RNA Biology

Circular RNA Circ_0002762 promotes cell migration and invasion in cervical squamous cell carcinoma via activating RelA/nuclear factor kappa B (Nf-kB) signalling pathway

Cervical cancer is a leading cause of cancer-related deaths, with cervical squamous cell carcinoma (CSCC) accounting for a majority of cases. Circular RNAs (circRNAs) have been repeatedly suggested as crucial effectors in modulating the development of multiple malignancies. The expression of circ_0002762 was predicted to be high in CSCC tissues in GEO dataset, but the functional role and underlying regulatory mechanism of circ_0002762 in CSCC was unclear. By series of functional assays and mechanism assays, supported by bioinformatics analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis and western blot assays, we identified that circ_0002762 aberrantly up-regulated in CSCC, promoting CSCC cell migration and invasion. Mechanically, circ_0002762 was transcriptionally activated by Fork head box A1 (FOXA1). Moreover, the involvement of nuclear factor kappa B (NF-kB) signalling in circ_0002762 regulation mechanism in CSCC cells was ascertained. Additionally, circ_0002762, predominantly accumulated in cell cytoplasm, was proved to recruit Mov10 RISC complex RNA helicase (MOV10) to enhance RelA mRNA stability, thus affecting CSCC cell migration and invasion. In summary, FOXA1-mediated circ_0002762 up-regulation could enhance the migratory and invasive abilities of CSCC cells via the MOV10/RelA/NF-kB pathway.

LncRBase V.2: an updated resource for multispecies lncRNAs and ClinicLSNP hosting genetic variants in lncRNAs for cancer patients

The recent discovery of long non-coding RNA as a regulatory molecule in the cellular system has altered the concept of the functional aptitude of the genome. Since our publication of the first version of LncRBase in 2014, there has been an enormous increase in the number of annotated lncRNAs of multiple species other than Human and Mouse. LncRBase V.2 hosts information of 549,648 lncRNAs corresponding to six additional species besides Human and Mouse, viz. Rat, Fruitfly, Zebrafish, Chicken, Cow and

Human papillomavirus-encoded microRNAs: key regulators in cervical cancer development

Human papillomaviruses (HPVs) cause diverse cutaneous and mucosal diseases, with several genotypes strongly associated with cervical cancer. Beyond the well-established role of cellular microRNAs (miRNAs) in gene regulation, increasing evidence shows that HPV also encodes its own viral miRNAs (v-miRNAs). These v-miRNAs modulate both viral and host gene expression, influencing key pathways involved in oncogenesis, including cell cycle control, apoptosis, immune evasion, and epithelial - mesenchymal transition. By shaping these regulatory networks, HPV-derived miRNAs promote viral persistence and contribute to malignant transformation. Their stability and specificity also make them promising biomarkers for cervical cancer diagnosis and prognosis, although clinical translation remains challenging. This review provides an updated overview of HPV-encoded miRNAs, their validated molecular targets, and their roles in tumour development. It also highlights emerging therapeutic strategies and future perspectives for integrating miRNA-based approaches into precision oncology for HPV-related cervical cancer.

DARS-AS1 recruits METTL3/METTL14 to bind and enhance DARS mRNA m 6 A modification and translation for cytoprotective autophagy in cervical cancer

Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5' untranslated region (5'UTR) and promoting its translation. The present study demonstrated that the 'HIF1α/DARS-AS1/DARS/ATG5/ATG3' pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.

FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway

Although many studies have confirmed the relationship between obesity and endometrial cancer (EC), the molecular mechanism between obesity and EC progression has not been elucidated. Overexpression of fat mass and the obesity associated protein FTO leads to weight gain, although recently it has been discovered that FTO can serve as a demethylase which erases N6-methyladenosine (m6A) modification and regulates the metabolization of mRNAs. In this study, we found high expression of FTO in metastatic EC and that this action promote both metastasis and invasion in vivo and in vitro. Mechanistically, FTO can catalyse demethylation modification in 3'UTR region of HOXB13 mRNA, thereby abolishing m6A modification recognition with the YTHDF2 protein. Decreasing HOXB13 mRNA decay and increasing HOXB13 protein expression was accompanied by WNT signalling pathway activation and the expression of downstream proteins, leading to tumour metastasis and invasion. We also found the WNT signalling pathway inhibitor ICG-001 can block HOXB13 gene-induced tumour metastasis, therefore ICG-001 may be a promising molecular intervention. This study provides insight into the relationship between obesity and the pathogenesis of endometrial cancer while highlighting future areas of research.

m6A modification of RNA in cervical cancer: role and clinical perspectives

N6-methyladenosine (m6A) is widely recognized as the predominant form of RNA modification in higher organisms, with the capability to finely regulate RNA metabolism, thereby influencing a series of crucial physiological and pathological processes. These processes include regulation of gene expression, cell proliferation, invasion and metastasis, cell cycle control, programmed cell death, interactions within the tumour microenvironment, energy metabolism, and immune regulation. With advancing research into the mechanisms of RNA methylation, the pivotal role of m6A modification in the pathophysiology of reproductive system tumours, particularly cervical cancer, has been progressively unveiled. This discovery has opened new research avenues and presented significant potential for the diagnosis, prognostic evaluation, and treatment of diseases. This review delves deeply into the biological functions of m6A modification and its mechanisms of action in the onset and progression of cervical cancer. Furthermore, it explores the prospects of m6A modification in the precision diagnosis and treatment of cervical cancer, aiming to provide new perspectives and a theoretical basis for innovative and advanced treatment strategies for cervical cancer.

Comprehensive analysis of prognosis-related alternative splicing events in ovarian cancer

Ovarian cancer (OV) is characterized by high incidence and poor prognosis. Increasing evidence indicates that aberrant alternative splicing (AS) events are associated with the pathogenesis of cancer. We examined prognosis-related alternative splicing events and constructed a clinically applicable model to predict patients' outcomes. Public database including The Cancer Genome Atlas (TCGA), TCGA SpliceSeq, and the Genomics of Drug Sensitivity in Cancer databases were used to detect the AS expression, immune cell infiltration and IC50. The prognosis-related AS model was constructed and validated by using Cox regression, LASSO regression, C-index, calibration plots, and ROC curves. A total of eight AS events (including FLT3LG|50942|AP) were selected to establish the prognosis-related AS model. Compared with high-risk group, low-risk group had a better outcome (

The potential regulatory role of RNA methylation in ovarian cancer

Updates in whole genome sequencing technologies have revealed various RNA modifications in cancer, among which RNA methylation is a frequent posttranscriptional modification. RNA methylation is essential for regulating biological processes such as RNA transcription, splicing, structure, stability, and translation. Its dysfunction is strongly associated with the development of human malignancies. Research advances with respect to the regulatory role of RNA modifications in ovarian cancer include N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G). Numerous studies have demonstrated that epigenetic modifications of RNA can influence the progression and metastasis of ovarian cancer and may provide excellent targets for cancer therapy. This review highlights advances in research on RNA methylation modifications and ovarian cancer prognosis, carcinogenesis, and resistance, which could provide a theoretical foundation for designing therapeutic strategies for ovarian cancer based on RNA methylation modifications.

IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HGSOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here, we show that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in an RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation, only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HGSOC.

Long non-coding RNAs in ovarian cancer: expression profile and functional spectrum

Long non-coding RNAs (lncRNAs), initially recognized as byproducts of the transcription process, have been proven to play crucial modulatory roles in preserving overall homoeostasis of cells and tissues. Furthermore, aberrant levels of these transcripts have been shown to contribute many diseases, including cancer. Among these, many aspects of ovarian cancer biology have been found to be regulated by lncRNAs, including cancer initiation, progression and dissemination. In this review, we summarize recent studies to highlight the various roles of lncRNAs in ovary in normal and pathological conditions, immune system, diagnosis, prognosis, and therapy. We address lncRNAs that have been extensively studied in ovarian cancer and their contribution to cellular dynamics.