SCARB1-encoded circ _0029343 induces p73 splicing to promote growth and metastasis of hepatocellular carcinoma via miR-486-5p/SRSF3 axis.

Circular RNAs (circRNAs) exhibit essential regulation in the malignant development of hepatocellular carcinoma (HCC). This study aims to investigate the physiological mechanisms of circ_0029343 encoded by scavenger receptor class B member 1 (SCARB1) involved in the growth and metastasis of HCC. Differentially expressed mRNAs in HCC were obtained, followed by the prediction of target genes of differentially expressed miRNAs and gene ontology and kyoto encyclopedia of genes and genomes analysis on the differentially expressed mRNAs. Moreover, the regulatory relationship between circRNAs encoded by SCARB1 and differentially expressed miRNAs was predicted. In vitro cell experiments were performed to verify the effects of circ_0029343, miR-486-5p, and SRSF3 on the malignant features of HCC cells using the gain- or loss-of-function experiments. Finally, the effects of circ_0029343 on the growth and metastasis of HCC cells in xenograft mouse models were also explored. It was found that miR-486-5p might interact with seven circRNAs encoded by SCARB1, and its possible downstream target gene was SRSF3. Moreover, SRSF3 was associated with the splicing of various RNA. circ_0029343 could sponge miR-486-5p to up-regulate SRSF3 and activate PDGF-PDGFRB (platelet-derived growth factor and its receptor, receptor beta) signaling pathway by inducing p73 splicing, thus promoting the proliferation, migration, and invasion and inhibiting apoptosis of HCC cells. In vivo, animal experiments further confirmed that overexpression of circ_0029343 could promote the growth and metastasis of HCC cells in nude mice. circ_0029343 encoded by SCARB1 may induce p73 splicing and activate the PDGF-PDGFRB signaling pathway through the miR-486-5p/SRSF3 axis, thus promoting the growth and metastasis of HCC cells.

LOXL4 Shuttled by Tumor Cells-derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis.

Emerging evidence has validated that extracellular vesicles (EVs) regulate hepatocellular carcinoma (HCC) progression, while its role in HCC immune escape remains to be elucidated. This study investigates the role of EVs-encapsulated lysyl oxidase like-4 (LOXL4) derived from tumor cells in HCC immune escape. HCC-related microarray data sets GSE36376 and GSE87630 were obtained for differential analysis, followed by identifying the essential genes related to the prognosis of HCC patients. Bone marrow-derived macrophages were treated with EVs derived from mouse Hepa 1-6 cells and cocultured with CD8 + T cells to observe the CD8 + T-cell activity. At last, a mouse HCC orthotopic xenograft model was constructed to verify the effects of HCC cell-derived EVs on the immune escape of HCC cells and tumorigenicity in vivo by delivering LOXL4. It was found that ACAT1, C4BPA, EHHADH, and LOXL4 may be the essential genes related to the prognosis of HCC patients. On the basis of the TIMER database, there was a close correlation between LOXL4 and macrophage infiltration in HCC. Besides, STAT1 was closely related to LOXL4. In vitro experiments demonstrated that LOXL4 could induce programmed death-ligand 1 expression in macrophages and immunosuppression by activating STAT1. In vivo experiments also verified that HCC cell-derived EVs promoted the immune escape of HCC cells and tumorigenicity by delivering LOXL4. LOXL4 was delivered into macrophages via EVs to induce programmed death-ligand 1 by activating STAT1 and inhibiting the killing ability of CD8 + T cells to HCC cells, thus promoting immune escape in HCC.

Retinogenesis in a Dish: Bibliometric Analysis and Visualization of Retinal Organoids From 2011 to 2022.

