Fingerprint Profiling of Glycans on Extracellular Vesicles via Lectin-Induced Aggregation Strategy for Precise Cancer Diagnostics.

Extracellular vesicles (EVs) harbor abundant glycans that mediate various functions, such as intercellular communication and disease advancement, which play significant roles in disease progression. However, the presence of EV heterogeneity in body fluids and the complex nature of the glycan structures have posed challenges for the detection of EV glycans. In this study, we provide a streamlined method integrated, membrane-specific separation with lectin-induced aggregation strategy (MESSAGE), for multiplexed profiling of EV glycans. By leveraging a rationally designed lectin-induced aggregation strategy, the expression of EV glycans is converted to size-based signals. With the assistance learning machine algorithms, the MESSAGE strategy with high sensitivity, specificity, and simplicity can be used for early cancer diagnosis and classification, as well as monitoring cancer metastasis via 20 µL plasma sample within 2 h. Furthermore, our platform holds promise for advancing the field of EV-based liquid biopsy for clinical applications, opening new possibilities for the profiling of EV glycan signatures in various disease states.

Fast Isolation and Sensitive Multicolor Visual Detection of Small Extracellular Vesicles by Multifunctional Polydopamine Nanospheres.

Small extracellular vesicles (sEVs) assume pivotal roles as vital messengers in intercellular communication, boasting a plethora of biological functions and promising clinical applications. However, efficient isolation and sensitive detection of sEVs continue to present formidable challenges. In this study, we report a novel method for fast isolation and highly sensitive multicolor visual detection of sEVs using aptamer-functionalized polydopamine nanospheres (SIMPLE). In the SIMPLE strategy, aptamer-functionalized polydopamine nanospheres (Apt-PDANS) with 170 nm diameters were synthesized and exhibited a remarkable ability to selectively bind to specific proteins on the surface of sEVs. The binding between sEVs and Apt-PDANS engenders an increase in the overall size of the sEVs, allowing fast isolation of sEVs by filtration (a filter membrane with a pore size of 200 nm). The fast isolation strategy not only circumvents the interference posed by unbound proteins and excessive probes as well as the intricacies associated with conventional ultracentrifugation methods but also expedites the separation of sEVs. Concurrently, the incorporation of Fe3+-doped PDANS permits the multicolor visual detection of sEVs, enabling quantitative analysis by the discernment of visual cues. The proposed strategy achieves a detection limit of 3.2 × 104 sEV mL-1 within 1 h, devoid of any reliance on instrumental apparatus. Furthermore, we showcase the potential application of this methodology in epithelial-mesenchymal transition monitoring and cancer diagnosis, while also envisioning its widespread adoption as a straightforward, rapid, sensitive, and versatile platform for disease monitoring and functional exploration.

Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer.

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

Risk factors for diabetic retinopathy, diabetic macular edema, and sight-threatening diabetic retinopathy.

OBJECTIVE: To identify the risk factors for the development of diabetic retinopathy (DR), diabetic macular edema (DME), and sight-threatening DR (STDR) based on a city-wide diabetes screening program. RESEARCH DESIGN AND METHODS: Diabetic patients were prospectively recruited between June 2016 and December 2022. All patients underwent dilated fundus photography centered on the disc and macula or macular spectral domain optical coherence tomography (SD-OCT) scan. Complete medical history was documented. Systematic examination, blood analysis, and urinalysis were performed. Multivariate logistic regression analysis adjusting for age and sex was conducted. RESULTS: Out of 7274 diabetic patients, 6840 had gradable images, among which 3054 (42.0%) were graded as DR, 1153 (15.9%) as DME, and 1500 (20.6%) as STDR. The factors associated with DR, DME, and STDR included younger age (odds ratio [OR]: 0.96, 0.97, and 0.96 respectively), lower BMI (OR: 0.97, 0.95, and 0.95 respectively), longer duration of diabetes (OR: 1.07, 1.03, and 1.05 respectively) and positive of urinary albumin (OR: 2.22, 2.56, and 2.88 respectively). Other associated factors included elevated blood urea nitrogen (OR: 1.22, 1.28, and 1.27 respectively), higher LDL-cholesterol, lower blood hemoglobin (OR: 0.98, 0.98, and 0.98), insulin intake, presence of diabetic foot pathologies and diabetic peripheral neuropathy. We also identified novel risk factors, including high serum potassium (OR: 1.37, 1.46, and 1.55 respectively), high-serum sodium (OR: 1.02, 1.02, and 1.04 respectively). Better family income was a protective factor for DR, DME, and STDR. Alcohol consumption once a week was also identified as a protective factor for DR. CONCLUSIONS: Similar risk factors for DR, DME, and STDR were found in this study. Our data also indicates high serum sodium, high serum potassium, low blood hemoglobin, and level of family income as novel associated factors for DR, DME, and STDR, which can help with DR monitoring and management.

