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MicroRNAs (miRNAs) silence genes by binding to messenger RNAs, whereas long non-coding RNAs (lncRNAs) act as competitive endogenous RNAs (ceRNAs) that can relieve miRNA silencing effects and upregulate target gene expression. The ceRNA association between lncRNAs and miRNAs has been a research hotspot due to its medical importance, but it is challenging to verify experimentally. In this paper, we propose a novel deep learning scheme, i.e. sequence pre-training-based graph neural network (SPGNN), that combines pre-training and fine-tuning stages to predict lncRNA-miRNA associations from RNA sequences and the existing interactions represented as a graph. First, we utilize a sequence-to-vector technique to generate pre-trained embeddings based on the sequences of all RNAs during the pre-training stage. In the fine-tuning stage, we use Graph Neural Network to learn node representations from the heterogeneous graph constructed using lncRNA-miRNA association information. We evaluate our proposed scheme SPGNN on our newly collected animal lncRNA-miRNA association dataset and demonstrate that combining the $k$-mer technique and Doc2vec model for pre-training with the Simple Graph Convolution Network for fine-tuning is effective in predicting lncRNA-miRNA associations. Our approach outperforms state-of-the-art baselines across various evaluation metrics. We also conduct an ablation study and hyperparameter analysis to verify the effectiveness of each component and parameter of our scheme. The complete code and dataset are available on GitHub: https://github.com/zixwang/SPGNN., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Circular RNA (CircRNA) is a type of non-coding RNAs in which both ends are covalently linked. Researchers have demonstrated that many circRNAs can act as biomarkers of diseases. However, traditional experimental methods for circRNA-disease associations identification are labor-intensive. In this work, we propose a novel method based on the heterogeneous graph neural network and metapaths for circRNA-disease associations prediction termed as HMCDA. First, a heterogeneous graph consisting of circRNA-disease associations, circRNA-miRNA associations, miRNA-disease associations and disease-disease associations are constructed. Then, six metapaths are defined and generated according to the biomedical pathways. Afterwards, the entity content transformation, intra-metapath and inter-metapath aggregation are implemented to learn the embeddings of circRNA and disease entities. Finally, the learned embeddings are used to predict novel circRNA-disase associations. In particular, the result of extensive experiments demonstrates that HMCDA outperforms four state-of-the-art models in fivefold cross validation. In addition, our case study indicates that HMCDA has the ability to identify novel circRNA-disease associations., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Circular RNAs (circRNAs), according to a growing body of research, are thought to be important in the initiation and development of a number of cancers. However, more research is needed to fully understand how circRNAs work at the molecular level in triple-negative breast cancer (TNBC). RNA sequencing was conducted on four sets of TNBC samples and their corresponding adjacent noncancerous tissues (ANTs). The circSNX25 expression was assessed using quantitative real-time PCR in TNBC tissues and cells. Several in vitro and in vivo experiments were conducted in order to examine the function of circSNX25 in TNBC carcinogenesis. Through luciferase reporter and chromatin immunoprecipitation (ChIP) assays, we also investigated the potential regulation of circSNX25 biogenesis by specificity protein 1 (SP1). To further validate the relationship between circSNX25 and COPI coat complex subunit beta 1 (COPB1) in TNBC, we conducted circRNA pull-down and RNA immunoprecipitation (RIP) assays using the MS2/MS2-CP system. Online databases were analyzed to examine the clinical implications and prognostic value of COPB1 in TNBC. A higher circSNX25 expression levels were observed in tissues and cells of TNBC. Silencing circSNX25 notably inhibited TNBC cell proliferation, triggered apoptosis, and hindered tumor growth in vivo. Conversely, upregulation of circSNX25 had the opposite effects. Mechanistically, circSNX25 was found to physically interact with COPB1. Importantly, we identified that SP1 may enhance circSNX25 biogenesis. COPB1 levels were markedly higher in TNBC cells. Analysis of online databases revealed that TNBC patients with elevated COPB1 levels had a poorer prognosis. Our findings demonstrate that SP1-mediated circSNX25 promotes TNBC carcinogenesis and development. CircSNX25 may therefore serve as both a diagnostic and therapeutic biomarker for TNBC patients., Competing Interests: Declaration of Competing Interest The authors report no potential conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Adenosylmethionine decarboxylase 1 (AMD1) has been implicated in carcinogenesis and tumor progression. However, the potential biomechanism and biological implications of AMD1 in breast cancer (BC) remain unclear. The purpose of this