Retinal organoid (RO) is the three-dimensional (3D) retinal culture derived from pluripotent or embryonic stem cells which recapitulates organ functions, which was a revolutionary milestone in stem cell technology. The purpose of this study is to explore the hotspots and future directions on ROs, as well as to better understand the fields of greatest research opportunities. Eligible publications related to RO from 2011 to 2022 were acquired from the Web of Science (WoS) Core Collection database. Bibliometric analysis was performed by using software including VOSviewer, CiteSpace, and ArcGIS. A total of 520 articles were included, and the number of annual publications showed a rapid increase with an average rate of 40.86%. The United States published the most articles (241/520, 46.35%) with highest total citation frequencies (5,344). University College London (UK) contributed the largest publication output (40/520, 7.69%) and received highest total citation frequencies. Investigative Ophthalmology & Visual Science was the most productive journal with 129 articles. Majlinda Lako contributed the most research with 32 articles, while Olivier Goureau has the strongest collaboration work. Research could be subdivided into four keyword clusters: "culture and differentiation," "morphogenesis and modeling," "gene therapy," and "transplantation and visual restoration," and evolution of keywords was identified. Last decade has witnessed the huge progress in the field of RO, which is a young and promising research area with extensive and in-depth studies. More attention should be paid to RO-related models and therapies based on specific retinal diseases, especially inherited retinopathies.

JMJD6-BRD4 complex stimulates lncRNA HOTAIR transcription by binding to the promoter region of HOTAIR and induces radioresistance in liver cancer stem cells.

BACKGROUND: Long non-coding RNA (lncRNA) HOTAIR acts importantly in liver cancer development, but its effect on radioresistance remains poorly understood. Here, our study probed into the possible impact of HOTAIR in radioresistance in liver cancer stem cells (LCSCs) and to elucidate its molecular basis. METHODS: Following sorting of stem and non-stem liver cancer cells, LCSCs were identified and subjected to RNA-seq analysis for selecting differentially expressed genes. Expression of HOTAIR was determined in liver cancer tissues and CSCs. The stemness, proliferation, apoptosis and radioresistance of LCSCs were then detected in response to altered expression of HOTAIR-LSD1-JMJD6-BRD4. RESULTS: Ectopic HOTAIR expression was found to promote radioresistance of LCSCs by maintaining its stemness. Mechanistic investigations indicated that HOTAIR recruited LSD1 to the MAPK1 promoter region and reduced the level of H3K9me2 in the promoter region, thus elevating ERK2 (MAPK1) expression. JMJD6-BRD4 complex promoted HOTAIR transcription by forming a complex and positively regulated ERK2 (MAPK1) expression, maintaining the stemness of LCSCs, and ultimately promoting their radioresistance in vitro and in vivo. CONCLUSION: Collectively, our work highlights the promoting effect of the JMJD6-BRD4 complex on the radioresistance of LCSCs through a HOTAIR-dependent mechanism.

Extracellular Vesicle-Loaded Oncogenic lncRNA NEAT1 from Adipose-Derived Mesenchymal Stem Cells Confers Gemcitabine Resistance in Pancreatic Cancer via miR-491-5p/Snail/SOCS3 Axis.

It is becoming increasingly evident that key mechanisms of mesenchymal stem cell (MSC) efficacy appear to associate with paracrine activities, and the delivery of cargos through extracellular vesicles (EVs) controls the mechanistic actions of MSCs. Thus, this study clarified a possible mechanism by which EV-encapsulated NEAT1 from adipose-derived mesenchymal stem cells (ADSCs) might mediate gemcitabine resistance in pancreatic cancer (PCa). Microarray profile suggested a differentially expressed lncRNA NEAT1 in PCa, and we determined its expression in PCa cells. NEAT1 was found to be upregulated in PCa. The binding affinity among NEAT1, miR-491-5p, and Snail was identified through bioinformatic analysis and experimental validation. NEAT1 competitively bound to miR-491-5p to elevate Snail expression and diminish SOCS3 expression. PCa cells were cocultured with EVs extracted from ADSCs, followed by assessment of malignant phenotypes, tumorigenesis, and gemcitabine resistance of PCa cells using gain- or loss-of-function experiments. ADSC-derived EVs carrying NEAT1 promoted PCa cell proliferation, migration, and gemcitabine resistance in vitro and enhanced tumorigenicity in vivo by inhibiting miR-491-5p and SOCS3 and upregulating Snail. Collectively, the findings from our study found a new potential strategy for gemcitabine resistance in PCa by illustrating the mechanistic insights of oncogenic ADSC-derived EVs-loaded NEAT1 via regulating the miR-491-5p/Snail/SOCS3 axis.

