HCC patients, which might improve prognosis and contribute to clinical individualized decision-making.

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m6A Regulator-Mediated Tumour Infiltration and Methylation Modification in Cervical Cancer Microenvironment

Cited by 19 publications

References 32 publications

MiR-95-3p acts as a prognostic marker and promotes cervical cancer progression by targeting VCAM1

MiR-95-3p acts as a prognostic marker and promotes cervical cancer progression by targeting VCAM1

Gene signature of m6A RNA regulators in diagnosis, prognosis, treatment, and immune microenvironment for cervical cancer

M6A regulator-mediated immune infiltration and methylation modification in hepatocellular carcinoma microenvironment and immunotherapy

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