ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells.

Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-ß1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-ß1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

Near-Infrared Luminescent Materials Incorporating Rare Earth/Transition Metal Ions: From Materials to Applications.

The spotlight has shifted to near-infrared (NIR) luminescent materials emitting beyond 1000 nm, with growing interest due to their unique characteristics. The ability of NIR-II emission (1000-1700 nm) to penetrate deeply and transmit independently positions these NIR luminescent materials for applications in optical-communication devices, bioimaging, and photodetectors. The combination of rare earth metals/transition metals with a variety of matrix materials provides a new platform for creating new chemical and physical properties for materials science and device applications. In this review, the recent advancements in NIR emission activated by rare earth and transition metal ions are summarized and their role in applications spanning bioimaging, sensing, and optoelectronics is illustrated. It started with various synthesis techniques and explored how rare earths/transition metals can be skillfully incorporated into various matrixes, thereby endowing them with unique characteristics. The discussion to strategies of enhancing excitation absorption and emission efficiency, spotlighting innovations like dye sensitization and surface plasmon resonance effects is then extended. Subsequently, a significant focus is placed on functionalization strategies and their applications. Finally, a comprehensive analysis of the challenges and proposed strategies for rare earth/transition metal ion-doped near-infrared luminescent materials, summarizing the insights of each section is provided.

Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans.

Ribosome biogenesis is initiated by RNA polymerase I (Pol I)-mediated synthesis of pre-ribosomal RNA (pre-rRNA). Pol I activity was previously linked to longevity, but the underlying mechanisms were not studied beyond effects on nucleolar structure and protein translation. Here we use multi-omics and functional tests to show that curtailment of Pol I activity remodels the lipidome and preserves mitochondrial function to promote longevity in Caenorhabditis elegans. Reduced pre-rRNA synthesis improves energy homeostasis and metabolic plasticity also in human primary cells. Conversely, the enhancement of pre-rRNA synthesis boosts growth and neuromuscular performance of young nematodes at the cost of accelerated metabolic decline, mitochondrial stress and premature aging. Moreover, restriction of Pol I activity extends lifespan more potently than direct repression of protein synthesis, and confers geroprotection even when initiated late in life, showcasing this intervention as an effective longevity and metabolic health treatment not limited by aging.

WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer.

Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/ß-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2-SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2-SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2-SOX4 axis may be a potential therapeutic target for gastric cancer treatment.

Targeting LGSN restores sensitivity to chemotherapy in gastric cancer stem cells by triggering pyroptosis.

Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gastric cancer stem cells (GCSCs) remains largely unknown. Here, we present evidence that lengsin, lens protein with glutamine synthetase domain (LGSN), a vital cell fate determinant, is overexpressed in GCSCs and is highly correlated with malignant progression and poor survival in GC patients. Ectopic overexpression of LGSN in GCSC-derived differentiated cells facilitated their dedifferentiation and treatment resistance by interacting with vimentin and inducing an epithelial-to-mesenchymal transition. Notably, genetic interference of LGSN effectively suppressed tumor formation by inhibiting GCSC stemness maintenance and provoking gasdermin-D-mediated pyroptosis through vimentin degradation/NLRP3 signaling. Depletion of LGSN combined with the chemo-drugs 5-fluorouracil and oxaliplatin could offer a unique and promising approach to synergistically rendering this deadly cancer eradicable in vivo. Our data place focus on the role of LGSN in GCSC regeneration and emphasize the critical importance of pyroptosis in battling GCSC.

Effect of Arabinoxylan and Xylo-Oligosaccharide on Growth Performance and Intestinal Barrier Function in Weaned Piglets.