Tumor-suppressor p53 specifically binds to miR-29c-3p and reduces ADAM12 expression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an extremely aggressive malignant tumor associated with high migratory and invasive potential. The present study intends to explore regulatory mechanism of p53/microRNA (miR)-29c-3p/A disintegrin and metalloproteinase 12 (ADAM12) axis in HCC based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology. METHODS: Putative miR-29c-3p binding sites on ADAM12 3'UTR were verified by a luciferase assay. The binding affinity of p53 to miR-29c-3p was assessed based on CRISPR/Cas9 technology to construct a p53 knockout (p53-/-) HCCLM3 cell line. Furthermore, the effect of p53/miR-29c-3p/ADAM12 was assessed on maligant phenotypes in vitro and tumor formation and metastasis in nude mice. RESULTS: ADAM12 was highly expressed but miR-29c-3p was poorly expressed in HCC. miR-29c-3p inhibited migratory and invasive abilities of HCC cells by targeting ADAM12 expression. p53 was found to target and upregulate miR-29c-3p, thus downregulating ADAM12 and conferring inhibitory effect on HCC cell activities. Moreover, ADAM12 knockout or p53 overexpression reduced HCC tumor formation and metastasis, which were reversed by further silencing of miR-29c-3p. CONCLUSION: The identification of the p53/miR-29c-3p/ADAM12 axis in migration and invasion of HCC may potentially further our understanding of mechanisms underpinning HCC, and also bear translational value as novel molecular targets.

Suppression of histone deacetylase 1 by JSL-1 attenuates the progression and metastasis of cholangiocarcinoma via the TPX2/Snail axis.

Histone deacetylases (HDACs) are entwined with the pathogenesis of various cancers and potentially serve as promising therapeutic targets. Herein, we intend to explore the potential role of HDAC1 inhibitor (JSL-1) in the tumorigenesis and metastasis of cholangiocarcinoma (CC) and to highlight the molecular basis of its function. As shown by bioinformatics analysis and immunohistochemical detection, high HDAC1 expression was witnessed in CC tissues relative to matched controls from patients with cholecystitis. The molecular network that HDAC1 silencing reduced the enrichment of HDAC1 and Snail on the TPX2 promoter was identified using immunoprecipitation and chromatin immunoprecipitation assays. Both short hairpin RNA (shRNA)-mediated knockdown of HDAC1 and JSL-1 treatment exhibited anti-proliferative, anti-migration and anti-invasion effects on CC cells through downregulation of TPX2. The in vivo xenograft model was developed in nude mice. Consistently, the anti-tumorigenic and anti-metastatic properties of shRNA against HDAC1 and HDAC1 inhibitor were validated in the in vivo settings. Taken together, our data supported the notion that HDAC1 inhibitor retards the initiation and development of CC via mediating the TPX2/Snail axis, highlighting the anti-tumor molecular network functioned in CC.

Tumor suppressive lncRNA MEG3 binds to EZH2 and enhances CXCL3 methylation in gallbladder cancer.

Gallbladder cancer is a malignant tumor with a high mortality rate. Accumulating evidence supports that lncRNA MEG3 may halt the progression of gallbladder cancer, while the downstream mechanism is rarely studied. Thus, we aim to investigate the molecular basis of the tumor-suppressing role of lncRNA MEG3 in gallbladder cancer. The expression of lncRNA MEG3 and CXCL3 was measured in patient serum and cell lines of gallbladder cancer. The viability, apoptosis, migration, and invasion of gallbladder cancer cells were assessed following ectopic MEG3 expression, as detected by CCK-8, flow cytometry, and Transwell assays. The interaction among lncRNA MEG3, EZH2, and CXCL3 was explored through ChIP, RNA pull-down, and RIP assays. The effects of lncRNA MEG3 and CXCL3 on tumor growth were evaluated by a mouse xenograft model. lncRNA MEG3 was expressed at a low level in gallbladder cancer patient serum and cell lines, while CXCL3 was highly expressed. MEG3 overexpression repressed the malignant behaviors of gallbladder cancer cells and promoted their apoptosis. MEG3 was mainly localized in the nucleus. MEG3 bound to EZH2, and EZH2 catalyzed the H3K27 trimethylation of the CXCL3 promoter region. MEG3 downregulated CXCL3 by activating EZH2-mediated H3K27 trimethylation of CXCL3; MEG3 overexpression attenuated cancer cell malignant behaviors in vitro and suppressed tumor growth in vivo in gallbladder cancer by inhibiting CXCL3 expression. Altogether, our results indicate that lncRNA MEG3 impedes gallbladder cancer development via the EZH2-CXCL3 axis, offering potential biomarkers for gallbladder cancer management.

