• Epithelial-mesenchymal transition (EMT)
• Hepatocellular carcinoma
• TGF-β signaling pathway
• Targeted therapy
• miRNAs

• Humans
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• beta Catenin/metabolism
• Cell Line, Tumor
• Wnt Signaling Pathway/physiology
• Transforming Growth Factor beta/metabolism
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Cell Movement

• Hsa-miR-214-3p
• biomarkers
• hsa-miR-3178
• hsa-miR-3182
• hsa-miR-4488
• next generation sequencing

The tumor microenvironment (TME) is a well-recognized system that plays an essential role in tumor initiation, development, and progression. Intense intercellular communication between tumor cells and other cells (especially macrophages) occurs in the TME and is mediated by cell-to-cell contact and/or soluble messengers. Emerging evidence indicates that noncoding RNAs (ncRNAs) are critical regulators of the relationship between cells within the TME. In this review, we provide an update on the regulation of ncRNAs (primarily micro RNAs [miRNAs], long ncRNAs [lncRNAs], and circular RNAs [circRNAs]) in the crosstalk between macrophages and tumor cells in hepatocellular carcinoma (HCC). These ncRNAs are derived from macrophages or tumor cells and act as oncogenes or tumor suppressors, contributing to tumor progression not only by regulating the physiological and pathological processes of tumor cells but also by controlling macrophage infiltration, activation, polarization, and function. Herein, we also explore the options available for clinical therapeutic strategies targeting crosstalk-related ncRNAs to treat HCC. A better understanding of the relationship between macrophages and tumor cells mediated by ncRNAs will uncover new diagnostic biomarkers and pharmacological targets in cancer.

• circular RNA (circRNA)
• hepatocellular carcinoma (HCC)
• long noncoding RNA (lncRNA)
• microRNA (miRNA)
• noncoding RNA (ncRNA)
• tumor microenvironment (TME)
• tumor-associated macrophage (TAM)

Hepatocellular carcinoma (HCC) has threatened the health of humans, and few therapeutic strategies can completely uproot this illness. Bioinformatics methods have been widely used for investigating the pathological mechanisms of disease. In this study, datasets including GSE20077 and GSE108724, obtained from the Gene Expression Omnibus (GEO) database, were used for investigating the biomarker and molecular mechanism of HCC. The differentially expressed genes (DEGs) in the datasets were identified, and the targets of the miRNAs were searched in the miRDIP and miRNET databases. Enrichment analysis was performed for delving the molecular mechanism of DEGs, and protein-protein interaction (PPI) networks and miRNA-mRNA networks were used to reveal the hub nodes and the related interaction relationships. Moreover, the expression and diagnostic values of hub nodes were analyzed with the GEPIA2 database. The results showed that 53 upregulated miRNAs and 48 downregulated miRNAs were found in GSE20077, and 55 upregulated miRNAs and 69 downregulated miRNAs were found in GSE108724. Moreover, seven common miRNAs including miR-146b-5p, miR-338-3p, miR-375, miR-502-3p, miR-532-3p, miR-532-5p, and miR-557 were found in the datasets. The targets of the common miRNAs were related with the P53, HIF1, Wnt, and NF-κB pathways. Besides, YWHAZ and CDC42 were identified as the hub nodes and served as the downstream targets of miR-375-3p. The GEPIA2 database showed that YWHAZ and CDC42 were related with the survival rate of the patients. In conclusion, this study suggests that miR-375-3p functions as a tumor suppressor which could inhibit the progression of HCC via targeting YWHAZ and CDC42.

• National Natural Science Foundation of China

Liver cancer is one of the most highly malignant cancers, characterized by easy metastasis and chemoradiotherapy resistance. Emerging evidence indicates that long noncoding RNAs (LncRNAs), including Lnc524369, are highly involved in the initiation, progression, radioresistance, and chemoresistance of hepatocellular carcinoma (HCC). However, the function of Lnc524369 remains unclear.

To explore the function of Lnc524369 in HCC.

