Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy.

Exosomes are increasingly recognized as important mediators of intercellular communication in cancer biology. Exosomes can be derived from cancer cells as well as cellular components in tumor microenvironment. After secretion, the exosomes carrying a wide range of bioactive cargos can be ingested by local or distant recipient cells. The released cargos act through a variety of mechanisms to elicit multiple biological effects and impact most if not all hallmarks of cancer. Moreover, owing to their excellent biocompatibility and capability of being easily engineered or modified, exosomes are currently exploited as a promising platform for cancer targeted therapy. In this review, we first summarize the current knowledge of roles of exosomes in risk and etiology, initiation and progression of cancer, as well as their underlying molecular mechanisms. The aptamer-modified exosome as a promising platform for cancer targeted therapy is then briefly introduced. We also discuss the future directions for emerging roles of exosome in tumor biology and perspective of aptamer-modified exosomes in cancer therapy.

Comprehensive transcriptomic analysis of three varieties with different brown planthopper-resistance identifies leaf sheath lncRNAs in rice.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been brought great attention for their crucial roles in diverse biological processes. However, systematic identification of lncRNAs associated with specialized rice pest, brown planthopper (BPH), defense in rice remains unexplored. RESULTS: In this study, a genome-wide high throughput sequencing analysis was performed using leaf sheaths of susceptible rice Taichung Native 1 (TN1) and resistant rice IR36 and R476 with and without BPH feeding. A total of 2283 lncRNAs were identified, of which 649 lncRNAs were differentially expressed. During BPH infestation, 84 (120 in total), 52 (70 in total) and 63 (94 in total) of differentially expressed lncRNAs were found only in TN1, IR36 and R476, respectively. Through analyzing their cis-, trans-, and target mimic-activities, not only the lncRNAs targeting resistance genes (NBS-LRR and RLKs) and transcription factors, but also the lncRNAs acting as the targets of the well-studied stress-related miRNAs (miR2118, miR528, and miR1320) in each variety were identified. Before the BPH feeding, 238 and 312 lncRNAs were found to be differentially expressed in TN1 vs. IR36 and TN1 vs. R476, respectively. Among their putative targets, the plant-pathogen interaction pathway was significantly enriched. It is speculated that the resistant rice was in a priming state by the regulation of lncRNAs. Furthermore, the lncRNAs extensively involved in response to BPH feeding were identified by Weighted Gene Co-expression Network Analysis (WGCNA), and the possible regulation networks of the key lncRNAs were constructed. These lncRNAs regulate different pathways that contribute to the basal defense and specific resistance of rice to the BPH. CONCLUSION: In summary, we identified the specific lncRNAs targeting the well-studied stress-related miRNAs, resistance genes, and transcription factors in each variety during BPH infestation. Additionally, the possible regulating network of the lncRNAs extensively responding to BPH feeding revealed by WGCNA were constructed. These findings will provide further understanding of the regulatory roles of lncRNAs in BPH defense, and lay a foundation for functional research on the candidate lncRNAs.

Unilateral bi-portal endoscopy for the treatment of thalassemia with extramedullary hematopoietic compression of the spinal cord: Two case reports.

RATIONALE: Thalassemia combined with extramedullary hematopoietic spinal cord compression is extremely rare; its ideal treatment is still controversial. Herein, we present 2 cases of thalassemia combined with extramedullary hematopoietic compression of the spinal cord wherein satisfactory results were obtained using unilateral bi-portal endoscopy (UBE). PATIENT CONCERNS: Case 1 was of a 43-year-old male who presented with a chief complaint of numbness of the left lower limb since 1-month. Case 2 involved a 23-year-old male who was admitted to the hospital with a chief complaint of numbness in both toes since 3 months and walking instability since 2 weeks. Both cases had a history of being diagnosed with thalassemia. DIAGNOSES: Computed tomography and magnetic resonance imaging showed spinal canal space-occupying lesions causing dural compression and spinal stenosis. Postoperative pathology confirmed the spinal canal lesions to be extramedullary hematopoietic tissue. INTERVENTIONS: For spinal canal decompression, UBE supplemented by blood transfusion was performed for both cases. OUTCOMES: All preoperative symptoms were relieved postoperatively; no recurrence was noted at the 6-month follow-up. LESSONS: Thalassemia combined with extramedullary hematopoiesis can lead to acute spinal cord compression. UBE significantly relieves spinal stenosis symptoms; furthermore, UBE combined with blood transfusion for spinal canal extramedullary hematopoiesis gives satisfactory results, is safe, and has a low risk of spinal cord injury.