Transcription factor ZIC2 regulates the tumorigenic phenotypes associated with both bulk and cancer stem cells in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in North America. Current therapeutic regimens are ineffective against advanced EOC. A better understanding of the molecular mechanisms that regulate the biology of EOC will be a critical step toward developing more efficacious therapies against EOC. Herein, we demonstrate that elevated expression of transcription factor ZIC2 was associated with lower survival of EOC patients. Knockout of endogenous ZIC2 in EOC cells attenuated the tumorigenic phenotypes associated with both bulk and cancer stem cells in vitro and in vivo, indicating a pro-tumorigenic role of ZIC2 in EOC. On the other hand, however, overexpression of ZIC2 in EOC cells that do not express endogenous ZIC2 promoted cell migration and sphere formation, but inhibited cell growth and colony formation in vitro and tumor growth in vivo, indicating that the role for ZIC2 in EOC is context dependent. Our transcriptomic analysis showed that ZIC2-regulated genes were involved in multiple biological processes and signaling pathways associated with tumor progression. In conclusion, our findings reveal a context-dependent role for ZIC2 in regulating tumorigenic phenotypes in EOC, providing evidence that ZIC2 can be a potential therapeutic target for EOCs that express a high level of ZIC2.

Magnetically separable Pd-iron-oxides composites as highly efficient and recyclable catalysts for ultra-rapid degradation and debromination of polybrominated diphenyl ethers.

When precious nano-metals are used as environmental catalysts, it is important to tune the particle sizes and the reusability of the nano-metals for achieving their highly efficient catalytic performance at a low cost. In the present work, magnetic iron oxides (FeOx-Y) nanoparticles were pre-prepared as supports of nano-metals, where Y represented the mole percentage of Fe(III) in the total iron (Y ≥ 50 %). FeOx-Y (support), PdCl42- (Pd source) and NaBH4 (reducing agent) were added into the organic pollutant solution containing 2,2',4,4'-tetrabromodiphenyl ether (BDE47). After the NaBH4 was added, the followed reaction realized not only the rapid in-situ preparation of a Pd-loaded FeOx-Y composite catalyst (Pd-FeOx-Y), but also the ultra-fast and complete debromination of BDE47 within 30 s. Comparing the case without adding FeOx-Y, the debromination efficiency of BDE47 was much promoted in the presence of FeOx-Y. The support-induced enhancing effect on the catalytic ability of Pd nanoparticles was improved by increasing the Fe(III) content in the support, being attributed to the much more hydroxyl groups on the support surface. Considering both the catalytic and recovery abilities of Pd-FeOx-Y, Pd-FeOx-75 was the optimal choice because it could be magnetically recovered and re-used for multiple cycles with high catalytic activities. The presently developed "catalyst preparation-pollutant degradation" one-pot system could be applied to conduct complete debromination of all the PBDEs.

A Magnetically Driven Tandem Chip Enables Rapid Isolation and Multiplexed Profiling of Extracellular Vesicles.

The protein phenotypes of extracellular vesicles (EVs) have emerged as promising biomarkers for cancer diagnosis and treatment monitoring. However, the technical challenges in rapid isolation and multiplexed molecular detection of EVs have limited their clinical practice. Herein, we developed a magnetically driven tandem chip to achieve streamlined rapid isolation and multiplexed profiling of surface protein biomarkers of EVs. Driven by magnetic force, the magnetic nanomixers not only act as tiny stir bars to promote mass transfer and enhance reaction efficiency of EVs, but also transport on communicating vessels of the tandem chip continuously and expedite the assay workflow. We designed cyclic surface enhancement of Raman scattering (SERS) tags to bind with target EVs and then release them by exonuclease I, eliminating steric hindrance and amplifying the SERS signal of multiple protein biomarkers on EVs. Due to the excellent assay performance, six breast cancer biomarkers were detected simultaneously on EVs using only 10 µL plasma within 1.5 h. The unweighted SUM signature offers great accuracy in discriminating breast cancer patients from healthy donors. Overall, the dynamic magnetic driving tandem chip offers a new avenue to advance the clinical application of EV-based liquid biopsy.

