How does economic inequality shape conspiracy theories? Empirical evidence from China.

Conspiracy theories tend to be prevalent, particularly in societies with high economic inequality. However, few studies have examined the relationship between economic inequality and belief in conspiracy theories. We propose that economic inequality leads people to believe conspiracy theories about economically advantaged groups (i.e., upwards conspiracy theories) and that moral evaluations of those groups mediate this relationship. Study 1 (N = 300) found support for these ideas in a survey among Chinese residents. Study 2 (N = 160) manipulated participants' perceptions of economic inequality in a virtual society. The manipulation shaped moral evaluations of economically advantaged groups, and conspiracy beliefs, in the predicted manner. In Study 3 (N = 191) and Study 4 (N = 210), we experimentally manipulated participants' perceptions of economic inequality in real Chinese society and replicated the results of Study 2. In addition, in Study 4, we find that economic inequality predicts belief in conspiracy theories about economically disadvantaged groups (i.e., downward conspiracy theories), which was mediated by anomie. We conclude that perceived economic inequality predicts conspiracy theories about economically advantaged groups and that moral evaluations account for this effect. Also, upward and downward conspiracy theory beliefs are associated with different psychological processes.

Porous polydimethylsiloxane films with specific surface wettability but distinct regular physical structures fabricated by 3D printing.

Porous polydimethylsiloxane (PDMS) films with special surface wettability have potential applications in the biomedical, environmental, and structural mechanical fields. However, preparing porous PDMS films with a regular surface pattern using conventional methods, such as chemical foaming or physical pore formation, is challenging. In this study, porous PDMS films with a regular surface pattern are designed and prepared using 3D printing to ensure the formation of controllable and regular physical structures. First, the effect of the surface wettability of glass substrates with different surface energies (commercial hydrophilic glass and hydrophobic glass (F-glass) obtained by treating regular glass with 1H,1H,2H,2H-perfluorooctyl-trichlorosilane) on the structural characteristics of the 3D printed PDMS filaments is investigated systematically. Additionally, the effect of the printing speed and the surface wettability of the glass substrate on the PDMS filament morphology is investigated synchronously. Next, using the F-glass substrate and an optimized printing speed, the effects of the number of printed layers on both the morphologies of the individual PDMS filaments and porous PDMS films, and the surface wettability of the films are studied. This study reveals that regularly patterned porous PDMS films with distinct structural designs but the same controllable surface wettability, such as anisotropic surface wettability and superhydrophobicity, can be easily fabricated through 3D printing. This study provides a new method for fabricating porous PDMS films with a specific surface wettability, which can potentially expand the application of porous PDMS films.

MCM5 is an oncogene of colon adenocarcinoma and promotes progression through cell cycle control.

Many patients with colon adenocarcinoma (COAD) are diagnosed at an advanced stage, and the molecular mechanism of COAD progression is intricate and controversial. Therefore, there is an urgent need to identify more novel prognosis biomarkers for COAD and elucidate the molecular mechanism of this disease. The present study aimed to screen out key genes correlated with COAD prognosis. In this study, a key module was identified and four hub genes (MCM5 (encoding minichromosome maintenance complex component 5), NOLC1 (encoding nucleolar and coiled-body phosphoprotein 1), MYC (encoding MYC proto-oncogene, BHLH transcription factor), and CDK4 (encoding cyclin dependent kinase 4)) were selected that correlated with COAD prognosis, based on the GSE9348 dataset in Gene Expression Omnibus database. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that MCM5 correlated with the cell cycle. Furthermore, MCM5 expression was upregulated in tumor tissues of patients with COAD compared with that in adjacent tissues, based on various databases, including The Cancer Genome Atlas, the Clinical Proteomic Tumor Analysis Consortium database, and the Human Protein Atlas database. Small interfering RNA-mediated knockdown of MCM5 inhibited the cell cycle and migration of colorectal cancer cells in vitro. And western blotting results indicated that factors correlated with cell cycle (CDK2/6, Cyclin D3, P21) were downregulated after knockdown of MCM5 in vitro. Besides, downregulation of MCM5 was demonstrated to inhibit lung metastasis of COAD in nude mice model. In conclusion, MCM5 is an oncogene of COAD that promotes COAD progression via cell cycle control.