Recycling and Recovery of Deactivated CsPbBr3 Perovskite after Photocatalytic CO2 Reduction Reaction.

CsPbBr3 perovskite nanocrystals have emerged as promising candidates for photocatalysis. However, their conversion efficiency is hampered by material instability, and the accumulation of deactivated perovskites produced after photocatalytic reactions raises significant environmental concerns. To address this issue, we developed a mechanochemical grinding approach assisted by oleylamine as an additive to restore the optical properties and photocatalytic activity of deactivated CsPbBr3, which was due to aggregation in the photocatalytic CO2 reduction reaction. Upon regeneration, the CsPbBr3 nanocrystals exhibited an average length of 34.21 nm and an average width of 20.86 nm, demonstrating optical properties comparable to those of the pristine CsPbBr3 nanocrystals. Moreover, they achieved a conversion efficiency of 88.7% compared with pristine CsPbBr3 nanocrystals in the photocatalytic CO2 reduction reaction. This method effectively enhanced the utilization of CsPbBr3, offering a novel approach for the recycling and recovery of perovskite materials and thereby minimizing material waste and environmental pollution.

Plant long noncoding RNAs: Recent progress in understanding their roles in growth, development, and stress responses.

Long noncoding RNA (lncRNA) transcripts are longer than 200 nt and are not translated into proteins. LncRNAs function in a wide variety of processes in plants and animals, but, perhaps because of their lower expression and conservation levels, plant lncRNAs had attracted less attention than protein-coding mRNAs. Now, recent studies have made remarkable progress in identifying lncRNAs and understanding their functions. In this review, we discuss a number of lncRNAs that have important functions in growth, development, reproduction, responses to abiotic stresses, and regulation of disease and insect resistance in plants. Additionally, we describe the known mechanisms of action of plant lncRNAs according to their origins within the genome. This review thus provides a guide for identifying and functionally characterizing new lncRNAs in plants.

Analysis and Experimental Validation of Rheumatoid Arthritis Innate Immunity Gene CYFIP2 and Pan-Cancer.

Rheumatoid arthritis (RA) is a chronic, heterogeneous autoimmune disease. Its high disability rate has a serious impact on society and individuals, but there is still a lack of effective and reliable diagnostic markers and therapeutic targets for RA. In this study, we integrated RA patient information from three GEO databases for differential gene expression analysis. Additionally, we also obtained pan-cancer-related genes from the TCGA and GTEx databases. For RA-related differential genes, we performed functional enrichment analysis and constructed a weighted gene co-expression network (WGCNA). Then, we obtained 490 key genes by intersecting the significant module genes selected by WGCNA and the differential genes. After using the RanddomForest, SVM-REF, and LASSO three algorithms to analyze these key genes and take the intersection, based on the four core genes (BTN3A2, CYFIP2, ST8SIA1, and TYMS) that we found, we constructed an RA diagnosis. The nomogram model showed good reliability and validity after evaluation, and the ROC curves of the four genes showed that these four genes played an important role in the pathogenesis of RA. After further gene correlation analysis, immune infiltration analysis, and mouse gene expression validation, we finally selected CYFIP2 as the cut-in gene for pan-cancer analysis. The results of the pan-cancer analysis showed that CYFIP2 was closely related to the prognosis of patients with various tumors, the degree of immune cell infiltration, as well as TMB, MSI, and other indicators, suggesting that this gene may be a potential intervention target for human diseases including RA and tumors.

Integrated metabolomic and transcriptomic analyses of two peanut (Arachis hypogaea L.) cultivars differing in amino acid metabolism of the seeds.