Simultaneous subset tracing and miRNA profiling of tumor-derived exosomes via dual-surface-protein orthogonal barcoding.

The clinical potential of miRNA-based liquid biopsy has been largely limited by the heterogeneous sources in plasma and tedious assay processes. Here, we develop a precise and robust one-pot assay called dual-surface-protein-guided orthogonal recognition of tumor-derived exosomes and in situ profiling of microRNAs (SORTER) to detect tumor-derived exosomal miRNAs and enhance the diagnostic accuracy of prostate cancer (PCa). The SORTER uses two allosteric aptamers against exosomal marker CD63 and tumor marker EpCAM to create an orthogonal labeling barcode and achieve selective sorting of tumor-specific exosome subtypes. Furthermore, the labeled barcode on tumor-derived exosomes initiated targeted membrane fusion with liposome probes to import miRNA detection reagents, enabling in situ sensitive profiling of tumor-derived exosomal miRNAs. With a signature of six miRNAs, SORTER differentiated PCa and benign prostatic hyperplasia with an accuracy of 100%. Notably, the diagnostic accuracy reached 90.6% in the classification of metastatic and nonmetastatic PCa. We envision that the SORTER will promote the clinical adaptability of miRNA-based liquid biopsy.

Establishment and validation of preclinical models of SMARCA4-inactivated and ARID1A/ARID1B co-inactivated dedifferentiated endometrial carcinoma.

OBJECTIVE: Dedifferentiated endometrial cancer (DDEC) is an uncommon and clinically highly aggressive subtype of endometrial cancer characterized by genomic inactivation of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex protein. It responds poorly to conventional systemic treatment and its rapidly progressive clinical course limits the therapeutic windows to trial additional lines of therapies. This underscores a pressing need for biologically accurate preclinical tumor models to accelerate therapeutic development. METHODS: DDEC tumor from surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and cell line development. The histologic, immunophenotypic, genetic and epigenetic features of the patient tumors and the established PDX models were characterized. The SMARCA4-deficienct DDEC model was evaluated for its sensitivity toward a KDM6A/B inhibitor (GSK-J4) that was previously reported to be effective therapy for other SMARCA4-deficient cancer types. RESULTS: All three DDEC models exhibited rapid growth in vitro and in vivo, with two PDX models showing spontaneous development of metastases in vivo. The PDX tumors maintained the same undifferentiated histology and immunophenotype, and exhibited identical genomic and methylation profiles as seen in the respective parental tumors, including a mismatch repair (MMR)-deficient DDEC with genomic inactivation of SMARCA4, and two MMR-deficient DDECs with genomic inactivation of both ARID1A and ARID1B. Although the SMARCA4-deficient cell line showed low micromolecular sensitivity to GSK-J4, no significant tumor growth inhibition was observed in the corresponding PDX model. CONCLUSIONS: These established patient tumor-derived models accurately depict DDEC and represent valuable preclinical tools to gain therapeutic insights into this aggressive tumor type.

Evaluation and comparison of ocular biometric parameters obtained with Tomey OA-2000 in silicone oil-filled aphakic eyes.