Annexin A9 promotes cell proliferation by regulating the Wnt signaling pathway in colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Expression of Annexin A9 (ANXA9), a member of the annexin A family, is upregulated in CRC. However, the molecular role of ANXA9 in CRC remains unknown. In the present study, we aimed to investigate the function of ANXA9 and to elucidate the mechanisms underlying its regulation in CRC. In this study, mRNA expression data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and GEPIA database, respectively. Kaplan-Meier analysis was used to analyze the survival rates. LinkedOmics and Metascape databases were used to explore the potential mechanisms of regulation of ANXA9 and to identify genes co-expressed with ANXA9. Finally, in vitro experiments were used to evaluate the function of ANXA9 and explore potential mechanisms. We found that ANXA9 expression was significantly elevated in CRC tissue and cells. High ANXA9 expression was associated with shorter overall survival, poorer disease specific survival, as well as with patient age, clinical stage, M stage, and OS events in CRC. Knockdown of ANXA9 inhibited cell proliferation, invasion, migratory potential, and cell cycle arrest. Mechanistically, functional analysis revealed that genes co-expressed with ANXA9 were mainly enriched in the Wnt signaling pathway. ANXA9 deletion suppressed cell proliferation via the Wnt signaling pathway, while Wnt activation reversed the effects of ANXA9. In conclusion, ANXA9 may promote CRC progression by regulating the Wnt signaling pathway and may be a potential diagnostic biomarker in the clinical management of CRC.

Sini Decoction Inhibits Tumor Progression and Enhances the Anti-Tumor Immune Response in a Murine Model of Colon Cancer.

BACKGROUND: Sini decoction (SND) is a widely used Traditional Chinese Medicine (TCM). The reports of SND application in colorectal cancer (CRC) is limited. OBJECTIVE: The objective of this study is to investigate the anti-tumor activity of SND in the treatmeant of CRC. METHODS: SND was analyzed using high-performance liquid chromatography. A CRC metastasis model was established using murine CT-26 cells. Whole-body fluorescence imaging was used to observe CRC liver metastasis. Liver morphology was determined using hematoxylin-eosin staining. Cytokine mRNA expression (interleukin-2 (IL-2), interleukin-10 (IL-10), interferon-gamma (IFN-γ), and tumor necrosis factor beta (TNF-ß)) were determined using real-time reverse transcription polymerase chain reaction. Spectral flow cytometry was used to detect mouse tumor immune subgroups. Databases were used to find potential target genes of SND. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to identify potential signaling pathways of target genes. RESULTS: SND suppressed CRC liver metastasis and alleviated liver injury in vivo. After SND treatment, IL-2 and IFN-γ were upregulated, whereas IL-10 and TGF-ß were downregulated. Moreover, CD3+, CD8+T cells, natural killer T cells, and macrophages increased significantly after SND treatment, while CD4+CD25+T cells decreased significantly. Importantly, increasing the aconite concentration had a better anti-tumor effect. Fifty-50 compounds in SND were screened, and 611 potential target genes were identified. Functional analyses showed that the genes were associated with the PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and HIF-1 signaling pathway. CONCLUSION: SND exerts anti-tumor activity by inhibiting tumor progression and enhancing antitumor immunity in mice, suggesting its application to prevent and treat CRC.

Propofol mediates bone metastasis by regulating PC-derived exosomal miR-142-3p.