Peanut is an important economic crop worldwide. The content of amino acids, especially essential amino acids, is an important nutritional quality trait of peanut seeds. However, the regulation of amino acid metabolism in peanut seeds is poorly understood. Here, two peanut cultivars, Zhonghuahei 1 and Zhongkaihua 151, with high and low free amino acids in mature seeds, respectively, were selected to investigate the regulatory mechanisms of amino acids during seed development. Zhonghuahei 1 is composed of significantly higher arginine (Arg), asparagine (Asn), and glutamate (Glu) contents than Zhongkaihua 151. However, the metabolomic analyses indicated that the contents of most amino acids were significantly lower in Zhonghuahei 1 at the early developmental stage, while they were reverse at the middle and late stages. Transcriptomic analyses also revealed that the differentially expressed genes between the two cultivars during different stages were enriched in multiple pathways associated with amino acid metabolism. Among them, the Arg biosynthesis pathway showed different regulatory profiles between the two cultivars according to the temporal analysis of gene expression patterns. Subsequent gene co-expression network analysis showed that the gene module darkorange was significantly correlated with Arg content, with an enriched Arg biosynthesis pathway. Accordingly, a gene regulatory network for Arg biosynthesis and metabolism, including key genes (ALDH, ASS1, OTC, and GAD) and transcription factors (GATA, HEX, and ATF), was constructed. These findings provide insights into the regulatory network of amino acid metabolism in peanuts and provide candidate genes that can be applied to facilitate peanut breeding with desirable seeds.

CLP1 is a Prognosis-Related Biomarker and Correlates With Immune Infiltrates in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, heterogeneous autoimmune disease with a high disability rate that seriously affects society and individuals. However, there is a lack of effective and reliable diagnostic markers and therapeutic targets. In this study, we identified diagnostic markers of RA based on RNA modification and explored its role as well as degree of immune cell infiltration. We used the gene expression profile data of three synovial tissues (GSE55235, GSE55457, GSE77298) from the Gene Expression Omnibus (GEO) database and the gene of 5 RNA modification genes (including m6A, m1A, m5C, APA, A-1), combined with cluster analysis, identified four RNA modifiers closely related to RA (YTHDC1, LRPPRC, NOP2, and CLP1) and five immune cells namely T cell CD8, CD4 memory resting, T cells regulatory (Tregs) Macrophages M0, and Neutrophils. Based on the LASSO regression algorithm, hub genes and immune cell prediction models were established respectively in RA and a nomogram based on the immune cell model was built. Around 4 key RNA modification regulator genes, miRNA-mRNA, mRNA-TF networks have been established, and GSEA-GO, KEGG-GSEA enrichment analysis has been carried out. Finally, CLP1 was established as an effective RA diagnostic marker, and was highly positively correlated with T cells follicular helper (Tfh) infiltration. On the other hand, highly negatively correlated with the expression of mast cells. In short, CLP1 may play a non-negligible role in the onset and development of RA by altering immune cell infiltration, and it is predicted to represent a novel target for RA clinical diagnosis and therapy.

Bone marrow mesenchymal stem cells-derived exosomal microRNA-16-5p restrains epithelial-mesenchymal transition in breast cancer cells via EPHA1/NF-κB signaling axis.

OBJECTIVE: This study intends to conquer the mystery of microRNA-16-5p/erythropoietin-producing hepatocellular A1/nuclear factor-κB signaling (miR-16-5p/EPHA1/NF-κB signaling) in breast cancer. METHODS: Expression of miR-16-5p, EPHA1 and NF-κB signaling-related proteins were detected. Gene overexpression or silencing was used to examine the biological roles of bone marrow mesenchymal stem cells (BMSCs)-derived exo-miR-16-5p in breast cancer. The effect of exo-miR-16-5p on tumorigenesis of breast cancer was confirmed by the xenograft nude mouse model. RESULTS: Low miR-16-5p and high EPHA1 expression were examined in breast cancer. BMSCs-derived exosomes, up-regulated miR-16-5p or down-regulated EPHA1 restrained epithelial-mesenchymal transition (EMT) of breast cancer cells and tumor growth in nude mice. Down-regulated miR-16-5p or up-regulated EPHA1 activated NF-κB signaling. Knockdown of EPHA1 or inhibition of NF-κB signaling reversed the effects of down-regulated miR-16-5p on breast cancer cells. CONCLUSION: BMSCs-derived exosomal miR-16-5p hinders breast cancer cells progression via EPHA1/NF-κB signaling axis.

Comparison of clinical and radiological outcomes of full-endoscopic versus microscopic lumbar decompression laminectomy for the treatment of lumbar spinal stenosis: a systematic review and meta-analysis.