To investigate the effect of Lnc524369, tissue from 41 HCC patients were analyzed using CCK8, migration, and invasion assays. Lnc524369 and YWHAZ (also named 14-3-3ζ) mRNA were detected by qPCR, and YWHAZ and RAF1 proteins were detected by western blot in liver cancer cell lines and human HCC tissues. The Cancer Cell Line Encyclopedia (CCLE) databases, STRING database, Human Protein Atlas database, and the TCGA database were used for bioinformatic analysis.

Lnc524369 was significantly upregulated in the nucleus of liver cancer cells and human HCC tissues. Overexpression of Lnc524369 was associated with the proliferation, migration, and invasion of liver cancer cells. YWHAZ and RAF1 proteins and YWHAZ mRNA were overexpressed in liver cancer, which could be attenuated by overexpression of Lnc524369. Lnc524369 and its downstream target YWHAZ and RAF1 proteins were negatively associated with overall survival time.

Lnc524369 might be a promising target of HCC as it can enhance liver cancer progression and decrease the overall survival time of HCC by activating the YWHAZ/RAF1 pathway.

• Long noncoding RNAs
• Lnc524369
• Hepatocellular carcinoma
• YWHAZ
• RAF1

The role of circular RNAs has made breakthroughs in understanding the mechanisms of tumor development. Bladder cancer has an increasing incidence, high recurrence rate, high metastatic potential, poor prognosis, and susceptibility to chemotherapy resistance. Thus, it is essential to identify molecules related to the tumorigenesis of bladder cancer. In this review, we summarize current knowledge about the expression of circular RNAs in bladder cancer and their implications in vesical carcinogenesis. We further discuss the limitations of existing studies and provide an outlook for future studies in the hopes of better revealing the association between circular RNAs and bladder cancer.

Bladder cancer (BC) is among the top ten most common cancer types worldwide and is a serious threat to human health. Circular RNAs (circRNAs) are a new class of non-coding RNAs generated by covalently closed loops through back-splicing. As an emerging research hotspot, circRNAs have attracted considerable attention due to their high conservation, stability, abundance, and specificity of tissue development. Accumulating evidence has revealed different form of circRNAs are closely related to the malignant phenotype, prognosis and chemotherapy resistance of BC, suggesting that different circRNAs may be promising biomarkers and have therapeutic significance in BC. The intention of this review is to summarize the mechanisms of circRNA-mediated BC progression and their diagnostic and prognostic value as biomarkers, as well as to further explore their roles in chemotherapy resistance.

• biomarker
• bladder cancer
• circular RNA
• drug resistance
• signaling pathways

• competing endogenous RNA
• hepatocellular carcinoma
• long noncoding RNA
• microRNA

• ovarian granulosa cells
• polycystic ovary syndrome
• propofol

The present study aimed to investigate whether microRNA (miR)-451a plays a role in polycystic ovary syndrome by regulating the biological function of ovarian granulosa cells and investigate the underlying molecular mechanism. In the present study, reverse transcription-quantitative PCR (RT-qPCR) analysis detected markedly low expression of miR-451a in KGN cells. TargetScan predicted that cyclic AMP-dependent transcription factor ATF-2 (ATF2) was a potential target gene of miR-451a, which was confirmed by a Dual-Luciferase reporter gene assay. Moreover, western blotting and RT-qPCR experiments indicated that ATF2 was significantly overexpressed in KGN cells. In addition, western blotting and RT-qPCR experiments were utilized to assess cell transfection efficiency, and it was found that miR-451a mimic significantly increased miR-451a expression in KGN cells. Subsequently, MTT assay was performed to detect cell proliferation and flow cytometry was utilized to detect cell apoptosis. Western blot and RT-qPCR assays were utilized to assess the protein and mRNA expression of ATF2 and cyclin D1. The results confirmed that miR-451a mimic significantly decreased ATF2 protein and mRNA expression in KGN cells, and this decrease was reversed by ATF2-plasmid co-transfection. Moreover, miR-451a mimic inhibited cell proliferation, enhanced cell apoptosis, reduced cyclin D1 expression, increased caspase-3 activity and cleaved caspase-3 protein levels, while it reduced pro-caspase 3 protein levels in KGN cells, and these effects were significantly reversed by ATF2-plasmid. The present preliminary results demonstrated that miR-451a regulated the proliferation and apoptosis of ovarian granulosa cells by targeting ATF2. Thus, the miR-451a/ATF2 axis may be a new potential target for the treatment of polycystic ovary syndrome.

