The fragile sites are defined as specific segments of genes that are particularly susceptible to breakage under conditions of accelerated replication stress or certain external influences. It has been demonstrated that fragile sites can influence the progression of various tumors. However, the majority of existing studies have focused on the functions of well-characterized common fragile sites, such as FHIT, WWOX, and PARK2, in different oncogenic processes, with insufficient attention directed towards other fragile sites. This article presents an analysis of recent investigations into the fragile sites, fragile site-associated tumor suppressor (FATS) and fragile X mental retardation 1 (FMR1), across various tumor types. The article discusses the mechanisms and signaling pathways regulated by these sites in a range of cancers, as well as their clinical implications for tumor treatment. The review highlights the significance of the fragile sites FATS and FMR1 in various cancers and their clinical relevance.

RNA-binding proteins (RBPs) act as crucial regulators of gene expression within cells, exerting precise control over processes such as RNA splicing, transport, localization, stability, and translation through their specific binding to RNA molecules. The diversity and complexity of RBPs are particularly significant in cancer biology, as they directly impact a multitude of RNA metabolic events closely associated with tumor initiation and progression. The fragile X mental retardation protein (FMRP), as a member of the RBP family, is central to the neurodevelopmental disorder fragile X syndrome and increasingly recognized in the modulation of cancer biology through its influence on RNA metabolism. The protein's versatility, stemming from its diverse RNA-binding domains, enables it to govern a wide array of transcript processing events. Modifications in FMRP's expression or localization have been associated with the regulation of mRNAs linked to various processes pertinent to cancer, including tumor proliferation, metastasis, epithelial-mesenchymal transition, cellular senescence, chemotherapy/radiotherapy resistance, and immunotherapy evasion. In this review, we emphasize recent findings and analyses that suggest contrasting functions of this protein family in tumorigenesis. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention of cancer, some of which have already moved into clinical trials or clinical practice.

Epithelial ovarian cancer (EOC) is the most common subtype of ovarian cancer and is a highly recurrent and lethal malignancy of the female reproductive system. Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) play pivotal roles in tumorigenesis. Long intergenic non-protein coding RNA 704 (LINC00704) has been recognized as an oncogenic lncRNA in several malignancies. However, its specific role in EOC remains unclear. In this study, RT-qPCR revealed the upregulation of LINC00704 in EOC tissues and cell lines. CCK-8 and EdU assays showed that LINC00704 knockdown inhibited EOC cell proliferation. Flow cytometry analysis demonstrated that LINC00704 silencing induced EOC cell cycle arrest and apoptosis. Transwell assays indicated the inhibitory effects of LINC00704 silencing on EOC cell migration and invasion. Mechanistically, bioinformatics analysis, RNA pull-down, luciferase reporter and RNA immunoprecipitation assays revealed that LINC00704 upregulated SLC44A1 expression by competitively binding to miR-323a-3p. Moreover, rescue experiments showed that SLC44A1 overexpression could reverse LINC00704 silencing-mediated effects on the malignant behaviors of EOC cells. In conclusion, LINC00704 promotes EOC cell aggressiveness in vitro by regulating the miR-323a-3p/SLC44A1 axis.

The Fragile X mental retardation type 1 gene (FMR1) contains a CGG triplet cluster of varied length (30 repeats on average) located in its 5' UTR. In its premutated state (54-200 repeats), FMR1 contributes to the pathogenesis of premature ovarian insufficiency (POI). Its gray zone alleles (41-54 repeats) are supposed to impair the ovarian function as well. In the case of a CGG repeat length > 200, Fragile X syndrome occurs. Post-transcriptional expression of FMR1 is regulated by microRNAs. Although miR-323a-3p overexpression suppresses FMR1 in various tissues, this relationship has not been evaluated in the human ovary. Additionally, this microRNA targets SMADs, which are suggested regulators of ovarian cell proliferation, growth, and function. This study investigated how FMR1 allele lengths with CGG repeat numbers n < 55 (normal and gray zone genotypes) relate to miR-323a-3p expression and how they may impact associated SMAD expression in human granulosa cells. COV434 cells and patient-derived GCs were used to evaluate FMR1, miR-323a-3p, and BMP/SMAD-pathway member expression levels. Briefly, miR-323a-3p was significantly upregulated in GCs of the gray zone group compared to the normal allele group (p < 0.0001), while the FMR1 level did not vary. Furthermore, the gray zone group showed a significant upregulation of BMPR2, SMAD1, SMAD4, and SMAD9. In contrast, the miR-323a-3p transfection of COV434 cells significantly downregulated SMAD3, SMAD4, SMAD5, and SMAD9, while the FMR1 and SMAD1 levels remained stable. Our findings highlight a CGG repeat number-dependent upregulation of miR-323a-3p and an alteration of the BMP/SMAD pathway, suggesting that these changes happen and contribute to impaired ovarian function independently.

The 5-methylcytosine (m5C) modification is a crucial epigenetic RNA modification, which is involved in the post-transcriptional regulation of genes. It plays an important role in various biological processes, including cell metabolism, growth, apoptosis, and tumorigenesis. By affecting the proliferation, migration, invasion, and drug sensitivity of tumor cells, m5C methylation modification plays a vital part in the initiation and progression of tumors and is closely associated with the poor tumor prognosis. m5C-related proteins are categorized into three functional groups: m5C methyltransferases (m5C writers), m5C demethylases (m5C erasers), and m5C methyl-binding proteins (m5C readers). This paper introduces several common methodologies for detecting m5C methylation; and reviews the molecular structure and biological functions of m5C readers, including ALYREF, YBX1, YBX2, RAD52, YTHDF2, FMRP, and SRSF2. It further summarizes their roles and regulatory mechanisms in tumors, offering novel targets and insights for tumor treatment.