Enhancer of zeste homolog 2 promotes hepatocellular cancer progression and chemoresistance by enhancing protein kinase B activation through microRNA-381-mediated SET domain bifurcated 1.

Metastasis and chemoresistance are the leading causes of death in patients with hepatocellular carcinoma (HCC). microRNAs (miRNAs or miRs) may be useful as diagnostic, therapeutic and prognostic markers for HCC. In this study, we set out to investigate the possible role of miR-381 in HCC development and chemoresistance along with the related mechanism. Microarray-based gene expression profiling was carried out to analyze the expression of SET domain bifurcated 1 (SETDB1) and histone methyltransferase enhancer of zeste homolog 2 (EZH2) followed by validation in clinical HCC tissues and cells. The potential binding between miR-381 and SETDB1 was found and verified. Then, the role of SETDB1 in HCC in relation to miR-381 and protein kinase B (AKT) pathway was explored through gain- and loss-of-function approaches. After expression determination of EZH2, SETDB1, miR-381, and AKT pathway-related factors, their reactions were analyzed and their functional roles in HCC progression and chemoresistance were investigated in vitro and in vivo. SETDB1 was aberrantly upregulated in clinical HCC tissues and cells. This upregulation activated AKT pathway by promoting its tri-methylation on K64. SETDB1 promoted the proliferation, migration and chemoresistance through the AKT pathway in HCC cells. In a xenograft mouse model, SETDB1 promoted HCC cell tumorigenesis in vivo by activating the AKT pathway. Furthermore, EZH2 suppressed miR-381 by catalyzing the activity of H3K27me3 on its promoter region. In conclusion, EZH2 suppressed miR-381 expression by promoting H3K27me3 activity on its promoter region to facilitate SETDB1 expression, thereby activating the AKT pathway to promote hepatocarcinogenesis and chemoresistance.

Overview of global publications on machine learning in diabetic retinopathy from 2011 to 2021: Bibliometric analysis.

Purpose: To comprehensively analyze and discuss the publications on machine learning (ML) in diabetic retinopathy (DR) following a bibliometric approach. Methods: The global publications on ML in DR from 2011 to 2021 were retrieved from the Web of Science Core Collection (WoSCC) database. We analyzed the publication and citation trend over time and identified highly-cited articles, prolific countries, institutions, journals and the most relevant research domains. VOSviewer and Wordcloud are used to visualize the mainstream research topics and evolution of subtopics in the form of co-occurrence maps of keywords. Results: By analyzing a total of 1147 relevant publications, this study found a rapid increase in the number of annual publications, with an average growth rate of 42.68%. India and China were the most productive countries. IEEE Access was the most productive journal in this field. In addition, some notable common points were found in the highly-cited articles. The keywords analysis showed that "diabetic retinopathy", "classification", and "fundus images" were the most frequent keywords for the entire period, as automatic diagnosis of DR was always the mainstream topic in the relevant field. The evolution of keywords highlighted some breakthroughs, including "deep learning" and "optical coherence tomography", indicating the advance in technologies and changes in the research attention. Conclusions: As new research topics have emerged and evolved, studies are becoming increasingly diverse and extensive. Multiple modalities of medical data, new ML techniques and constantly optimized algorithms are the future trends in this multidisciplinary field.

