Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors.

Immune Checkpoint Inhibitors (ICIs) therapy has advanced significantly in treating malignant tumors, though most 'cold' tumors show no response. This resistance mainly arises from the varied immune evasion mechanisms. Hence, understanding the transformation from 'cold' to 'hot' tumors is essential in developing effective cancer treatments. Furthermore, tumor immune profiling is critical, requiring a range of diagnostic techniques and biomarkers for evaluation. The success of immunotherapy relies on T cells' ability to recognize and eliminate tumor cells. In 'cold' tumors, the absence of T cell infiltration leads to the ineffectiveness of ICI therapy. Addressing these challenges, especially the impairment in T cell activation and homing, is crucial to enhance ICI therapy's efficacy. Concurrently, strategies to convert 'cold' tumors into 'hot' ones, including boosting T cell infiltration and adoptive therapies such as T cell-recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, are under extensive exploration. Thus, identifying key factors that impact tumor T cell infiltration is vital for creating effective treatments targeting 'cold' tumors.

[Retracted] Resveratrol reduces acute lung injury in a LPS­induced sepsis mouse model via activation of Sirt1.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the ß­actin control western blotting data shown in Fig. 3D on p. 1893 were very similar to the contol data shown in Fig. 4A on p. 1894; furthermore, the data shown for the MMP­9 and the INOS protein bands in Fig. 4C were remarkably similar to the data shown for the IL­1ß and IL­6 proteins, respectively, albeit the backgrounds surrounding the bands were different. Moreover, various of the western blotting data shown in these figures were strikingly similar to data that had already been published in different form in other articles written by (largely) different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, and due to the number of apparent duplications of strikingly similar data between Figs. 3 and 4, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 7: 1889­1895, 2013; DOI: 10.3892/mmr.2013.1444].

Integrative analysis of multi-omics data reveals inhibition of RB1 signaling promotes apatinib resistance of hepatocellular carcinoma.

Although apatinib is a promising drug for the treatment of liver cancer, the underlying drug resistance mechanism is still unclear. Here, we constructed apatinib-resistant HepG2 cells. We then characterized the epigenomic, transcriptomic, and proteomic landscapes both in apatinib-resistant and non-resistant HepG2 cells. Differential expression, ATAC-seq, and proteomic data analyses were performed. We found that the cell cycle related protein RB1 may play an essential role in the process of apatinib resistant to hepatocarcinoma. Moreover, there were extensive variations at the transcriptome, epigenetic, and proteomic level. Finally, quantitative PCR (qPCR) and western blot analysis showed that expression level of RB1 in apatinib-resistant cell as well as the samples of patients in progressive disease were significantly lower than that in controls. Those results also showed that the RB1 pathway inhibitors CDK2-IN-73 and Palbociclib could relieve the resistance of apatinib resistant cells. Our results further enhance our understanding of the anti-tumorigenic and anti-angiogenic efficacy of apatinib in liver cancer and provide a novel perspective regarding apatinib resistance. Furthermore, we proved that CDKN2B inhibition of RB1 signaling promoted apatinib resistance in hepatocellular carcinoma. Those findings have greatly important biological significance for the resistance of apatinib and the treatment of liver cancer.

The Regulation Network of Glycerolipid Metabolism as Coregulators of Immunotherapy-Related Myocarditis.

Background: To date, immunotherapy for patients with malignant tumors has shown a significant association with myocarditis. However, the mechanism of metabolic reprogramming changes for immunotherapy-related cardiotoxicity is still not well understood. Methods: The CD45+ single-cell RNA sequencing (scRNA-seq) of the Pdcd1-/-Ctla4+/- and wild-type mouse heart in GSE213486 was downloaded to demonstrate the heterogeneity of immunocyte atlas in immunotherapy-related myocarditis. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectrum metabolomics analysis detects the metabolic network differences. The drug prediction, organelle level interaction, mitochondrial level regulatory network, and phosphorylation site prediction for key regulators have also been screened via multibioinformatics analysis methods. Results: The scRNA analysis shows that the T cell is the main regulatory cell subpopulation in the pathological progress of immunotherapy-related myocarditis. Mitochondrial regulation pathway significantly participated in pseudotime trajectory- (PTT-) related differential expressed genes (DEGs) in the T cell subpopulation. Additionally, both the gene set enrichment analysis (GSEA) of PTT-related DEGs and LC-MS/MS metabolomics analysis showed that mitochondrial-regulated glycerolipid metabolism plays a central role in metabolic reprogramming changes for immunotherapy-related cardiotoxicity. Finally, the hub-regulated protease of diacylglycerol kinase zeta (Dgkz) was significantly identified and widely played various roles in glycerolipid metabolism, oxidative phosphorylation, and lipid kinase activation. Conclusion: Mitochondrial-regulated glycerolipid metabolism, especially the DGKZ protein, plays a key role in the metabolic reprogramming of immunotherapy-related myocarditis.