BACKGROUND: To determine the clinical and radiological outcomes of full-endoscopic (FE) versus microscopic (MI) lumbar decompression laminectomy in the treatment of lumbar spinal stenosis (LSS), we performed a meta-analysis to explore the best choice for patients with LSS requiring surgical relief. METHODS: Literature searches of the PubMed, the Cochrane Library, Embase, Medline, Embase, and Web of Science databases were performed. The searches covered all indexed studies published between 2008 and 2020, using keywords identifying the patient group (lumbar spine stenosis) and the interventions (full-endoscopic lumbar decompression laminectomy and microscopic lumbar decompression laminectomy). A total of 1,727 patients were included in 10 studies. The primary outcomes of the analysis were visual analogue scale (VAS) scores for leg and back pain, and Oswestry Disability Index (ODI) score. RESULTS: The meta-analysis of the VAS score for low back pain showed that in the first 24 hours postoperatively, participants who underwent FE had better pain control than those who underwent MI [FE: mean difference (MD) =-0.78, 95% confidence interval (CI): -1.11, -0.45; MI: MD =-1.53, 95% CI: -1.94, -1.12]. In all subgroup analyses, the VAS score for back pain was lower in the FE group than in the MI group (MD =-0.71, 95% CI: -0.96, -0.47). Regarding the VAS score for leg pain, the FE group had a significantly lower score than the MI group in the first 24 hours (Total: MD =-1.02, 95% CI: -1.31, -0.73). The meta-analysis demonstrated that the FE group had a significantly lower ODI score than the MI group (MD =-1.03, 9% CI: -1.54, -0.51). At 6 months, the MI group had a significantly lower score than the FE group (MD =1.09, 95% CI: 0.53, 1.64), but at 12 months, the FE group had a significantly lower score than the MI group (MD =-2.40, 95% CI: -3.12, -1.67). DISCUSSION: Compared to MI decompression, the FE decompression method resulted in better pain control in the early postoperative period, both in the lower back and legs, as well as shorter operative and shorter hospitalization times.

MiR-30a-5p frequently downregulated in prostate cancer inhibits cell proliferation via targeting PCLAF.

MicroRNAs (miRNAs) have vastly expanded our view of RNA world in intracellular signal regulating networks. Here, we functionally characterized a normally highly expressed miRNA, miR-30a-5p (MIMAT0000087), which exhibits downregulated expression profiles in prostate cancer samples. MiR-30a-5p knockdown and overexpression in PC-3 cell line alters cell proliferation supporting a tumour suppressor role. We also discovered that PCLAF is the direct target of miR-30a-5p. Notably, PC-3 cell proliferation is inhibited by miR-30a-5p/PCLAF axis. miR-30a-5p represents a novel molecule of functionally important miRNAs which may shed light on the novel therapeutic targets for prostate cancer.

Identification of differentially expressed genes and signaling pathways using bioinformatics in interstitial lung disease due to tyrosine kinase inhibitors targeting the epidermal growth factor receptor.

Interstitial lung disease (ILD) is a rare but lethal adverse effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment. The specific mechanism of this disease is not fully understood. To systematically analyze genes associated with EGFR-TKI induced ILD, gene data of EGFR-TKI induced ILD were extracted initially using text mining, and then the intersection between genes from text mining and Gene Expression Omnibus (GEO) dataset was taken for further protein-protein interaction (PPI) analysis using String-bd database. Go ontology (GO) and pathway enrichment analysis was also conducted based on Database of Annotation, Visualization and Integrated Discovery (DAVID) platform. The PPI network generated by STRING was visualized by Cytoscape, and the topology scores, functional regions and gene annotations were analyzed using plugins of CytoNCA, molecular complex detection (MCODE) and ClueGo. 37 genes were identified as EGFR-TKI induced ILD related. Gene enrichment analysis yield 18 enriched GO terms and 12 associated pathways. A PPI network that included 199 interactions for a total of 35 genes was constructed. Ten genes were selected as hub genes using CytoNCA plugin, and four highly connected clusters were identified using MCODE plugin. GO and pathway annotation analysis for the cluster one revealed that five genes were associated with either response to dexamethasone or with lung fibrosis, including CTGF, CCL2, IGF1, EGFR and ICAM1. Our data might be useful to reveal the pathological mechanisms of EGFR-TKI induced ILD and provide evidence for the diagnosis and treatment in the future.

miR-24-3p/FGFR3 Signaling as a Novel Axis Is Involved in Epithelial-Mesenchymal Transition and Regulates Lung Adenocarcinoma Progression.