Tumor-derived extracellular vesicles containing long noncoding RNA PART1 exert oncogenic effect in hepatocellular carcinoma by polarizing macrophages into M2.

AIM: We explored whether tumor-derived extracellular vesicles (EVs) could deliver long noncoding RNA (lncRNA) PART1 into macrophage to orchestrate macrophage polarization in the progression of hepatocellular carcinoma (HCC). METHOD: The expression patterns of PART1, microRNA (miR)-372-3p and TLR4 were detected by RT-qPCR in the HCC tissues and HCC cells. PART1 was silenced or overexpressed in HCC cells to assess its effects on the HCC cell process. EVs were isolated from PART1-overexpressed HCC cells, and co-cultured with macrophages, and gain- and loss-of-function assays were implemented in macrophages to evaluate their role in macrophage polarization. Relationship among PART1, miR-372-3p, and TLR4 was evaluated. Effect of EV-PART1 on tumorigenicity in vivo was detected by subcutaneous tumorigenicity test in nude mice. RESULT: PART1 and TLR4 were upregulated while miR-372-3p was downregulated in HCC tissues and cells. PART1 increased HCC cell proliferation, migration, invasion, and EMT. Mechanistically, PART1 bound to miR-372-3p to downregulate its expression, whereas TLR4 was negatively targeted by miR-372-3p in the macrophages. EVs containing PART1, TLR4 overexpression, or miR-372-3p inhibition induced M2 polarization of macrophages. Also, EVs containing PART1 promoted M2 polarization of macrophages and the occurrence of HCC by affecting miR-372-3p/TLR4 axis. CONCLUSION: HCC cell-derived EVs might up-regulate TLR4 by inhibiting miR-372-3p via PART1 delivery to promote macrophage M2 polarization in HCC.

Research progress on neonatal Fc receptor and its application.

Neonatal Fc receptor (FcRn) is a specific receptor for immunoglobulin G (IgG) and albumin, which binds to them in a pH-dependent manner and prevents them from lysosomal degradation to keep a long plasma half-life. In addition, FcRn plays an important role in transmembrane transport of IgG and albumin and in antigen presentation. In autoimmune diseases, anti-FcRn antibody can promote the degradation of pathogenic IgG by competitive binding to FcRn. In infectious diseases, the half-life of drugs can be prolonged by increasing the affinity between therapeutic antibody and FcRn, while the combination of viral antigen and Fc fragment of IgG can cause local immune response of mucosa for disease prevention and treatment. In cancer, albumin as a carrier of anticancer drugs can achieve efficient drug delivery, and FcRn itself may be used as a predictor of the prognosis of cancer patients. This review details the functions of FcRn, highlights its role in autoimmune diseases, infectious diseases and cancer, as well as the mechanism of drug development based on FcRn, to provide a reference for the clinical application and drug development of FcRn.

Human gene therapy: A patent analysis.

Although seen as a revolution in modern science, gene therapy has been plagued by failed clinical trials and controversial ethics in the last thirty years. Moreover, there is no comprehensive, in-depth, high-quality analysis of global gene therapy patents. This paper proposes a method to correctly retrieve patents to address the issue and use it for the patent landscape. The results show the global patent landscape of gene therapy, with the United States dominating the field, while China has emerged as a leader in recent years. For various reasons, the EU, Korea, and Japan lag in the development of patented technologies. China has edged closer to the US in both live and indefinite patents, with the Chinese Academy of Military Medical Sciences and the Chinese Academy of Sciences leading the way, surpassing primary applicants such as the US Department of Health and Human Services, the University of California, and the University of Pennsylvania. The study also reveals four broad categories of technologies that have been extensively studied in gene therapy: basic biology of the gene and diseases, diseases being treated, gene delivery methods, and potential adverse events. What is more, Adeno-Associated Virus, Retrovirus, and Lentivirus are the most prevalent gene therapy delivery vectors after 2014. The industrial development trend revealed in this paper can provide an evidence-based basis for scientific research management and decision-making.

A Decade of CRISPR Gene Editing in China and Beyond: A Scientometric Landscape.