[Corrigendum] Crocetin induces apoptosis of BGC­823 human gastric cancer cells.

Following the publication of the above article, an interested reader drew to the authors' attention that Fig. 2 (showing morphological characteristics of cultured BGC­823 cells as visualized by microscopic analysis) and Fig. 3 (showing crocetin­induced apoptosis of the BGC­823 cells) on p. 523 appeared to feature panels containing overlapping data. The authors re­examined their original data, and realized that inadvertent errors were made during the compilation of these figures; specifically, the data shown in Fig. 2C (for the the 5­µM docetaxel group) and Fig. 3D (for the DMSO group) were selected incorrectly. The corrected versions of Figs. 2 and 3 are shown below and on the next page, now featuring the correct data for Figs. 2C and 3D. All the authors agree with the publication of this corrigendum, and are grateful of the Editor of Molecular Medicine Reports for granting them the opportunity to publish this. Furthermore, they regret that these errors were introduced into the paper, even though they did not substantially alter any of the major conclusions reported in the paper, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 9: 521­526, 2014; DOI: 10.3892/mmr.2013.1851].

[Retracted] MicroRNA­449 suppresses proliferation of hepatoma cell lines through blockade lipid metabolic pathway related to SIRT1.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that several of the protein bands featured in the western blot assay data shown in Fig. 3A­D on p. 2147 were strikingly similar to other protein bands, both comparing the data within the same gel slices and comparing the data across the four different parts of the figure. In addition, the control blots featured in Fig. 3A, B and D had already appeared in a different form written by (largely) different authors at different research institutes. After having conducted an independent review of the data in this Figure in the Editorial Office, the concerns of the reader were found to be validated. Therefore, since contentious data in the above article had already been published prior to its submission to International Journal of Oncology, and owing to an overall lack of confidence in the presented data, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 45: 2143­2152, 2014; DOI: 10.3892/ijo.2014.2596].

[Retracted] FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that lanes 1­3 of the EMSA results shown in Fig. 6 on p. 1278 were strikingly similar to data that had already appeared in a different form in the following publication by different authors at different research institutes: Qiu K, Li Z, Chen J, Wu S, Zhu X, Gao S, Gao J, Ren G and Zhou X: EIN3 and ORE1 accelerate degreening during ethylene­mediated leaf senescence by directly activating chlorophyll catabolic genes in Arabidopsis. PLoS Genet 11: e1005399, 2015. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 1273­1280, 2016; DOI: 10.3892/or.2015.4485.

[Retracted] SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the control ß­actin western blots shown in Figs. 1B and 6 were strikingly similar to data that had already appeared in a different form in the following publication: Lei Y, Liu H, Yang Y, Wang X, Ren N, Li B, Liu S, Cheng J, Fu X and Zhang J: Interaction of LHBs with C53 promotes hepatocyte mitotic entry: A novel mechanism for HBV­induced hepatocellular carcinoma. Oncol Rep 29: 151­159, 2012. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 28: 311­318, 2012; DOI: 10.3892/or.2012.1788].

[Retracted] FAM172A induces S phase arrest of HepG2 cells via Notch 3.

Following the publication of the above article, a concerned reader drew to the Editor's attention that the western blots featured in Figs. 1G, 2B, 3B and 4E contained groupings of bands that were markedly similar in appearance, both within the same gel slices and comparing across different gel slices between the figures in the case of Figs. 3 and 4. After having conducted an internal investigation of this matter, the Editor of Oncology Reports has judged that the anomalous groupings of data were too extensive that their apperance could have been attributed to pure coincidence. Therefore, the Editor has decided that this article should be retracted from the publication on the grounds of an overall lack of confidence in the data. After having been in contact with the authors of this study, they accepted the Editor's decision to retract this article. The Editor sincerely apologizes to the readership for any incovenience caused, and we thank the reader for bringing this matter to our attention. [Oncology Reports 29: 1154­1160, 2013; DOI: 10.3892/or.2013.2235].