PURPOSE: To evaluate a new non-contact instrument (OA-2000) measuring the ocular biometry parameters of silicone oil (SO)-filled aphakic eyes, as compared with IOLMaster 700. METHODS: Forty SO-filled aphakic eyes of 40 patients were enrolled in this cross-sectional clinical trial. The axial length (AL), central corneal thickness (CCT), keratometry ((flattest keratometry) Kf and (steep keratometry, 90° apart from Kf) Ks), and axis of the Kf (Ax1) were measured with OA-2000 and IOLMaster 700. The coefficient of variation (CoV) was calculated to assess the repeatability. The correlation was evaluated by the Pearson coefficient. Bland-Altman analysis and paired t test were used to analyze the agreements and differences of parameters measured by the two devices, respectively. RESULTS: The mean AL obtained with the OA-2000 was 23.57 ± 0.93 mm (range: 21.50 to 25.68 mm), and that obtained with the IOLMaster 700 was 23.69 ± 0.94 mm (range: 21.85 to 25.86 mm), resulting in a mean offset of 0.124 ± 0.125 mm (p < 0.001). The mean offset of CCT measured by OA-2000 and IOLMaster 700 was 14.6 ± 7.5 µm (p < 0.001). However, the Kf, Ks and Ax1 values from the two devices were comparable (p > 0.05). All the measured parameters of the two devices showed strong linear correlations (all r ≥ 0.966). The Bland-Altman analysis showed a narrow 95% limits of agreement (LoA) of Kf, Ks and AL, but 95%LoA of CCT and Ax1 was wide, which were - 29.3 ~ 0.1 µm and-25.9 ~ 30.7°respectively. The CoVs of the biometric parameters obtained with OA-2000 were lower than 1%. CONCLUSION: In SO-filled aphakic eyes, the ocular parameters (including AL, Kf, Ks, Ax1, and CCT) measured by the OA-2000 and IOLMaster 700 had a good correlation. Two devices had an excellent agreement on ocular biometric measurements of Kf, Ks and AL. The OA-2000 provided excellent repeatability of ocular parameters in SO-filled aphakic eyes.

Upregulation of Formaldehyde in Parkinson's Disease Found by a Near-Infrared Lysosome-Targeted Fluorescent Probe.

Parkinson's disease (PD) is one of the major neurodegenerative diseases caused by complex pathological processes. As a signal molecule, formaldehyde is closely linked to nervous systems, but the relationship between PD and formaldehyde levels remains largely unclear. We speculated that formaldehyde might be a potential biomarker for PD. To prove it, we constructed the first near-infrared (NIR) lysosome-targeted formaldehyde fluorescent probe (named NIR-Lyso-FA) to explore the relationship between formaldehyde and PD. The novel fluorescent probe achieves formaldehyde detection in vitro and in vivo, thanks to its excellent properties such as NIR emission, large Stokes shift, and fast response to formaldehyde. Crucially, utilizing the novel probe NIR-Lyso-FA, formaldehyde overexpression was discovered for the first time in cellular, zebrafish, and mouse PD models, supporting our guess that formaldehyde can function as a possible biomarker for PD. We anticipate that this finding will offer insightful information for PD pathophysiology, diagnosis, medication development, and treatment.

Intra-articular delivery of antioxidative polymer-based nanospheres reduces intracellular reactive oxygen species in macrophages and alleviates cartilage damage in a rat model.

Cartilage damage is frequent in various joint diseases, mainly manifested by the loss of type II collagen and the degradation of proteoglycans. Diclofenac sodium is a commonly used drug for the treatment of joint diseases, but simple administration is often affected by drug clearance and rapid metabolism. Intra-articular drug delivery is an effective method for local enrichment of high concentration of drugs. However, due to the short half-life of diclofenac sodium, prolonging the stability and duration of the drug can alleviate the disadvantages of direct intra-articular application. Nanospheres for delivering drugs to treat joint diseases could be a remedy for cartilage damage. In addition, excessive production of reactive oxygen species (ROS) by macrophages activated in damaged cartilage would aggravate cartilage damage. Therefore, this study intends to use poly lactic-co-glycolic acid nanospheres to load and deliver diclofenac sodium to inhibit chondrocyte death while regulating the generation of ROS, thereby promoting the treatment of cartilage damage.

[Effect of Dimethyl Fumarate (DMF) on T-cell Acute Lymphoblastic Leukemia].