• apoptosis
• microRNA-451a
• ovarian granulosa cells
• polycystic ovary syndrome
• proliferation

• Chromosome loop
• DNA methylation
• EZH2
• Hepatocellular carcinoma
• Mir-144
• Tumor-associated macrophage
• miR-451a

• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Disease Progression
• Down-Regulation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Hepatocyte Growth Factor/genetics
• Histones/metabolism
• Humans
• Intramolecular Oxidoreductases/genetics
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Macrophage Migration-Inhibitory Factors/genetics
• Male
• Mice
• MicroRNAs/genetics
• Neoplasm Transplantation
• Paracrine Communication
• Sequence Analysis, RNA
• Tumor-Associated Macrophages/pathology

• National Natural Science Foundation of China
• National Nature Science Foundation of China

• 3-phosphoinositide-dependent protein kinase-1
• PI3K/AKT signaling pathway
• cutaneous squamous cell carcinoma
• invasion
• microRNA-451a
• migration

Osteosarcoma is the most common bone tumor and is characterized by the presence of malignant mesenchymal cells produced in the bone stroma. MiRNAs are known to function as post-transcriptional negative regulators of gene expression. Emerging evidence showed that miR-1225-5P functions as a tumor suppressor in several types of cancers. The detailed mechanisms of which miR-1225-5P suppresses tumor growth are not fully understood. The objective of the present study was to test the hypothesis that miR-1225-5P inhibits osteosarcoma cell growth in vitro and tumor growth in vivo by targeting YWHAZ expression.

Real-time PCR and Western blot were carried out to test the expression of miR-1225-5P and YWHAZ in osteosarcoma cell lines. Luciferase assay was used to demonstrate whether miR-1225-5P targets YWHAZ 3ʹ UTR. To assess the function of miR-1225-5P in human osteosarcoma cell lines, gain-of-function and loss-of-function of miR-1225-5P were performed by transfecting miR-1225-5P mimic or miR-1225-5P inhibitor into osteosarcoma cell lines. Furthermore, cell cycle analysis was performed to elucidate the possible mechanisms of the action of miR-1225-5P and YWHAZ in human osteosarcoma cells. The potential therapeutic effect of miR-1225-5p was tested in human osteosarcoma xenograft mouse model, by intravenous injection of miR-1225-5P into nude mice. Tumor sizes were measured and lung metastasis was counted after the mice were sacrificed.

The expression of miR-1225-5P was inversely correlated with the expression of YWHAZ in human osteosarcoma cell lines. Database search revealed that miR-1225-5P targeted YWHAZ 3ʹ UTR. Transfection of miR-1225-5P mimic downregulated YWHAZ expression, which was demonstrated by real-time PCR, Western blot and luciferase assay. Over-expression of miR-1225-5P reduced human osteosarcoma cell growth, migration and invasion by downregulating YWHAZ expression. Cell growth, migration and invasion were increased by inhibiting miR-1225-5P in human osteosarcoma cells. The inhibition of cell growth, migration and invasion was rescued by over-expression of YWHAZ in osteosarcoma cells. Cell cycle analysis revealed that miR-1225-5P inhibited G1/G0 phase exit. In vivo xenograft model demonstrated that miR-1225-5P inhibited in vivo osteosarcoma tumor growth and lung metastasis.

Our findings suggested that miR-1225-5P inhibits osteosarcoma cell growth in vitro and tumor growth in vivo by targeting YWHAZ. This study suggested that miR-1225-5P can serve as a potential therapeutic method for treating osteosarcoma.

• YWHAZ
• metastasis
• miR-1225-5P
• microRNA
• osteosarcoma

Paclitaxel is an effective chemotherapeutic agent for the treatment of cancer patients. Accumulating evidence suggests that circular RNAs (circRNAs) play critical roles in the occurrence and development of human cancers. However, there are few studies on interactions between paclitaxel and circRNAs in hepatocellular carcinoma (HCC).