CircVAPA contributes to hyper-proliferation and inflammation of keratinocytes through miR-125b-5p/sirt6 axis in psoriasis.

Psoriasis is an autoimmune skin disease with abnormal keratinocyte hyperproliferation. The important roles of circular RNAs (circRNAs) in various inflammatory diseases have been revealed. The present study aimed to investigate the roles of circVAPA and its molecular mechanisms in psoriasis. Quantitative real-time polymerase chain reaction was performed to measure the RNA expression. Enzyme-linked immunosorbent assays were employed to examine the production of inflammatory factors. Cell-counting kit-8, EDU and flow cytometry assay were conducted to examine the cell viability, proliferation and apoptosis respectively. Dual-luciferase reporter assay and ribonucleoprotein immunoprecipitation (RIP) were conducted to verify the target relationship between miR-125b-5p and circVAPA or Sirt6. Herein our findings showed increased expression of circVAPA and Sirt6 and decreased level of miR-125b-5p in psoriatic lesional tissues and M5-stimulated keratinocytes. Mechanistically, circVAPA knockdown significantly suppressed the promotion of M5 on cell viability, proliferation, and inflammation of HaCaT cells. circVAPA was verified to interact with miR-125b-5p, while inhibition of miR-125b-5p counteracted circVAPA knockdown-mediated effects in M5-stimulated HaCaT cells. Sirt6 was confirmed as a target of miR-125b-5p, and miR-125b-5p overexpression inhibited cell growth and inflammation partly by targeting Sirt6 in M5-stimulated HaCaT cells. Moreover, circVAPA was featured as a competing endogenous RNA by directly sponging miR-125b-5p to up-regulate the expression of Sirt6. CircVAPA participate in the progression of psoriasis through miR-125b-5p/sirt6 axis by regulating proliferation and inflammation of keratinocytes, highlighting a potential therapeutic target for psoriasis.

Distinct binding pattern of EZH2 and JARID2 on RNAs and DNAs in hepatocellular carcinoma development.

Hepatocellular carcinoma (HCC) is one of the most malignant cancers worldwide, with high mortality. However, the molecular regulatory mechanisms of liver cancer, especially transcriptional and post-transcriptional mechanisms, should be further studied. Here we used chromatin and cross-linking immunoprecipitation with high throughput sequencing methods (ChIP-seq and CLIP-seq) to capture the global binding profiles on RNAs and DNAs of Enhancer of zeste homolog 2 (EZH2) and its partner Jumonji And AT-Rich Interaction Domain Containing 2 (JARID2) in liver carcinoma cell lines (HepG2) and normal liver cell line (THLE-2), respectively. We also integrated HCC transcriptome data from the TCGA to analyze the expression pattern of bound genes. We found that EZH2 and JARID2 both showed distinct binding profiles between HepG2 and THLE-2 cells. By binding to the primary RNAs, bound transcripts of EZH2 and JARID2 in HepG2 showed significantly increased transcriptional levels in HCC patients. By performing gene set enrichment analysis (GSEA), the bound transcripts were also highly related to HCC development. We also found EZH2 and JARID2 could specifically bind to several long noncoding RNAs (lncRNAs), including H19. By exploring the DNA binding profile, we detected a dramatically repressed DNA binding ability of EZH2 in HepG2 cells. We also found that the EZH2-bound genes showed slightly increased transcriptional levels in HepG2 cells. Integrating analysis of the RNA and DNA binding profiles suggests EZH2 and JARID2 shift their binding ability from DNA to RNA in HepG2 cells to promote cancer development in HCC. Our study provided a comprehensive and distinct binding profile on RNAs and DNAs of EZH2 and JARID2 in liver cancer cell lines, suggesting their potential novel functional manners to promote HCC development.