study was to investigate the effect of abnormal expression of AMD1 in BC. The expression of AMD1 in different human BC cell lines was studied by using western blotting and qRT-PCR. In vitro cell proliferation, clone formation, cell cycle and apoptosis assays were performed to explore the effect of AMD1 on cellular proliferation. Xenograft mouse models were established to elucidate the role of AMD1 in BC growth. The expression profiles of AMD1 in 28 pairs of BC tissues and adjacent noncancerous tissues (ANTs) were investigated by using western blotting and immunohistochemistry. The clinical implication and prognostic evaluation of AMD1 in BC were examined by excavating the online database. We found that the expression levels of AMD1 in BC cell lines were significantly higher than those in the normal human breast epithelial cell line MCF-10A. In addition, AMD1 potentiated proliferation, induced cell cycle progression and inhibited apoptosis in BC cells. Subcutaneous tumor xenografts also supported the promotive role of AMD1 in BC growth. We discovered that the level of AMD1 in BC tissues was significantly higher than that in ANTs. Using the online database, increased AMD1 was found to be associated with clinical indicators and predicted a poor prognosis in patients with BC. Our findings indicate that AMD1 elicits potent oncogenic effects on the malignant progression of BC. AMD1 might serve as a promising diagnostic biomarker and therapeutic target for patients with BC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Liver cancer is a prevalent tumor with high incidence and mortality. MicroRNAs participate in cancer pathogenesis and miR-15a-5p may influence tumor suppression in many cancers. Herein, we analyzed the effect of miR-15a-5p in liver cancer cell migration, apoptosis, and the cell cycle. RT-PCR was performed to measure miR-15a-5p expression levels, transwell assays were applied to investigate the effect of miR-15a-5p on cell migration, and flow cytometry was performed to explore the impact of miR-15a-5p on apoptosis and the cell cycle in Hep3B and HepG2 cells. Luciferase reporter assays and Western blotting were employed to determinate the relationship between E2F3 and miR-15a-5p in liver cancer cells. Expression of E2F3 was detected by bioinformatics analysis and RT-PCR in liver cancer. Small interfering RNA (si-RNA) was used to silence E2F3 expression and assess the effect on migration, apoptosis, and the cell cycle in Hep3B/HepG2 cells. The results demonstrated that miR-15a-5p was downregulated in human liver cancer tissue, and enhancing the expression of miR-15a-5p suppressed migration in liver cancer cells, induced apoptosis, and caused G1 phase arrest. In vivo assays were further performed and miR-15a-5p inhibited the growth of liver cancer. miR-15a-5p appeared to target E2F3, and RT-PCR and bioinformatic analyses indicated that E2F3 expression was higher in liver cancer than control tissues. Silencing E2F3 expression decreased cell migration, induced apoptosis, and caused G1 phase arrest in Hep3B/HepG2 cells. These findings indicate that miR-15a-5p regulates liver cancer cell migration, apoptosis, and growth by targeting E2F3. Thus, miR-15a-5p may act as a suppressor role in liver cancer.

MicroRNAs (MiRNAs) play critical roles in regulating target gene expression and multiple cellular processes in human cancer malignant progression. However, the function of miR-194 in gastric cancer (GC) remains unclear and controversial. In this study, we identified a series of miRNAs that can serve as prognostic biomarkers for GC by analysis of miRNA expression using The Cancer Genome Atlas data. Among them, miR-100, miR-125b, miR-199a, and miR-194 were the four most promising prognostic biomarkers in GC due to their significant associations with various clinical characteristics of patients. miR-100, miR-125b, and miR-199a predicted poor prognosis in GC, while miR-194 predicted favorable prognosis in GC. We also provide the first comprehensive transcriptome analysis of miR-194 in GC. Our data suggest that miR-194 tends to regulate target genes by binding to their 3' UTRs in a 7-mer-A1, 7-mer-m8, or 8-mer manner. KEGG pathway analysis showed that the cell cycle was one of the pathways most affected by miR-194 in GC. Moreover, CCND1 was shown to be a novel target gene of miR-194 in GC. Additionally, downregulation of CCND1 by miR-194 in GC further led to cell growth inhibition and cell cycle arrest. In conclusion, miR-100, miR-125b, miR-199a, and miR-194 may have potential as prognostic and diagnostic biomarkers for GC. miR-194 suppresses GC cell growth mainly through targeting CCND1 and induction of cell cycle arrest., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Several studies have shown an important role for long non-coding RNA (lncRNA) in breast cancer progression. The present study investigated the role of lncRNA Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) in the progression of breast cancer. OIP5-AS1 was significantly upregulated in breast cancer tissues and in breast cancer cell lines, and OIP5-AS1 downregulation inhibited the malignant behavior of breast cancer in vitro and in vivo. For in-depth exploration of the