In this study we investigated the role of propofol in mediating prostate cancer (PCa) bone metastasis through regulating exosomal factors derived from PCa. We isolated exosomes from PCa cells and co-cultured them with mesenchymal stem cells (MSCs). PCa-derived exosomes increased calcium deposition of MSCs and upregulated ALPL'Alkaline phosphatase, tissue-nonspecific isozyme) and BGLAP (Bone Gamma-Carboxyglutamate Protein) expression. Propofol treatment reduced alkaline phosphatase (ALP) activity, and ALPL and BGLAP expression that was induced by PCa-derived exosomes in MSCs. miRNAs present in cancer cell-derived exosomes increased osteogenesis in these cells. We evaluated miRNA expression in PCa cells after treatment with propofol, and found that miR-142-3p was upregulated in PCa cells. Furthermore, we transfected MSCs with miR-142-3p mimics or inhibitors and revealed that miR-142-3p mimics reduced calcium deposition and downregulated ALP activity, and ALPL and BGLAP levels, while miR-142-3p inhibitors increased calcium deposition and increased ALP activity, and ALPL and BGLAP levels. Finally, we determined that MSCs co-cultured with PCa-derived exosomes and transfected with miR-142-3p mimic exhibited reduced calcium deposition and lower ALP activity, and expression of ALPL and BGLAP. These data demonstrate that propofol inhibits osteogenic differentiation and mineralization of MSCs induced by PCa-derived exosomes by regulation of miR-142-3p levels.

Protection of adipose-derived mesenchymal stromal cells during acute lung injury requires autophagy maintained by mTOR.

Previous studies suggest that mesenchymal stem cells may represent a promising cellular therapy for acute lung injury (ALI); however, the underlying relevant molecular mechanisms remain unclear. Adipose-derived mesenchymal stem cells (ADSCs) were isolated and characterized by alizarin red staining, oil red staining, and flow cytometry. Lung injury and inflammatory cell infiltration were determined using the Evans blue method, wet/dry weight ratio, and H&E staining. An ELISA was used to detect the concentrations of IFN-γ, IL-2, and TNF-α. Autophagy was detected with an mRFP-GFP-LC3 dual-fluorescence autophagy indicator system, Western blotting, and electron microscopy. We first demonstrated that ADSCs did alleviate the inflammatory responses and tissue damage in lipopolysaccharide (LPS)-induced ALI. Next, we further demonstrated in vivo that autophagy plays a key role in the maintenance of ADSC therapeutic efficacy. In vitro experiments demonstrated that ADSCs co-cultured with alveolar epithelial cells depend on autophagy for significant anti-inflammatory functions. Moreover, the mammalian target of rapamycin (mTOR) is a key regulator of autophagy. Taken together, our findings demonstrate that the effect of ADSC on ALI, especially on alveolar epithelial cells, is dependent on mTOR-mediated autophagy maintenance. The significance of our study for ALI therapy is discussed with respect to a more complete understanding of the therapeutic strategy paradigm.

HOTAIR/miR-1277-5p/ZEB1 axis mediates hypoxia-induced oxaliplatin resistance via regulating epithelial-mesenchymal transition in colorectal cancer.

The hypoxic microenvironment contributes to the chemoresistance of many malignant tumors including colorectal cancer (CRC). Accumulating studies have indicated that long non-coding RNAs (lncRNAs) play important roles in chemotherapy resistance. In this study, we aimed to determine the effect of lncRNAs in hypoxia-mediated resistance in CRC and its potential mechanism. Here, we discovered that hypoxia-induced oxaliplatin resistance and HOX transcript antisense RNA (HOTAIR) expression was increased in hypoxia-treated CRC cell lines and CRC tumors. Knockdown of HOTAIR by siRNA reduced the viability and proliferation of CRC cells treated with oxaliplatin and reversed hypoxia-induced resistance. Mechanically, we found that HOTAIR modulates zinc finger E-box binding homeobox 1 (ZEB1) expression by negative regulations of miR-1277-5p. When miR-1277-5p was silenced, knockdown of HOTAIR was unable to reduce the oxaliplatin resistance in CRC cells. In mouse models of CRC, HOTAIR knockdown markedly inhibited the tumor growth when treated with oxaliplatin. Thus, HOTAIR/miR-1277-5p/ZEB1 axis appears a promising therapeutic target for improving the oxaliplatin efficacy in CRC.