Cell counting kit-8 (CCK-8) assay and colony formation assay were conducted to determine cell proliferation. Cell apoptosis was assessed by flow cytometry. The expression levels of circRNA baculoviral IAP repeat-containing 6 (circ-BIRC6), microRNA-877-5p (miR-877-5p), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta (YWHAZ) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The mice xenograft model was established to investigate the roles of circ-BIRC6 and paclitaxel in vivo. The interaction between miR-877-5p and circ-BIRC6 or YWHAZ was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay. Western blot assay was applied for measuring the protein expression of YWHAZ.

Paclitaxel suppressed HCC tumorigenesis through decreasing cell proliferation and accelerating apoptosis. Circ-BIRC6 and YWHAZ were upregulated, and miR-877-5p was downregulated in HCC tissues and cells. Paclitaxel treatment inhibited the expression of circ-BIRC6 and YWHAZ while promoted the expression of miR-877-5p. Circ-BIRC6 overexpression or miR-877-5p interference reversed the inhibitory effect of paclitaxel on HCC tumorigenesis. Moreover, miR-877-5p could specially bind to YWHAZ, and its knockdown abated the suppressive effect of circ-BIRC6 depletion on HCC tumorigenesis. Additionally, YWHAZ was identified as a direct target of miR-877-5p. Besides, circ-BIRC6 functioned as a molecular sponge of miR-877-5p to regulate YWHAZ expression.

Paclitaxel limited HCC tumorigenesis via modulating circ-BIRC6/miR-877-5p/YWHAZ axis, providing a novel therapeutic approach for the treatment of HCC.

• YWHAZ
• circ-BIRC6
• hepatocellular carcinoma
• miR-877-5p
• paclitaxel

• RT-qPCR
• follicular adenoma
• follicular thyroid cancer
• invasion
• miRNA
• reciprocal dysregulation

• Adenocarcinoma, Follicular/genetics
• Adenocarcinoma, Follicular/metabolism
• Adenocarcinoma, Follicular/pathology
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Female
• Humans
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Neoplasm Invasiveness
• Phenotype
• Thyroid Neoplasms/genetics
• Thyroid Neoplasms/metabolism
• Thyroid Neoplasms/pathology

• bladder cancer
• cancer therapy
• epithelial-to-mesenchymal transition (EMT)
• metastasis
• microRNA (miRNA)

• Epithelial-Mesenchymal Transition/drug effects
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System/genetics
• MAP Kinase Signaling System/immunology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasm Metastasis
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Transforming Growth Factor beta/metabolism
• Urinary Bladder Neoplasms/genetics
• Urinary Bladder Neoplasms/metabolism
• Urinary Bladder Neoplasms/pathology
• Wnt Signaling Pathway/genetics

YWHAZ (also named 14-3-3ζ) is a central hub protein for many signal transduction pathways and plays a significant role in tumor progression. Accumulating evidences have demonstrated that YWHAZ is frequently up-regulated in multiple types of cancers and acts as an oncogene in a wide range of cell activities including cell growth, cell cycle, apoptosis, migration, and invasion. Moreover, YWHAZ was reported to be regulated by microRNAs (miRNAs) or long non-coding RNAs and exerted its malignant functions by targeting downstream molecules like protein kinase, apoptosis proteins, and metastasis-related molecules. Additionally, YWHAZ may be a potential biomarker of diagnosis, prognosis and chemoresistance in several cancers. Targeting YWHAZ by siRNA, shRNA or miRNA was reported to have great help in suppressing malignant properties of cancer cells. In this review, we perform literature and bioinformatics analysis to reveal the oncogenic role and molecular mechanism of YWHAZ in cancer, and discuss the potential clinical applications of YWHAZ concerning diagnosis, prognosis, and therapy in malignant tumors.

• YWHAZ
• biomarker
• cancer
• function
• molecular mechanism

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.

• HCC
• animal models
• microRNA