Since its Nobel Prize-winning breakthrough in 2012, CRISPR-Cas-based gene-editing system has emerged as one of the most promising biotechnologies in decades. In this article, we present an objective and comprehensive evaluation of CRISPR-based gene-editing technologies, including base editing and prime editing, based on the bibliometric analysis of 22,902 published records. We also assessed the status of CRISPR gene-editing technologies in academia from 2010 to 2020 globally, with respect to countries, institutions, and researchers, and used text clustering methods to assess technical trends and research hotspots. Our results indicate, not surprisingly, that this is a thriving and prominent area of research. By comparing the relevance and growth of CRISPR gene-editing technologies in China with other countries by several metrics, we show that the Chinese scientific community attaches considerable importance to the field of plant genome engineering, with more scholars from agricultural sectors than other sectors.

CAR-based cell therapy: evaluation with bibliometrics and patent analysis.

Chimeric antigen receptors-based cell therapies have shown impressive preclinical and clinical success and revolutionized biomedicine. However, the link between science and invention, the impact of international cooperation, and the influence and prestige of CARs research have not been explored. This study analyzed the landscape of peer-reviewed articles and patents related to CARs. A total of 5,681 publications were analyzed using bibliometrics and machine learning-based text mining to assess publication metrics, subject areas, and research hotspots. 5,010 Inpadoc families were also analyzed for patent filing trends, priority countries, and applicant and inventor rankings. The results show that CARs research has the following distinctive features: high research prestige among research community; strong global geographical bias in both academic output and patenting patterns; strong links between science and invention, but significant differences among countries; and an inverse relationship between country size and international collaboration rates.

Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease.

Mitochondria damage exacerbates NAFLD through trigerring AIM2 inflammasome activation and hepatocyte pyroptosis. This study provides novel insights into the underlying mechanisms of mitochondrial DNA synthesis in NAFLD and also suggests potential therapeutic targets for the treatment of NAFLD.

Human gene therapy: A scientometric analysis.

To provide a clear landscape, trends, and research frontiers of gene therapy, we systematically retrieved a total of 62,961 peer-viewed studies published between 1996 and 2020 from the Scopus, Web of Science, and 42,120 Inpadoc patent families from Derwent Innovation databases. Multiple bibliometric approaches suggest that gene therapy began to recover in 2013 after a period of significant decline. However, metrics in terms of authors and scholarly output growth, FWCI, annual citations, percentage of high-impact journal literature, and patent-citations per scholarly output are still weak at this stage, indicating a lack of research momentum. We also visualized gene therapy's knowledge structure by employing citation analysis, co-citation analysis, and co-word analysis, revealing its research hotspots and trends by text mining with Natural Language Processing. For the current predicament, we propose that the future success of gene therapy may depend on breakthroughs in more advanced and exhilarating technologies such as the CRISPR-Cas system, CAR-T cell therapies, and gene delivery vector technology. The results show that evidence-based bibliometrics allows the dissection of gene therapy to inform scientific planning and decision-making.

The potential mechanisms of piRNA to induce hepatocellular carcinoma in human.

The hepatocellular carcinoma, as one of the most frequently happened types of cancer in the world, has very complicated intracellular and extracellular molecular underlying pathogenic mechanisms. The role of genome and proteome in the proliferation and metastasis of the hepatocellular carcinoma has been thoroughly investigated, and many theories have been proposed. The subsequent developments, such as the targeted anti-cancer medicine or the treatment strategy, has profoundly influenced the prognosis of patients with hepatocellular carcinoma. As for the transcriptome, it is undeniable that the function of mRNA, rRNA even the long non-coding RNA have been discussed, while as a particular type of RNA-piRNA is not paid enough attention by the academy. piRNA is named because it always interacts with the piwi protein to achieve its physiological functions, with a length that is no more than 30 nucleotides. It is widely distributed in the reproductive organs such as the testis, the ovarian, and the stem cells. Previous studies have elucidated that the piRNA is closely closely related to the maturation of the sperms or the oocytes, even the progression of lung cancer. While the role and underlying molecular mechanisms of piRNA in the proliferation of hepatocellular carcinoma is not thoroughly researched and remained unknown. The authors in this article proposed potential mechanisms of piRNA to initiate the proliferation of hepatocellular carcinoma. We are hoping to provide a unique perspective to the academy and the following researches.