The relationship between prescription of ultrafiltration and intradialytic hypotension in Chinese hemodialysis patients.

BACKGROUND: Intradialytic hypotension (IDH) remains the most frequent severe side effect of hemodialysis (HD) and increases patient morbidity and mortality. Excessive ultrafiltration (UF) is considered the leading cause of IDH. This study developed a suitable prescription of UF to reduce the incidences of IDH episodes. METHODS: A retrospective study was performed to analyze 33,224 HD/hemodiafiltration (HDF) treatments in 312 patients. The prescription of UF were determined following the International Society of Peritoneal Dialysis (ISPD) guideline. The Pearson's method was used to study the correlation between relative variables. The receiver operating characteristic (ROC) curve was used to predict the value of the UF/weight ratio (UF/Wt) for IDH in all patients to establish a diagnostic cut-off point. Univariate and multivariate logistic regression analyses were applied to study the risk factors of IDH. RESULTS: Twelve thousand five hundred and fifty-eight sessions of IDH (38.7%) were identified, among which 1,224 (3.6%) were recorded with intervention against IDH. Both the systolic blood pressure (SBP) and mean arterial pressure (MAP) of the hemodialytic patients were positively correlated with the UF quantity and the UF/Wt, but negatively correlated with blood flow. The ROC curve showed that UF/Wt =0.04 was the cut-off point for IDH. Age [per 10-year increment, odds ratio (OR) =1.005, 95% confidence interval (CI): 1.004 to 1.007, P=0.000], diabetes mellitus (OR =1.209, 95% CI: 1.122 to 1.303, P=0.000), and UF/Wt >0.04 (OR =1.605, 95% CI: 1.532 to 1.682, P=0.000) were all independently associated with higher incidences of IDH. CONCLUSIONS: IDH commonly occurs during HD in Chinese patients. Unchangeable factors such as diabetes and age, and modifiable factors including UF were associated with IDH. A UF/Wt threshold more than 0.04 may be a potential alert for avoiding IDH, especially in the elderly and diabetic patients.

LncRNA-HOTAIR activates autophagy and promotes the imatinib resistance of gastrointestinal stromal tumor cells through a mechanism involving the miR-130a/ATG2B pathway.

Gastrointestinal stromal tumors (GISTs) are common neoplasms of the gastrointestinal tract that can be treated successfully using C-kit target therapy and surgery; however, imatinib chemoresistance is a major barrier to success in therapy. The present study aimed to discover alternative pathways in imatinib-resistant GISTs. Long noncoding RNAs (lncRNAs) are newly discovered regulators of chemoresistance. Previously, we showed that the lncRNA HOTAIR was upregulated in recurrent GISTs. In this study, we analyzed differentially expressed lncRNAs after imatinib treatment and found that HOTAIR displayed the largest increase. The distribution of HOTAIR in GISTs was shifted from nucleus to cytoplasm after imatinib treatments. The expression of HOTAIR was validated as related to drug sensitivity through Cell Counting Kit-8 assays. Moreover, HOTAIR was associated strongly with cell autophagy and regulated drug sensitivity via autophagy. Mechanistically, HOTAIR correlated negatively with miRNA-130a in GISTs. The downregulation of miRNA-130a reversed HOTAIR-small interfering RNA-induced suppression of autophagy and imatinib sensitivity. We identified autophagy-related protein 2 homolog B (ATG2B) as a downstream target of miR-130a and HOTAIR. ATG2B downregulation reversed the effect of pEX-3-HOTAIR/miR-130a inhibitor on imatinib sensitivity. Finally, HOTAIR was shown to influence the autophagy and imatinib sensitivity of GIST cells in mouse tumor models. Our results suggested that HOTAIR targets the ATG2B inhibitor miR-130a to upregulate the level of cell autophagy so that promotes the imatinib resistance in GISTs.