Early detection of colorectal cancer based on circular DNA and common clinical detection indicators.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide, and it is the second leading cause of death from cancer in the world, accounting for approximately 9% of all cancer deaths. Early detection of CRC is urgently needed in clinical practice. AIM: To build a multi-parameter diagnostic model for early detection of CRC. METHODS: Total 59 colorectal polyps (CRP) groups, and 101 CRC patients (38 early-stage CRC and 63 advanced CRC) for model establishment. In addition, 30 CRP groups, and 62 CRC patients (30 early-stage CRC and 32 advanced CRC) were separately included to validate the model. 51 commonly used clinical detection indicators and the 4 extrachromosomal circular DNA markers NDUFB7, CAMK1D, PIK3CD and PSEN2 that we screened earlier. Four multi-parameter joint analysis methods: binary logistic regression analysis, discriminant analysis, classification tree and neural network to establish a multi-parameter joint diagnosis model. RESULTS: Neural network included carcinoembryonic antigen (CEA), ischemia-modified albumin (IMA), sialic acid (SA), PIK3CD and lipoprotein a (LPa) was chosen as the optimal multi-parameter combined auxiliary diagnosis model to distinguish CRP and CRC group, when it differentiated 59 CRP and 101 CRC, its overall accuracy was 90.8%, its area under the curve (AUC) was 0.959 (0.934, 0.985), and the sensitivity and specificity were 91.5% and 82.2%, respectively. After validation, when distinguishing based on 30 CRP and 62 CRC patients, the AUC was 0.965 (0.930-1.000), and its sensitivity and specificity were 66.1% and 70.0%. When distinguishing based on 30 CRP and 32 early-stage CRC patients, the AUC was 0.960 (0.916-1.000), with a sensitivity and specificity of 87.5% and 90.0%, distinguishing based on 30 CRP and 30 advanced CRC patients, the AUC was 0.970 (0.936-1.000), with a sensitivity and specificity of 96.7% and 86.7%. CONCLUSION: We built a multi-parameter neural network diagnostic model included CEA, IMA, SA, PIK3CD and LPa for early detection of CRC, compared to the conventional CEA, it showed significant improvement.

MiR-132-3p inhibits proliferation, invasion and migration of colorectal cancer cells via down-regulating FOXP2 expression.

OBJECTIVE: colorectal cancer (CRC) is a common cancer with high mortality. This study aimed to investigate the role of microRNA (miR)-132-3p on proliferation, invasion and migration of CRC cells. MATERIALS AND METHODS: qRT-PCR and Western blot analyses were used to determine the expression of miR-132-3p and forking box (FOX) protein 2 (FOXP2) in CRC cell line CACO-2. The expression of miR-132-3p and FOX was regulated using miR inhibitor and siRNA, and the viability and migration ability of the transfected cells were assessed. Cell cycle dependent kinase (CDK) 1, cyclin D1, matrix metalloproteinase (MMP)-2 and MMP-9 were detected using Western blots. The dual luciferase reporter gene assays were used to verify the targeting of miR-132-3p to FOXP2. RESULTS: Compared with control cells, FOXP2 and miR-132-3p expressions were decreased or increased significantly (P<0.05), respectively in CACO-2 cells. Up-regulation of miR-132-3p effectively inhibited the proliferation, migration and invasion of CACO-2 cells, and suppressed the expression of FORX2, cyclin-dependent kinase 1 (CDK1), cyclin D1, MMP-2 and MMP-9. Luciferase reporter gene assays reveled that FOXP2 expression was negatively regulated by miR-132-3p. Knockdown of FOXP2 using siRNA significantly reduced the proliferation and migration of CACO-2 cells, down-regulated the expression FOXP2 as well as CDK1, cyclin D1, MMP-2 and MMP-9. Since FOXP2 is targeted by miR-132-3p, it is likely that miR-132-3p-mediated reduction of proliferation and migration of CACO-2 cells was achieved via reduced translation of FOXP2 mRNA. CONCLUSIONS: miR-132-3p inhibits the proliferation, migration and invasion of CRC cells. This is likely achieved via negative regulation of the targeted FOXP2 expression. This role may be further explored for therapeutic applications in CRC.

SNAIL Induces EMT and Lung Metastasis of Tumours Secreting CXCL2 to Promote the Invasion of M2-Type Immunosuppressed Macrophages in Colorectal Cancer.