OBJECTIVE: To explore the effect and possible mechanism of dimethyl fumarate (DMF) on T-cell acute lymphoblastic leukemia (T-ALL), and provide experimental and theoretical basis for the clinical treatment of T-ALL. METHODS: Jurkat cells were treated with different concentrations of DMF for 24 hours, and then the proportion and absolute count of Ki67-positive Jurkat cells were analyzed by flow cytometry. Meanwhile, the protein levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and E3 ubiquitin ligase HACE1 in Jurkat cells treated with DMF for 24 hours were evaluated by Western blot. Nrf2 proteins were co-immunoprecipitated in Jurkat cells, and then HACE1 protein was assessed by Western blot. Plasmids of Flag-Nrf2 and different gradients of Flag-HACE1 were transfected into HEK293T cells, and the levels of Flag-Nrf2 were detected by Western blot after 48 hours. RESULTS: DMF could significantly inhibit the proportion and absolute count of Ki67-positive Jurkat cells, and DMF inhibited the proliferation of Jurkat cells in a dose-dependent manner (r=0.9595, r=0.9054). DMF could significantly up-regulate the protein levels of Nrf2 and E3 ubiquitin ligase HACE1 in Jurkat cells (P<0.01, P<0.01). HACE1 physically interacted with Nrf2 in Jurkat cells. Overexpression of Flag-HACE1 significantly increased the protein level of Flag-Nrf2 in a dose-dependent manner (r=0.9771). CONCLUSION: DMF inhibits the proliferation of T-cell acute lymphoblastic leukemia cell. The mechanism may be that, DMF significantly up-regulates the protein levels of Nrf2 and E3 ubiquitin ligase HACE1, and HACE1 interacts with Nrf2 and positively regulates Nrf2 protein level.

The Effect of GLUT1 on the Survival Rate and Immune Cell Infiltration of Lung Adenocarcinoma and Squamous Cell Carcinoma: A Meta and Bioinformatics Analysis.

BACKGROUND: Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are two major subtypes of Non-Small Cell Lung Cancer (NSCLC). Studies have shown that abnormal expression of glucose transport type 1 (GLUT1) in NSCLC patients has been associated with cancer progression, aggressiveness, and poor clinical outcome. However, the clinical effect of GLUT1 expression on LUAD and LUSC is unclear. OBJECTIVE: This study aims to learn more about the character of GLUT1 in LUAD and LUSC. METHODS: A meta-analysis was performed to evaluate the GLUT1 protein level, and the bioinformatics analysis was used to detect the GLUT1 mRNA expression level, survival differences, and the infiltration abundance of immune cells in samples from TCGA. Meanwhile, functional and network analysis was conducted to detect important signaling pathways and key genes with the Gene Expression Omnibus (GEO) dataset. RESULTS: Our results showed that GLUT1 was over-expressed both in LUAD and LUSC. LUAD patients with high GLUT1 expression had a poor prognosis. Additionally, GLUT1 was related to B cell and neutrophil infiltration of LUAD. In LUSC, GLUT1 was correlated with tumor purity, B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration. The GEO dataset analysis results suggested GLUT1 potentially participated in the p53 signaling pathway and metabolism of xenobiotics through cytochrome P450 and was associated with KDR, TOX3, AGR2, FOXA1, ERBB3, ANGPT1, and COL4A3 gene in LUAD and LUSC. CONCLUSION: GLUT1 might be a potential biomarker for aggressive progression and poor prognosis in LUAD, and a therapeutic biomarker in LUSC.

Downregulation of LEF1 Impairs Myeloma Cell Growth Through Modulating CYLD/NF-κB Signaling.

Aberrant expression of lymphoid enhancer-binding factor-1 (LEF1) has been identified in various hematological malignancies including multiple myeloma (MM). However, the exact role of LEF1 in MM remains largely unknown. Here, we showed that knockdown of LEF1 could apparently impair the proliferation, induce apoptosis and promote the ROS production in MM cell lines, suggesting that LEF1 might be involved in maintaining MM cell growth and survival. Moreover, we observed that the mRNA level of the deubiquitinase cylindromatosis (CYLD), a well-recognized tumor suppressor in MM, was significantly increased following LEF1 depletion in myeloma cells. Further study showed that LEF1 could directly associate with the promoter of CYLD gene and thus repress its transcription in MM cells. Intriguingly, LEF1 depletion-mediated CYLD upregulation was sufficient to negatively modulate NF-κB signaling pathway in MM cells. Moreover, the decrease in NF-κB activity following LEF1 knockdown could be largely rescued when CYLD was silenced in MM cells. Taken together, our study provided the compelling evidence to show that LEF1 may augment the proliferation and survival of MM cells through direct repression of CYLD transcription and subsequent activation of NF-κB signaling pathway, corroborating that LEF1 may become a potential therapeutic target against MM.