WZ4003 sensitizes non-small cell lung cancer cells to gefitinib via inhibition of ARK5 and epithelial-to-mesenchymal transition.

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC); however, its utility is hampered by the development of chemoresistance. This study aimed to investigate the synergistic role of WZ4003, a novel (nua) kinase (NUAK) inhibitor, in enhancing gefitinib sensitivity in NSCLC cells. Our data indicated WZ4003 enhances the sensitivity of NSCLC cells to gefitinib. We also found ARK5 knockdown in NSCLC cell lines increased their sensitivity to gefitinib. However, WZ4003 did not affect gefitinib sensitivity when ARK5 was knocked down in NSCLC cell lines (using siRNA). Both WZ4003 and ARK5 inhibition suppressed epithelial-to-mesenchymal transition by reducing the expression of vimentin and increasing E-cadherin expression. Together, our results demonstrate WZ4003 plays a vital role in releasing acquired resistance to gefitinib by inhibiting ARK5 and epithelial-to-mesenchymal transition. Therefore, synergistic use of WZ4003 and gefitinib may prevent the development of gefitinib resistance in NSCLC.

Determining the Clinical Value and Critical Pathway of GTPBP4 in Lung Adenocarcinoma Using a Bioinformatics Strategy: A Study Based on Datasets from The Cancer Genome Atlas.

Lung cancer is the leading cause of cancer-related death worldwide, and the most common histologic subtype is lung adenocarcinoma (LUAD). Due to the significant mortality and morbidity rates among patients with LUAD, the identification of novel biomarkers to guide diagnosis, prognosis, and therapy is urgent. Guanosine triphosphate-binding protein 4 (GTPBP4) has been found to be associated with tumorigenesis in recent years, but the underlying molecular mechanism remains to be elucidated. In the present study, we demonstrate that GTPBP4 is significantly overexpressed in LUAD primary tumors. A total of 55 genes were identified as potential targets of GTPBP4. GO enrichment analysis identified the top 25 pathways among these target genes, among which, ribosome biogenesis was shown to be the most central. Each target gene demonstrated strong and complex interactions with other genes. Of the potential target genes, 12 abnormally expressed candidates were associated with survival probability and correlated with GTPBP4 expression. These findings suggest that GTPBP4 is associated with LUAD progression. Finally, we highlight the importance of the role of GTPBP4 in LUAD in vitro. GTPBP4 knockdown in LUAD cells inhibited proliferation and metastasis, promoted apoptosis, and enhanced sensitivity to TP. Overall, we conclude that GTPBP4 may be considered as a potential biomarker of LUAD.

AMP­activated protein kinase family member 5 is an independent prognostic indicator of pancreatic adenocarcinoma: A study based on The Cancer Genome Atlas.