mechanism of OIP5-AS1 in breast cancer, we found that expression of microRNA-129-5p(miR-129-5p), which was found to bind sites in the sequence of OIP5-AS1, in breast cancer tissues was negatively correlated with OIP5-AS1. Also, luciferase assays indicated that OIP5-AS1 acted as a miR-129-5p sponge, resulting in upregulated expression of the sex-determining region Y-box 2 (SOX2) transcription factor. Our study showed that OIP5-AS1 plays a critical role in promoting breast cancer progression and that OIP5-AS1 downregulation targets SOX2 by miR-129-5p upregulation., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Numerous studies have revealed that microRNAs (miRNAs) are functional non‑coding RNAs that serve roles in a variety of biological processes. However, the expression patterns and regulatory networks, as well as the miRNAs involved in liver fibrosis remain to be elucidated. In the present study, a mouse model of liver fibrosis was constructed by CCl4 intraperitoneal injection and the total RNAs were extracted from the liver of the mice. The total RNAs were then sequenced on an Illumina HiSeq 2000 platform and an integrated analysis of miRNA and mRNA expression profiles in CCl4‑induced liver fibrosis was performed. Compared with normal liver samples, 56 and 15 miRNAs were found to be upregulated and downregulated in fibrotic livers, respectively. To predict the potential functions of these miRNAs, bioinformatics analysis, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, was used to assess target mRNAs. The results indicated that the mitogen‑activated protein kinase, phosphoinositide 3 kinase/protein kinase B and focal adhesion signaling pathways were the most significantly enriched. In addition, a regulatory network containing five dysregulated miRNAs and 22 target mRNAs was constructed based on their inverse correlation. Furthermore, the five dysregulated miRNAs were significantly upregulated and the expression of RELB, RAP1A, PPP3CB, MAP2K4, ARRB1, MAP3K4, FGF1 and PRKCB in the network was significantly decreased in LX‑2 cells following TGF‑β1 treatment which suggested that they were associated with the activation of human hepatic stellate cells. The miRNA‑mRNA regulatory network produced in the present study may provide novel insights into the role of miRNAs in liver fibrosis.

Adriamycin resistance is closely related to therapeutic efficacy in breast cancer patients and their prognosis. Increasing evidence has suggested that miRNA functions in Adriamycin resistance in various types of cancer. microRNA-129-5p (miR-129-5p) has been considered a tumor-suppressive miRNA in several cancers, but its potential role in Adriamycin resistance in breast cancer has not been fully elucidate. By qRT-PCR assay, we revealed that the expression of miR-129-5p was significantly decreased in breast cancer tissues and Adriamycin-resistant breast cancer cells (MDA-MB-231/ADR, MCF-7/ADR). CCK-8, colony formation, wound healing, Transwell invasion, and flow cytometric profiles were examined to determine the influence of miR-129-5p on Adriamycin-resistant breast cancer in vitro. The upregulation of miR-129-5p decreased the IC50 concentration of Adriamycin and invasion and promoted the apoptosis of MDA-MB-231/ADR cells in the presence of Adriamycin, whereas the upregulation of Sex-Determining Region Y-Box 2 (SOX2) reversed these effects. A luciferase reporter assay confirmed the binding of miR-129-5p to the 3'UTR of SOX2. Collectively, it was suggested that miR-129-5p suppresses Adriamycin resistance in breast cancer by directly targeting SOX2., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cancer related inflammation (CRI) plays an important role in the development of esophageal cancer (EC), and the target gene analysis shows that miR-302b potential target genes closely correlated to CRI important signaling pathways. The present study was to evaluate the inhibition of miR-302b on CRI in EC and its mechanism. We found that the expression levels of miR-302b in EC cells were lower than that in Het-1A cells, while TE11 with the lowest expression and OE33 with the highest. Inflammatory stimuli at 48 h significantly reduced expression of miR-302b in EC cells, but had no effect in Het-1A. After up-regulation of miR-302b in TE11 and down-regulation of miR-302b in OE33, it was found that miR-302b reduced CRI key transcription factors and representative cytokines. Then, over-expressed of miR-302b significantly altered potential target genes protein expressions and there was a negative correlation between miR-302b and potential target genes protein expressions (ERBB4, IRF2 and CXCR4) in EC tissues. Then reporter gene analysis revealed that miR-302b post-transcriptionally regulated expression of target genes by specific area of 3'-UTR. Transfected by target genes shRNA plasmids together could get the same effects of miR-302b on protein expression of CRI key transcription factors. Furthermore, miR-302b was able to repress tumor growth and transcription factors protein expression in vivo. These finding suggests that miR-302b inhibits key transcription factors and cytokines by targeting ERBB4, IRF2 and CXCR4, implicating its role in the inhibition of CRI in EC.