Our previous studies showed that Fibroblast growth factor receptor 3 (FGFR3) contributed to cell growth in lung cancer. However, the correlation between FGFR3 and tumor progression, coupled with the underlying mechanisms, are not fully understood. The clinical significance of FGFR3 was determined in two cohorts of clinical samples (n = 22, n = 78). A panel of biochemical assays and functional experiments was utilized to elucidate the underlying mechanisms and effects of FGFR3 and miR-24-3p on lung adenocarcinoma progression. Upregulated FGFR3 expression indicated an adverse prognosis for lung adenocarcinoma individuals and promoted metastatic potential of lung adenocarcinoma cells. Owing to the direct regulation towards FGFR3, miR-24-3p could interfere with the potential of proliferation, migration, and invasion in lung adenocarcinoma, following variations of EMT-related protein expression. As a significant marker of EMT, E-cadherin was negatively correlated with FGFR3, of which ectopic overexpression could neutralize the antitumour effects of miR-24-3p and reverse its regulatory effects on EMT markers. Taken together, these findings define a novel insight into the miR-24-3p/FGFR3 signaling axis in regulating lung adenocarcinoma progression and suggest that targeting the miR-24-3p/FGFR3 axis could be an effective and efficient way to prevent tumor progression.

Loss of scinderin decreased expression of epidermal growth factor receptor and promoted apoptosis of castration-resistant prostate cancer cells.

Most patients with prostate cancer will eventually develop the castration-resistant form characterised by metastasis. Cytoskeleton constituents, including F-actin, play important roles in maintaining epithelial integrity and their disruption is a major cause of cancer progression. We previously showed that scinderin (SCIN), an important regulator of F-actin organisation, is highly expressed in poorly differentiated cancer tissues. This study aimed to explore the mechanism of its regulation of cell proliferation. We discovered that SCIN knockdown significantly downregulated epidermal growth factor receptor (EGFR) protein expression, and inhibited epidermal growth factor (EGF)-mediated cell proliferation and activation of the downstream mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signalling pathway. Silencing of SCIN promoted apoptosis in two cell lines (PC-3 and DU145), inhibited B-cell lymphoma-extra-large (Bcl-xl) expression and activated caspase signalling. Furthermore, in vivo studies showed that SCIN deletion slowed tumour growth and decreased EGFR expression. Thus, we conclude that SCIN promotes prostate cancer cell survival by stabilising EGFR and MEK/ERK signalling.

Genetic Deletion of Fbw7 in the mouse intestinal epithelium aggravated dextran sodium sulfate-induced colitis by modulating the inflammatory response of NF-κB pathway.

Fbw7 is a type of E3 ubiquitin ligase that targets various proteins for degradation and has been found to have a high expression level in progenitor cells. Deletion of Fbw7 in the intestine results in the accumulation of progenitor cells. Moreover, Fbw7 loss increases the susceptibility of colorectal cancer. However, the involvement of Fbw7 in the progress and development of inflammatory bowel disease (IBD) is still controversial. To identify the function of Fbw7 on dextran sodium sulfate (DSS)-induced colonic inflammation, we generated Fbw7ΔG mice, lacking Fbw7 specifically in intestinal epithelium. Colitis was induced in male Fbw7 ΔG and wild-type (WT) mice (both age and body weight matched) by treating with 3% DSS in drinking water. We demonstrate that deletion of Fbw7 in the mouse intestinal epithelium aggravates DSS-induced colitis, showing inflammatory response and reduced survival rate. Furthermore, we found that Fbw7 loss caused activation of NF-κB signaling. Thus, FBW7 plays a protective role in acute intestinal inflammation by modulating the inflammatory response of NF-κB pathway.

Intranasal Delivery of Copper Oxide Nanoparticles Induces Pulmonary Toxicity and Fibrosis in C57BL/6 mice.