Background: There is increasing evidence that tumour-associated macrophages (TAMs) are critical in the formation of lung metastases. However, the molecular mechanisms of tumour interactions with TAMs via EMT are largely unknown. Methods: The mechanism of lung metastasis was studied in patient tissues. The mechanism of SNAIL regulation of the interaction between mesenchymal cells and M2 macrophages was elucidated using coculture of M2 macrophages and Transwell assays in vitro and in vivo in nude mice and NOD-SCID mice. Results: We demonstrated for the first time that SNAIL and CXCL2 were abnormally overexpressed in colorectal cancer, especially lung metastasis, and were associated with poor prognosis in colorectal cancer patients. We demonstrated that SNAIL promoted the secretion of CXCL2 by mesenchymal cells and induced the activation of M2 macrophages. We found that CXCL2 attracted M2-type macrophages to infiltrate and promote tumour metastasis. Conclusion: These findings suggest that SNAIL promotes epithelial tumour transformation, and that transformed mesenchymal cells secrete CXCL2, which promotes M2 macrophage infiltration and tumour cell metastasis. These findings elucidate the tumour-TAM interaction in the metastatic microenvironment, which is mediated by tumour-derived CXCL2 and affects lung metastasis. This study also provides a theoretical basis for the occurrence of secondary lung cancer.

Temporal and Spatial Characterization of Mononuclear Phagocytes in Circulating, Pulmonary Alveolar, and Interstitial Compartments in LPS-Induced Acute Lung Injury.

Peripheral circulating monocytes and resident macrophages are heterogeneous effector cells that play a critical role in the maintenance and restoration of pulmonary integrity. However, their detailed dynamic changes in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remain unclear. Here, we investigated the impact of mononuclear phagocyte cells in the development of LPS-induced ALI/Acute respiratory distress syndrome (ARDS) and described the relations between the dynamic phenotypic changes and pulmonary pathological evolution. In this study, mice were divided into two groups and intraperitoneally injected with normal saline (NS) or LPS, respectively. A series of flow cytometry assay was performed for the quantification of peripheral circulating monocyte subpopulations, detection of the polarization state of bronchoalveolar lavage fluid (BALF)-isolated alveolar macrophages (AMϕ) and pulmonary interstitial macrophages (IMϕ) separated from lung tissues. Circulating Ly6Clo monocytes expanded rapidly after the LPS challenge on day 1 and then decreased to day 7, while Ly6Chi monocytes gradually increased and returned to normal level on the 7th day. Furthermore, the expansion of M2-like AMϕ (CD64+CD206+) was peaked on day 1 and remained high on the third day, while the polarization state of IMϕ (CD64+ CD11b+) was not influenced by the LPS challenge at all the time points. Taken together, our findings show that Ly6Clo monocytes and M2-like AMϕ form the major peripheral circulation and pulmonary immune cell populations, respectively. The dynamic changes of mononuclear phagocyte in three compartments after the LPS challenge may provide novel protective strategies for mononuclear phagocytes.

Changes of Intestinal Microflora in Colorectal Cancer Patients after Surgical Resection and Chemotherapy.

OBJECTIVE: The change of bacterial flora structure in colorectal cancer (CRC) patients after treatment is not clear. The aim of this study was to explore the change and function of intestinal microflora in CRC before and after treatment. METHOD: The 16S conserved region V3+V4 of intestinal flora obtained from CRC patients was sequenced and analyzed. Alpha and beta diversity indices were used to analyze the abundance and structure of gut flora. FAPROTAX, BugBase, and Tax4Fun software were used to analyze the species phenotypes and Kyoto Encyclopedia of Genes and Genomes Ontology (KO) function pathways. RESULTS: Total abundance and structure of species in CRC patients were significantly increased compared with healthy people (control group) (P < 0.05), but there was no significant difference between CRC patients before and after treatment (P > 0.05). There was significant difference in relative abundance of bacteria at different levels (phylum, class, order, family, genus, and species) between the CRC group with after operation (CRC_O group) and chemotherapy (CRC_C group) treatment, particularly Prevotellaceae_UCG-001, Akkermansia, Fusicatenibacter, Tyzzerella_4, Megamonas, etc. in genus level. The KO function analysis showed that most of the bacteria with differences were mainly involved in the biosynthesis of lipopolysaccharide (Megamonas, Megasphaera, and Ruminococcus torques_group), protein digestion and absorption, renin-angiotensin system pathway (Akkermansia, Eubacterium_ruminantium_group, and Eubacterium_nodatum_group genus), adipocytokine signaling pathway and peroxisome pathway (Tyzzerella_4, Phascolarctobacterium, Ruminococcus_gnavus_group), and so on. CONCLUSION: The abundance of intestinal microflora in CRC patients was increased significantly contrasted to healthy people, and surgery and chemotherapy were hard to reduce this phenomenon. Megamonas was involved in lipopolysaccharide biosynthesis and carcinogenesis in colorectal cancer. Surgery and drug treatment did not reduced lipopolysaccharide biosynthesis but increased the number of probiotic Akkermansia population and reduced the pathogenic bacteria Tyzzerella_4, participate in adipocytokine signaling pathway, and affect metabolism.