Embryonic protein NODAL regulates the breast tumor microenvironment by reprogramming cancer-derived secretomes.

The tumor microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumorigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumor growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple-negative breast cancers and that it directly induces Cancer-associated fibroblasts phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g., CXCL1), cytokines (e.g., IL-6) and growth factors (e.g., PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.

Downregulation of long non-coding RNA LOC101928477 correlates with tumor progression by regulating the epithelial-mesenchymal transition in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignancies. There is a growing body of evidence showing that long non-coding RNAs (lncRNAs) play critical roles in ESCC oncogenesis. The present study aimed to explore the role of LOC101928477, a newly discovered lncRNA, in the development and metastasis of ESCC. METHODS: In this study, real-time PCR, western blotting, cell counting kit-8 (CCK-8), flow cytometry, colony formation, wound healing, transwell migration/invasion assay, immunofluorescence, and immunohistochemistry were used. We also applied an in situ xenograft mouse model and a lung metastasis mouse model to verify our findings. RESULTS: We determined that LOC101928477 expression was inhibited in ESCC tissue and ESCC cell lines when compared with controls. Moreover, forced expression of LOC101928477 effectively inhibited ESCC cell proliferation, colony formation, migration, and invasion via suppression of epithelial-mesenchymal transition (EMT). Furthermore, LOC101928477 overexpression inhibited in situ tumor growth and lung metastasis in a mouse model. CONCLUSIONS: Together, our results suggested that LOC101928477 could be a novel suppressor gene involved in ESCC progression.

Downregulation of USP12 inhibits tumor growth via the p38/MAPK pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Ubiquitin­specific protease 12 (USP12) is specifically upregulated in the tumor tissues of patients with HCC compared with the corresponding adjacent normal tissues. However, the relationship between USP12 and the growth of HCCs is not fully understood. In the present study, USP12 was knocked down in HCC cell lines to investigate its effects on proliferation and apoptosis. The results showed that USP12­knockdown could inhibit the proliferation and promote apoptosis in HCC cell lines. Flow cytometry analysis also showed that USP12 could induce cell cycle arrest at the G2/M stage. In vivo experiments showed that USP12­knockdown could suppress tumor growth in mice, and immuno­blotting revealed that USP12 could induce G2/M arrest through the cyclin dependent kinase 1/cyclinB1 axis, and trigger apoptosis via the p38/mitogen­activated protein kinase pathway. These data strongly indicate that USP12 is a potential target for the treatment of HCC.

Angiotensin II enhances the proliferation of Natural Killer/T-cell lymphoma cells via activating PI3K/Akt signaling pathway.

The present study was to determine the roles of Angiotensin (Ang) II in the growth of lymphoma in nude mice and the proliferation and viability of the human Natural Killer/T (NK/T)-cell lymphoma cell line SNK-6, and the activation of downstream signaling pathway. Lymphoma samples and corresponding normal tissues were obtained from lymphoma patients. Proliferation of SNK-6 cells was detected by CCK8 or MTT assay. The levels of Ang II and its receptor Ang II type 1 receptor (AT1R) were higher in lymphoma tissues than those in control tissues. Ang II increased the lymphoma volume and size in nude mice, the proliferation and viability and the proliferating cell nuclear antigen (PCNA) and Ki67 levels of SNK-6 cells. Losartan, an antagonist of AT1R, reduced lymphoma volume and size in nude mice, and the proliferation and viability and the PCNA and Ki67 levels of SNK-6 cells. The levels of phosphorylated phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase B (p-Akt) were increased by Ang II and then reduced by losartan in SNK-6 cells. The proliferation and viability of SNK-6 cells were increased by Ang II, but these increases were inhibited by PI3K inhibitor wortmannin and Akt inhibitor MK2206. The increases of PCNA and Ki67 induced by Ang II were inhibited by wortmannin or MK2206 in SNK-6 cells. These results indicate that Ang II/AT1R is activated in lymphoma, and Ang II promotes the progression of lymphoma in nude mice and the proliferation and viability of SNK-6 cells via activating PI3K/Akt signaling pathway.