Lower Serum Matrix Metalloproteinase­9 in Metastatic Patients with Esophageal Squamous Cell Carcinoma After Concurrent Radiotherapy Was Significant for Prognosis.

AIM: This study was designed to investigate the relationships of serum matrix metalloproteinase 9 (MMP-9) level and treatment response in esophageal squamous cell carcinoma (ESCC) patients treated with chemotherapy or concurrent radiotherapy. METHODS: Blood samples from ESCC patients after chemotherapy or concurrent radiotherapy were collected at four different intervals. Serum MMP-9 was determined via Luminex assay in 134 patients with chemotherapy, 73 patients with concurrent radiotherapy, and 183 healthy controls. RESULTS: Serum MMP-9 level was significantly higher in patients with ESCC than in healthy controls (P <0.001). Compared with the pre-treatment, a lower level of serum MMP-9 was maintained at four cycles of treatment in ESCC patients with concurrent radiotherapy (P < 0.001). Serum MMP-9 level was obviously lower in ESCC patients with metastasis after concurrent radiotherapy than after chemotherapy (P < 0.05). Patients with higher MMP-9 level (≥820.693 ng/mL) had a shorter mean survival time by 42 months versus lower MMP-9 level (<820.693 ng/mL) after chemotherapy or concurrent radiotherapy (P < 0.001). CONCLUSION: Serum MMP-9 is a potential prognostic biomarker for treatment response to chemotherapy or concurrent radiotherapy in terms of overall survival (OS) in ESCC patients.

hsa_circ_001653 up-regulates NR6A1 expression and elicits gastric cancer progression by binding to microRNA-377.

NEW FINDINGS: What is the central question of this study? Does hsa_circ_001653 influence the development of gastric cancer (GC) and if so how? What is the main finding and its importance? Bioinformatics analysis revealed the presence of differentially expressed hsa_circ_001653 in GC and adjacent normal tissues, and this was strongly related to the pathology of patients with GC. Knockdown of hsa_circ_001653 suppressed the proliferation, invasion and migration of GC cells, while inducing cell apoptosis via miR-377-mediated NR6A1 inhibition. The effect of hsa_circ_001653 and miR-377 on tumour growth in GC was further confirmed in vivo. ABSTRACT: Gastric cancer (GC) is one of the leading causes of human mortality through malignant tumours. Circular RNAs (circRNAs) have been identified as binding to microRNAs (miRNAs) to modulate the progression of tumours. This study explores the role of hsa_circ_001653, a newly identified circRNA, in the development of GC. hsa_circ_001653 expression was measured in 86 paired normal and tumour tissues surgically resected from GC patients. Cross-talk between hsa_circ_001653 and microRNA-377 (miR-377)/nuclear receptor subfamily 6, group A, member 1 (NR6A1) was assessed using bioinformatics analysis, dual-luciferase reporter assay, Ago2 immunoprecipitation and western blot analysis. A series of functional experiments were carried out to elucidate the role of hsa_circ_001653 in GC cell proliferation, invasion, migration and apoptosis, and its underlying molecular mechanisms. Nude mice were inoculated with GC cells for in vivo analysis. hsa_circ_001653 was found to be an up-regulated circRNA in GC tissues and cells. Down-regulation of hsa_circ_001653 inhibited GC cell proliferation, migration and invasion, while stimulating cell apoptosis. hsa_circ_001653 was found to bind to miR-377, which targeted NR6A1 and repressed its expression. Inhibition of miR-377 and overexpression of NR6A1 restored the proliferation, migration and invasion in GC cells lacking hsa_circ_001653. Furthermore, inhibition of hsa_circ_001653 attenuated tumour growth in nude mice inoculated with GC cells. Collectively, the demonstration that hsa_circ_001653 exerts its anticancer effects by regulating the miR-377-NR6A1 axis increases our understanding of gastric cancer pathophysiology. The findings uncover new potential therapeutic targets for GC.