Pancreatic adenocarcinoma (PAAD) is a common and highly malignant tumor. The identification of prognostic biomarkers for PAAD could provide invaluable information for clinical treatment. AMP­activated protein kinase family member 5 (ARK5) is a member of the AMPK family that mediates the migration of PAAD cells. In the present study, ARK5 expression was evaluated using bioinformatics analysis in public datasets from The Cancer Genome Atlas. The expression levels of ARK5 in PAAD tumor tissue were significantly increased, compared with matched non­cancerous tissues. ARK5 target genes were then predicted and Gene Ontology Biological Processes, Kyoto Encyclopedia of Genes and Genomes pathway analysis and Reactome gene sets were used to determine the functions associated with the target genes. A protein­protein interaction network was also constructed to find out the node genes and observe their association with the overall survival rate of PAAD. A total of nine node genes were identified in the PPI network, of which six were significantly upregulated in PAAD tissue, compared with matched normal tissue. The prognostic value of each node gene was evaluated by comparing the overall survival in patients with PAAD stratified according to the expression levels of these genes. Overall survival was significantly reduced in patients with high polo­like kinase­1 (PLK1) or protein phosphatase 1 catalytic subunit ß (PPP1CB) expression, compared with patients with low expression of these genes. To further evaluate the relationship between PAAD and ARK5, ARK5 immunohistochemical staining was performed in a tissue microarray consisting of 112 tumor samples from patients with PAAD and adjacent normal tissue samples. ARK5 protein expression in PAAD tissue was markedly increased, compared with non­cancerous tissue (P=7.631x10­11). Moreover, ARK5 protein levels were associated with N stage (P=0.018). The overall survival of patients with PAAD with high ARK5 protein expression levels was reduced (P=0.014), compared with patients with low expression. In conclusion, these findings suggested that ARK5 may represent an independent prognostic indicator of PAAD.

TBOPP enhances the anticancer effect of cisplatin by inhibiting DOCK1 in renal cell carcinoma.

The treatment of renal cell carcinoma (RCC) with chemotherapy remains a challenge; therefore, improving the knowledge of the molecular mechanisms underlying RCC chemoresistance and developing novel therapeutic strategies is important. Dedicator of cytokinesis 1 (DOCK1), the first member of the DOCK family to be discovered, displays various roles during tumorigenesis; however, its role during RCC progression is not completely understood. Therefore, the present study aimed to clarify the function of DOCK1 and 1­[2­(3'­(trifluoromethyl)­(1,1'­biphenyl)­4­yl)­2­oxoethyl]­5­pyrrolidinylsulfonyl­2 (1H)­pyridone (TBOPP), a DOCK1­sensitive inhibitor, during RCC development and chemoresistance. The results of CCK­8 and EdU assay indicated that TBOPP decreased RCC cell viability and proliferation compared with the control group, and sensitized RCC cells to cisplatin. Moreover, RCC cells with high DOCK1 expression levels displayed increased resistance to cisplatin, whereas DOCK1 knockdown enhanced the lethal effects of cisplatin on RCC cells. Furthermore, the results determined by western blotting, CCK­8 and cell apoptosis assay indicated that TBOPP effectively reduced DOCK1 expression levels compared with the control group, and the TBOPP­mediated cisplatin sensitizing effect was mediated by DOCK1 inhibition. The present study suggests that DOCK1 plays a vital role in RCC cell chemoresistance to cisplatin; therefore, TBOPP may serve as a novel therapeutic agent for RCC chemoresistance.

Long non­coding RNA H19 is involved in sorafenib resistance in hepatocellular carcinoma by upregulating miR­675.

Sorafenib is the first­line treatment for advanced hepatocellular carcinoma (HCC). Since many HCC patients experience drug resistance, there is an urgent need to discover more effective therapeutic strategies to overcome drug resistance. Long non­coding RNAs (lncRNAs) play an important role in tumor drug resistance. However, research on the role of lncRNA H19 in sorafenib resistance in HCC is quite limited. In the present study, CCK­8 assay, RT­qPCR, EdU staining, immunofluorescence staining, and western blot analysis were used to detect the effect of lncRNA H19 on sorafenib resistance of HCC cells. H19 expression was found to be negatively related to sorafenib sensitivity in HCC cells. Knockdown of lncRNA H19 elevated sorafenib sensitivity by suppressing epithelial­mesenchymal transition (EMT) in HCC cells. H19 upregulated miR­675 expression. miR­675 inhibitor decreased the cell viability in sorafenib­treated HCC cells, while miR­675 overexpression had the opposite effect on the treated cells. When the cells were pretreated with miR­675 mimic, H19 siRNA did not alter the effect of miR­675 on sorafenib sensitivity. In conclusion, our study provides new clues for further clinical treatment of sorafenib­resistant liver cancer patients.