Prostate adenocarcinoma (PRAD) is the second most common tumor associated with death. The role and mechanisms of the fragile X mental retardation 1 (FMR1) gene in PRAD remain unknown. We conducted an analysis of FMR1 expression in PRAD to determine its prognostic importance and connection to carcinogenic pathways such as PI3K_AKT_mTOR. Survival analyses were utilized to establish a correlation between FMR1 expression and patient outcomes. We used the integration of genomic data with bioinformatic predictions to predict the regulatory factors of the FMR1 gene in PRAD. Our data revealed that individuals with higher levels of FMR1 expression experience worse survival outcomes compared to those with lower expression (hazard ratio [HR] = 5.08, 95% confidence interval [CI] = 1.07 - 24, p = 0.0412). FMR1 expression was significantly higher in patients with advanced pathological tumor stages, particularly in the pT3 and pT4 combined stages and the pN1 nodal stage. Furthermore, patients with high Gleason scores (GSs) (combined GSs 8 and 9) exhibited increased levels of FMR1 expression. Our results further identify a possible regulatory link between FMR1 and key oncogenic pathways, including PI3K_AKT_mTOR, and predict the possible mechanism by which FMR1 is regulated in PRAD. Our data suggest that the FMR1 gene could serve as a biomarker for PRAD progression. However, in-depth investigations, including those with large patient samples and in vitro studies, are needed to validate this finding and understand the mechanisms involved.

The availability of circulating biomarkers that are predictive of treatment response or prognostic of overall outcome could enable the personalised and adaptive use of radiotherapy (RT) in patients with oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC).

A systematic review was carried out following Preferred Reporting Items for Systematic Reviews guidance. Medline, EMBASE, PubMed, Cochrane Library, CINAHL, Scopus and the Web of Science databases were searched for studies published between January 2005-February 2023 relating to circulating biomarkers evaluated in the context of neoadjuvant or definitive RT delivered for OAC/OSCC. Study quality was assessed using predefined criteria.

A total of 3012 studies were screened and 57 subsequently included, across which 61 biomarkers were reported. A majority (43/57,75.4%) of studies were of Asian origin and retrospective (40/57, 70.2%), with most (52/57, 91.2%) biomarkers reported in the context of patients with OSCC. There was marked inter-study heterogeneity in patient populations, treatment characteristics, biomarker measurement and the cut points used to define biomarker positivity. Nevertheless, there is evidence for the prognostic and predictive value of circulating tumour DNA and numerous miRNAs in OAC and OSCC, as well as for the prognostic and predictive value of circulating levels of CYFRA21.1 in OSCC.

There is consistent evidence for the potential predictive and prognostic value of a small number of biomarkers in OSCC and OAC, though these data are insufficient for translation to current clinical practice. Well-designed prospective studies are now required to validate their role in stratified and personalised RT treatment approaches.

Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.

Long non-coding RNA activated by DNA damage (NORAD) has recently been associated with pathologic mechanisms underlying cancer progression. Due to NORAD's extended range of interacting partners, there has been contradictory data on its oncogenic or tumor suppressor roles in BC. This review will summarize the function of NORAD in different BC subtypes and how NORAD impacts crucial signaling pathways in this pathology. Through the preferential binding to pumilio (PUM) proteins PUM1 and PUM2, NORAD has been shown to be involved in the control of cell cycle, angiogenesis, mitosis, DNA replication and transcription and protein translation. More recently, NORAD has been associated with PUM-independent roles, accomplished by interacting with other ncRNAs, mRNAs and proteins. The intricate network of NORAD-mediated signaling pathways may provide insights into the potential design of novel unexplored strategies to overcome chemotherapy resistance in BC treatment.

Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease with a poor prognosis and high heritability, characterized by elevated pulmonary vascular resistance (PVR) and pulmonary artery pressure. N6-methyladenosine (m6A) RNA modification influences many RNA metabolism pathways. However, the position of m6A methylation regulators in IPAH remains unknown. Therefore, the study aims to disclose the function m6A regulators exert in the pathological mechanisms of IPAH and the immune microenvironment involved. The GSE117261 dataset was downloaded from the Gene Expression Omnibus (GEO) to screen the differentially expressed genes (DEGs) between normal and IPAH samples. Functional and pathway enrichment analyses of DEGs were then conducted by Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG). We also identified the differentially-expressed m6A (DEm6A) regulators between normal and IPAH samples. Key m6A regulators related to the prediction of IPAH were selected using the random forest model. The results showed that FMR1, RBM15, HNRNPA2B1 and IGFBP3 were upregulated in IPAH. In contrast, LRPPRC was downregulated. The single sample gene set enrichment analysis (ssGSEA) method was then adopted to estimate the immune microenvironment in distinct m6A clusters and m6A phenotype-related genes (PRGs) clusters, respectively. Furthermore, we calculated the m6A score via principal component analysis (PCA), and the Sankey diagram was selected to present the correlation among the m6A clusters, m6A PRGs clusters and m6A score. Finally, quantitative RT-PCR and Western blotting were used to validate the key genes in human pulmonary artery smooth muscle cells (HPASMCs) treated by human platelet-derived growth factor-BB (PDGF-BB). The relative mRNA and protein expression levels of FMR1 were significantly elevated, however, the relative mRNA and protein expression levels of LRPPRC were downregulated. Besides, the relative mRNA level of HNRNPA2B1 was increased. Generally, this bioinformatics analysis might provoke more insights into diagnosing and treating IPAH.