Copper oxide nanoparticles (CuO NPs) are widely used as catalysts or semiconductors in material fields. Recent studies have suggested that CuO NPs have adverse genotoxicity and cytotoxicity effects on various cells. However, little is known about the toxicity of CuO NPs following exposure to murine lungs. The purpose of this fundamental research was to investigate whether CuO NPs could induce epithelial cell injury, pulmonary inflammation, and eventually fibrosis in C57BL/6 mice. Our studies showed that CuO NPs aggravated pulmonary inflammation in a dose-dependent manner. CuO NPs induced apoptosis of epithelial cells as indicated by TUNEL staining, flow cytometry and western blot analysis, which was partially caused by increased reactive oxygen species (ROS). In addition, CuO NPs exposure promoted collagen accumulation and expression of the progressive fibrosis marker α-SMA in the lung tissues, indicating that CuO NP inhalation could induce pulmonary fibrosis in C57BL/6 mice. All data provide novel evidence that there is an urgent need to prevent the adverse effects of CuO NPs in the human respiratory system.

Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization.

The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment.We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2-/-) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2-/- mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2-/- macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2-/- macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.

FBW7 loss promotes epithelial-to-mesenchymal transition in non-small cell lung cancer through the stabilization of Snail protein.

The E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) functions as a putative tumor suppressor in non-small cell lung cancer (NSCLC) due to its regulation of a set of oncogenic proteins associated with cell proliferation and mitosis. Increasing efforts have been focused on the understanding of FBW7 in determining cell cycle progression and apoptosis induction, however, the correlation between FBW7 and tumor metastasis is not fully understood. In this study, we reported a potential anti-metastatic effect of FBW7 in non-small cell lung cancer (NSCLC). In this model, FBW7 inhibited cancer cell metastasis primarily by inducing ubiquitination and proteolysis of the transcriptional factor Snail, which suppressed E-cadherin cell tight junction protein expression. Loss of FBW7 would stabilize the Snail protein, thus, inhibit E-cadherin expression and promote metastasis in vitro and in vivo. Moreover, Snail ubiquitination and degradation were also achieved by pharmacological approach, in which the FBW7 agonist oridonin treatment led to Snail proteolysis. Furthermore, FBW7 silencing stabilized Snail protein and induced epithelial-to mesenchymal transition (EMT), and acquisition of migration and invasion properties in NSCLC. Overall, our study provides new insights into the FBW7-Snail axis in regulating cell migration and invasion, and suggests that targeting FBW7 may be a potent approach to inhibit metastasis in NSCLC.

NDRG2 facilitates colorectal cancer differentiation through the regulation of Skp2-p21/p27 axis.

Poorly differentiated colorectal cancers (CRCs) are more aggressive and lack targeted therapies. We and others previously reported the predominant role of tumor-suppressor NDRG2 in promoting CRC differentiation, but the underlying mechanism is largely unknown. Herein, we demonstrate that NDRG2 induction of CRC cell differentiation is dependent on the repression of E3 ligase Skp2 activity. In patients and Ndrg2 knockout mice, NDRG2 and Skp2 are negatively correlated and associated with cell differentiation stage. Further, NDRG2 suppression of Skp2 contributes to the inductions and stabilizations of p21 and p27, which are Skp2 target proteins for degradation. The reduction of either p21 or p27 levels by shRNA can decrease NDRG2-induced AKP activity and resume cell growth inhibition, thus both p21 and p27 are required for NDRG2 effect on the promotion of cell differentiation in CRCs. The mechanistic study shows that NDRG2 suppresses ß-catenin nuclear translocation and decreases the occupancy of ß-catenin/TCF complex on Skp2 promoter, potentially through dephosphorylating GSK-3ß. By subjecting a series of NDRG2 deletion mutants to Skp2 expression, the loss of NH2-terminal domain can completely abolish NDRG2-dependent differentiation induction. Supporting the biological significance of the reciprocal relationship between NDRG2 and Skp2, an NDRG2low/Skp2high gene expression signature correlates with poor CRC patient outcome and could be considered as a diagnostic marker of CRCs.

Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of fibrosis and angiogenesis in the lung. In vitro cell studies showed that DDR2 can synergize the actions of both transforming growth factor (TGF)-ß and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor (VEGF) expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against DDR2 or its kinase inhibitor exhibited therapeutic efficacy against lung fibrosis. Thus, this study not only elucidated novel mechanisms by which DDR2 controls the development of pulmonary fibrosis, but also provided candidate target for the intervention of this stubborn disease.