MiR-223 regulates autophagy associated with cisplatin resistance by targeting FBXW7 in human non-small cell lung cancer.

BACKGROUND: Cisplatin is widely used as a first-line treatment for non-small cell lung cancer (NSCLC), but chemoresistance remains a major clinical obstacle for efficient use. As a microRNA, miR-223 was reported to promote the doxorubicin resistance of NSCLC. However, whether miR-223 is also involved in cisplatin resistance of NSCLC and the mechanism miR-223 involved in drug resistance is unclear. Accumulated evidence has shown that abnormal autophagy is associated with tumor chemoresistance. The study aimed to study the role of miR-223 on cisplatin sensitivity in NSCLC and uncover the potential mechanisms. METHODS: NSCLC cells transfected with mimic or inhibitor for miR-223 was assayed for chemoresistance in vitro. MiR-223 expression was assessed by quantitative real-time PCR (qRT-PCR). Western blot were used to study the expression level of F-box/WD repeat-containing protein 7 (FBXW7) and autophagy-related protein. The effect of miR-223 on cisplatin sensitivity was examined by using CCK-8, EdU assays and Autophagic flux assay. Luciferase assays, EdU assays and small interfering RNA were performed to identify the targets of miR-223 and the mechanism by which it promotes treatment resistance. Xenograft models were established to investigate the effect of mir-223 on cisplatin sensitivity. RESULTS: In the present study, we found that the level of miR-223 was significantly positively correlated with cisplatin resistance. MiR-223 overexpression made NSCLC cells resistant to cisplatin treatment. We further found that autophagy mediated miR-223-mediated cisplatin resistance in NSCLC cells. Further mechanistic research demonstrated that miR-223 directly targeted FBXW7. The overexpression of miR-223 could inhibit the level of FBXW7 protein expression, thus promoting autophagy and making NSCLC cells resistant to cisplatin. Finally, we confirmed the increased effect of cisplatin sensitivity by miR-223 Antagomir in xenograft models of NSCLC. CONCLUSIONS: Our results demonstrate that miR-223 could enhance autophagy by targeting FBXW7 in NSCLC cells. Inhibition of autophagy by miR-223 knockdown provides a novel treatment strategy to alleviate cisplatin resistance in NSCLC.

The long noncoding RNA TUG1 is required for TGF-ß/TWIST1/EMT-mediated metastasis in colorectal cancer cells.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and metastasis is the major cause of CRC-related mortality. Transforming growth factor-beta (TGF-ß) has a central role not only in the regulation of the normal colon but also in the development and metastasis of CRC. However, TGF-ß is not considered an ideal therapeutic target because it shows both pro-tumorigenic and anti-tumorigenic activity, depending on the tumor stage. Therefore, it is important to find a downstream signaling component of TGF-ß that can be targeted to impair CRC metastasis. Here, we show that TGF-ß promotes CRC migration and upregulates the expression of long-noncoding RNA Taurine Upregulated Gene 1 (TUG1). TUG1 knockdown inhibited migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells in vitro, and reduced CRC lung metastasis in vivo. TGF-ß induced metastasis, and TUG1 knockdown inhibited these effects. In addition, TGF-ß could not reverse the anti-metastasis effects of TUG1 knockdown. These data demonstrate that TUG1 is a downstream molecular of TGF-ß. Moreover, TWIST1 expression was increased with TGF-ß treatment, and TUG1 knockdown decreased TWIST1 expression in CRC cells. TWIST1 knockdown inhibited invasion and EMT in CRC cells; these effects were not changed by simultaneous TUG1 knockdown, indicating that TWIST1 is a downstream mediator of TUG1. Moreover, TUG1 was significantly overexpressed in CRC patients. In conclusion, TGF-ß promotes metastasis of CRC via a TUG1/TWIST1/EMT signaling pathway. TUG1 may be a promising drug target to inhibit TGF-ß pathway activation in the treatment of CRC.

Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis. Insights into the roles of MicroRNAs (miRNAs) in diseases, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Methods: Here, we employed a novel chimeric peptide supramolecular nanoparticle delivery system for plectin-1 (PL-1)-targeted PDAC-specific miR-9 delivery in vitro and in pancreatic cancer patient-derived xenograft (PDX) model. RT-PCR and immunohistochemistry (IHC) were conducted to detect the expression pattern of eIF5A2. mRFP-GFP-LC3 fluorescence microscopy and Western blot were carried out to determine autophagy. Luciferase reporter assays were performed to elucidate the regulatory role of miR-9/eIF5A2 axis. Results: PL-1/miR-9 nanocomplexes dramatically improve the anticancer effect of doxorubicin through downregulating eIF5A2 expression to inhibit autophagy and induce apoptosis in PDAC therapy in vivo. Mechanistically, miR-9 directly targets the eIF5A2 transcript by binding to its 3'-untranslated region (3'-UTR) to reduce the expression levels and the secreted protein of eIF5A2 in PDAC cells. Conclusion: PL-1/miR-9 nanoparticles can be used as a novel promising anti-cancer strategy with tumor targeting and miR-9/eIF5A2 may serve as a new potential therapeutic target for future synergic therapy against human PDAC.

MicroRNA-145 Inhibits Cell Migration and Invasion in Colorectal Cancer by Targeting TWIST.

INTRODUCTION: MicroRNAs function as oncogenes or tumor suppressors in the development of various human cancers. We investigated the effect of microRNA-145 (miR-145) on colorectal cancer (CRC) cell invasion and migration. METHODS: The levels of miR-145 in CRC cells were examined by quantitative PCR; Western blotting was used to detect TWIST1 (twist family bHLH transcription factor 1) protein and the epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, vimentin). Then, we transfected miR-145 mimics or inhibitor into CRC cells and used the wound healing and Transwell invasion assays to investigate their migration and invasive capability, respectively. RESULTS: The miR-145 mimics suppressed CRC cell invasion and migration significantly; in contrast, miR-145 downregulation had the opposite effect. Furthermore, miR-145 regulated TWIST1 levels negatively at transcriptional level. TWIST1 knockdown significantly inhibited the CRC cell migration ability and the number of CRC cells that crossed the Transwell membrane. There was no significant difference in terms of migration and invasive capability after the cells had been transfected with miR-145 mimics or inhibitor plus TWIST1 small interfering RNA (siRNA) as compared to the TWIST1 siRNA-only group. Furthermore, we demonstrate that the inhibition of miR-145 could enhance the capability for lung metastasis in vivo. CONCLUSION: Taken together, these findings indicate that miR-145 acts as a new tumor suppressor by regulating TWIST1 and plays a vital role in the invasive and migration ability of CRC cells.

miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells.

Doxorubicin is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. Autophagy, a conserved catabolic process for cellular self-protection and adaptation to the changing environment, is regarded as a potential clinical target to overcome doxorubicin resistance. In this study, the potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human HCC cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. We found that the well-defined miR-223 is expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibits the doxorubicin-induced autophagy that contributes to chemoresistance. Blockade of autophagic flux by chloroquine resulted in the failure of miR-223 inhibitor to suppress doxorubicin sensitivity of HCC cells. We further identified FOXO3a as a direct downstream target of miR-223 and primary mediator of the regulatory effect of miR-223 on doxorubicin-induced autophagy and chemoresistance in HCC cells. Finally, we confirmed the enhancement of doxorubicin sensitivity by agomiR-223 in xenograft models of HCC. These findings establish a novel miRNA-based approach for autophagy interference to reverse doxorubicin resistance in future chemotherapy regimens against human HCC.