Background: Increasing evidence has demonstrated that microRNAs play a critical role in breast cancer (BC) progression. microRNA-101 (miR-101) has been considered a tumor suppressive miRNA in different cancer types. This study aimed to investigate miR-101 expression in BC tissues and to investigate its roles in BC progression that are mediated by Sex-determining region Y-box 2 (SOX2), a critical oncogene in various cancers., Methods: qRT-PCR and immunohistochemistry were performed to detect miR-101 and SOX2 expression in BC tissues and paired normal tissues or BC cell lines. MTT, transwell migration, wound healing, colony formation, flow cytometric and xenograft assays were performed to determine the influence of miR-101 and SOX2 on the malignant behaviors of BC cells in vitro and in vivo., Results: miR-101 was significantly downregulated in BC tissues and cell lines. miR-101 overexpression inhibited the malignant behaviors of BC cells, both in vitro and in vivo. miR-101 downregulation had the converse effect. A miR-101 binding site was identified by luciferase reporter assay in the 3'UTR of SOX2. SOX2 was upregulated in BC tissues and cell lines, and its upregulation was associated with lymph node metastasis, pathological grade and TNM classification. SOX2 knockdown mimicked the effects of miR-101 overexpression on the malignant behaviors of BC cells, while SOX2 overexpression mitigated the miR-101-induced inhibition of these effects., Conclusions: Our study revealed that miR-101 plays a critical role in suppressing tumor progression by directly targeting SOX2., (The Author(s). Published by S. Karger AG, Basel.)

miR-21 has been shown to play fundamental role in diverse biological and pathological processes, including fibrotic diseases. In the present study, we investigated whether miR-21 regulated the fibrogenic epithelial-mesenchymal transition (EMT) in human hepatocytes QSG-7701 and explored underlying mechanisms. The results showed that treatment of QSG-7701 cells with pro-fibrogenic factor TGF-β1 resulted in increased expression of miR-21 and promoted fibrogenic EMT in hepatocytes. Downregulation of miR-21 expression by transfection of anti-miR-21 into QSG-7701 cells inhibited fibrogenic EMT induced by TGF-β1. Furthermore, overexpression of miR-21 alone also resulted in EMT-like transformation in QSG-7701 cells. TGF-β1 treatment resulted in decreased PTEN and increased Akt phosphorylation and anti-miR-21 abolished this effect. Overexpression of miR-21 in QSG-7701 cells also downregulated PTEN and upregulated Akt phosphralation. Inhibition of Akt signaling by specific inhibitor Akt inhibitor IV blocked TGF-β1 and miR-21-induced fibrogenic EMT. In summary, our results identify miR-21 as a key regulator of fibrogenic EMT in hepatocytes via PTEN/Akt pathway. Targeting miR-21 may provide a new therapeutic strategy against hepatic fibrosis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the role of miR-520a in regulation ErbB4 expression and the biological behavior of esophageal squamous cell carcinoma (ESCC)., Methods: The role of miR-520a in regulating the expression of ErbB4 was investigated by Western blotting and luciferase reporter assay system. The effect of miR-520a on the proliferation and invasion of ESCC cells was detected by MTT and Transwell invasion assay, respectively., Results: Western blotting and luciferase reporter assay revealed that miR-520a down-regulated the expression of ErbB4 in vitro. miR-520a significantly inhibited the proliferation and suppressed the invasion of ESCC cell line Eca109., Conclusion: miR-520a regulates the expression of ErbB4 and suppresses the proliferation and invasion of ESCC cells in vitro, suggesting its role as a tumor suppressor.

Background: ErbB4 expression has been noted in various tumors, but its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to investigate whether miR-302b regulates the expression of ErbB4 at the post-transcriptional level and to determine its expression, significance, and function in ESCC., Methods: We used real-time reverse transcriptase-polymerase chain reaction to quantify the expression of miR-302b in 50 ESCC tissues and analyzed its relationship with clinicopathological factors and survival. Then, we investigated the post-transcriptional regulation of ErbB4 expression using immunoblot analysis and luciferase reporter assays. Finally, the effects of miR-302b on proliferation, apoptosis, and invasion of ESCC cells was detected using MTT, flow cytometric analysis, and transwell invasion assays, respectively., Results: miR-302b was significantly down-regulated and correlated with tumor differentiation and lymph node metastasis in ESCC. Univariate and multivariate analyses indicated that low miR-302b expression might be a poor prognostic factor. Further studies demonstrated that miR-302b post-transcriptionally down-regulated the expression of ErbB4 in vitro. Moreover, miR-302b inhibited proliferation by inducing apoptosis and repressed invasion in the ESCC cell lines., Conclusions: miR-302b is a potential molecular marker of ESCC and functions as a tumor suppressor by post-transcriptionally regulating ErbB4.