Integrative epigenomic profiling reveal AP-1 is a key regulator in intrahepatich cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with poor prognosis while its mechanisms of pathogenesis remain elusive. In this study, we performed systemic epigenomic and transcriptomic profiling via MNase-seq, ChIP-seq and RNA-seq in normal cholangiocyte and ICC cell lines. We showed that active histone modifications (H3K4me3, H3K4me1 and H3K27ac) were less enriched on cancer-related genes in ICC cell lines compared to control. The region of different histone modification patterns is enrichment in sites of AP-1 motif. Subsequent analysis showed that ICC had different nucleosome occupancy in differentially expressed genes compared to a normal cell line. Furthermore, we found that AP-1 plays a key role in ICC and regulates ICC-related genes through its AP-1 binding site. This study is the first report showing the global features of histone modification, transcript, and nucleosome profiles in ICC; we also show that the transcription factor AP-1 might be a key target gene in ICC.

MiR-3188 regulates the proliferation and apoptosis of hepatocellular carcinoma cells by targeting CXCL14.

Aim: The study aimed to probe into the functions and mechanisms of miR-3188 in hepatocellular carcinoma (HCC). Materials & methods: Quantitative real-time PCR and western blot were implemented to detect the expressions of miR-3188 and CXCL14 in HCC tissues and cell lines. CCK-8, 5-ethynyl-2'-deoxyuridine and flow cytometry assays were performed to assess cell viability, proliferation and apoptosis. A dual-luciferase reporter assay was conducted to investigate the relationship between miR-3188 and CXCL14. Results: miR-3188 is up-regulated in HCC tissues. MiR-3188 overexpression promoted cell viability and proliferation but inhibited the apoptosis of HCC cells. CXCL14 was proven to be a target of miR-3188, and CXCL14 reversed the effects of miR-3188 on HCC cells. Conclusion: MiR-3188 regulates the growth and apoptosis of HCC cells by targeting CXCL14.

Circ_0072088 promotes progression of hepatocellular carcinoma by activating JAK2/STAT3 signaling pathway via miR-375.

Circular RNAs feature prominently in cancer development. Nonetheless, the role of circ_0072088 in hepatocellular carcinoma (HCC) remains unclear. GEO databases (GSE97332, GSE108724, GSE36915, and GSE33006) were used to screen out the differentially expressed circRNAs, miRNAs, and mRNA in HCC. The expressions of circ_0072088, miR-375, and Janus Kinase 2 (JAK2) mRNA in HCC tissue and cell lines were determined with quantitative real-time polymerase chain reaction. RNase R treatment assay was used to measure the stability of circ_0072088, and subcellular fraction assay was used to detect the localization of circ_0072088. Cell counting kit-8 assay, flow cytometry, and Transwell assay were used to measure proliferation, apoptosis, migration, and invasion of HCC cells. RNA immunoprecipitation and dual-luciferase reporter gene assay were employed for investigating the binding sequence between circ_0072088 and miR-375, as well as miR-375 and JAK2 3'UTR. Western blot assay was used to detect the expression of JAK2 and p-STAT3 after circ_0072088 and miR-375 were selectively regulated. Circ_0072088 and JAK2 mRNA expressions were highly expressed in HCC tissues and cell lines while miR-375 expression was remarkably downregulated. Circ_0072088 was resistant to RNase R treatment and mainly located in the cytoplasm of HCC cells. The transfection of circ_0072088 overexpression plasmid or miR-375 inhibitors promoted the proliferation, migration, and invasion, and inhibited the apoptosis of HCC cells, whereas transfection of circ_0072088 siRNA or miR-375 mimics exerted opposite effects. Besides, miR-375 was confirmed as a target of circ_0072088 and miR-375 could further downregulate the expression of JAK2. MiR-375 mimics could reverse the upregulation of JAK2 and p-STAT3 protein induced by circ_0072088 overexpression. Circ_0072088 can enhance the proliferation, migration, and invasion, and impede apoptosis of HCC cells. Mechanistically, circ_0072088 activates JAK2/STAT3 signaling pathway by serving as a molecular sponge of miR-375.