The purpose of this study was to determine the expression of miR-127 and analyze its prognostic and biological significance in breast cancer (BC). A quantitative reverse transcription PCR assay was performed to detect the expression of miR-127 in 15 pairs of BC and corresponding noncancerous tissues. The expression of miR-127 was detected in another 110 BC tissues and its correlations with clinicopathological factors of patients were examined. Univariate and multivariate analyses were performed to analyze the prognostic significance of miR-127 expression. The effects of miR-127 expression on malignant phenotypes of BC cells and its possible molecular mechanisms were further determined. miR-127 was significantly downregulated in BC tissues, and low miR-127 expression was significantly correlated with lymph node metastasis and advanced clinical stage. Patients with low miR-127 showed poorer overall survival than those with high miR-127. Multivariate analyses indicated that status of miR-127 was an independent prognostic factor for patients. Functional analyses showed that upregulation of miR-127 significantly inhibited growth, enhanced apoptosis, and reduced migration and invasion in BC cells by targeting the protooncogene BCL-6. Therefore, miR-127 may be a potential biomarker for predicting the survival of BC patients and might be a molecular target for treatment of human BCs.

Objective: Dysregulation of microRNAs (miRNAs) plays critical roles in tumor progression. The aim of this study was to investigate the clinicopathologic and prognostic significance of miR-497 expression in human breast cancer (BC)., Methods: Taqman qRT-PCR assay was performed to detect the expression of microRNA (miR)-497 in 30 pairs of BC tissues and corresponding noncancerous breast tissues. Additionally, the expression of this miRNA was detected in another 128 BC tissues and its correlations with clinicopathologic features of patients were analyzed. Kaplan-Meier analyses were used to assess survival of patients. Univariate and multivariate analyses were performed using the Cox proportional hazards model to analyze the prognostic significance of miR-497 expression., Results: Our data indicated that the relative level of miR-497 expression in BC tissues was significantly lower than that in corresponding noncancerous breast tissues (P = 0.0046). Of 128 BC patients, 74 (57.8%) were placed in the high-miR-497 group and 54 (42.2%) were placed in the low-miR-497 group. By statistical analyses, low miR-497 expression was observed to be closely correlated with higher differentiation grade, positive HER-2 expression, higher incidence of lymph node metastasis and advanced clinical stage. Moreover, patients with high miR-497 expression had better 5-year disease-free and overall survival compared with the low miR-497 group (P = 0.0124 and 0.0018, respectively). Univariate and multivariate analyses indicated that low miR-497 expression was an independent poor prognostic factor for BC patients., Conclusions: Our data provided the first evidence that downregulation of miR-497 was correlated with BC progression, and miR-497 might be a potential molecular biomarker for predicting the prognosis of patients., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2025828761093488.

Background: MicroRNA-206 (miR-206), as a homolog of miR-1, plays important roles in tumorigenesis and tumor progression of various human malignancies, including breast cancer, endometrial endometrioid carcinoma, rhabdomyosarcoma, glioma, lung cancer, and laryngeal cancer. However, its involvement in gastric cancer has remained unclear., Aim: To examine the expression patterns and clinical implications of miR-206 in gastric cancer., Materials and Methods: Quantitative RT-PCR was performed to evaluate the expression levels of miR-206 in 98 pairs of gastric cancer and normal adjacent mucosa. In addition, the clinicopathologic significance and the prognostic value of miR-206 expression were further determined., Results: At first, miR-206 expression was significantly downregulated in gastric cancer tissues when compared with normal adjacent mucosa (P<0.001). Next, tumors with low miR-206 expression had a greater extent of lymph node metastasis (P=0.01), presence of venous invasion (P=0.008), and hematogenous recurrence (P=0.01), and were at a worse stage (P=0.03) than the tumors with a high miR-206 expression. Then, the gastric cancer patients with a low miR-206 expression had shorter overall survival than those with a high miR-206 expression (P=0.02). Furthermore, multivariate analysis showed that miR-206 expression was an independent prognostic factor for patients with gastric cancer., Conclusion: Our results strongly suggest that the downregulation of miR-206 was significantly correlated with tumor progression and may be a potent prognostic marker of gastric cancer. miR-206 might serve as a promising therapeutic target for the treatment of this cancer.