The purpose of this study was to explore the effects of xylose with different polymerizations on growth performance, intestinal barrier function, and gut microbial composition in weaned piglets. A total of 144 weaned piglets were assigned to 3 dietary treatments in a completely randomized design according to their body weight and sex. Dietary treatments included a corn-soybean meal basal diet (CON) and 2 additional diets formulated with 1% arabinoxylan (AX) and 1% xylo-oligosaccharide (XOS), respectively. Results showed that dietary supplementation of XOS or AX reduced diarrhea incidence of weaned piglets compared with the CON group (p < 0.05). XOS or AX increased the ileal villus height and intestinal activity of antioxidases in weaned piglets compared with the CON group (p < 0.05). XOS or AX reduced the ileal and colonic IL-6 content and increased the colonic sIgA and IL-10 concentrations in weaned piglets compared with the CON group (p < 0.05). XOS or AX increased the total organic acids concentrations in the ileum and in vitro fermentation (p < 0.05). XOS increased the abundance of Lactobacillus and Bifidobacterium in the ileal digesta (p < 0.05), while AX increased the population of Lactobacillus in the ileal digesta and the abundance of Bifidobacterium in the colonic digesta of weaned piglets (p < 0.05). In conclusion, both XOS and AX reduce diarrhea incidence and improve antioxidant capacity, immune function, and populations of beneficial bacteria, while microbial fermentation of XOS with a lower polymerization and molecular mass can produce more organic acids and an increased abundance of Lactobacillus and Bifidobacterium in the upper gut of weaned pigs compared with AX.

Establishment and evaluation of module-based immune-associated gene signature to predict overall survival in patients of colon adenocarcinoma.

BACKGROUND: Patients with colon adenocarcinoma (COAD) exhibit significant heterogeneity in overall survival. The current tumor-node-metastasis staging system is insufficient to provide a precise prediction for prognosis. Identification and evaluation of new risk models by using big cancer data may provide a good way to identify prognosis-related signature. METHODS: We integrated different datasets and applied bioinformatic and statistical methods to construct a robust immune-associated risk model for COAD prognosis. Furthermore, a nomogram was constructed based on the gene signature and clinicopathological features to improve risk stratification and quantify risk assessment for individual patients. RESULTS: The immune-associated risk model discriminated high-risk patients in our investigated and validated cohorts. Survival analyses demonstrated that our gene signature served as an independent risk factor for overall survival and the nomogram exhibited high accuracy. Functional analysis interpreted the correlation between our risk model and its role in prognosis by classifying groups with different immune activities. Remarkably, patients in the low-risk group showed higher immune activity, while those in the high-risk group displayed a lower immune activity. CONCLUSIONS: Our study provides a novel tool that may contribute to the optimization of risk stratification for survival and personalized management of COAD.

Intelligent Supply Chain and Logistics Route Optimization Algorithm in Wireless Sensor Network.

This article first proposes the design of the ZigBee wireless sensor network node based on Arduino, from the design and implementation of the node hardware system to the design and implementation of the node software system, and expands on the design details. The node function was applied to the node design environment, and simulation tests were performed, and execution was tested to confirm the feasibility and practicability of the design. Based on this, the article proposes the service construction process of the software and hardware platform of the smart supply chain system, and then clarifies the basic mathematical problem of the distribution plan in line with the service strategy, that is, "the logistics route optimization algorithm with capacity and time constraint optimization," which aims to study statically design, define, and model, and test two precise solutions representing heuristic genetic algorithms and analyze their results. In addition, additional hardware such as smart supply chain and cabinet boards are tested and designed according to system requirements, and the interaction mechanism is adapted to the user interface and supporting structure design so as to ensure the completion of user-related business processes. Combining the existing theoretical knowledge, the first priority is to meet customer needs, build a smart supply chain model under the premise of on-time delivery, and solve the model in time. Based on this point, this article tries to use hybrid branch algorithm link and tabu search algorithm to increase the consideration of traffic conditions, collect accurate algorithms, and modern heuristic algorithms to solve the actual situation of the case. At the end, the article proposes some related issues for the above problems. Suggesting through the research of wireless sensor network, this paper applies it to the research of intelligent supply chain and logistics route optimization algorithm and promotes the development of more intelligent supply chain in the future.

Genetic Analysis of a Collection of Rice Germplasm (Oryza sativa L.) through High-Density SNP Array Provides Useful Information for Further Breeding Practices.

Traditional breeding strategies mainly focus on the evaluation of trait performance, but pay less attention to the changing genetic background. A comprehensive understanding of the genetic diversity of germplasms is crucial for the deliberate improvement of specific traits. A collection of 154 highland rice varieties were collected as the initial genetic resource in our breeding program to improve the pathogen resistance and eating and cooking qualities. These varieties were analyzed using a whole-genome SNP array and were clustered into three groups. Further analysis revealed that the favorable alleles of pathogen resistance genes are mostly absent in our collected varieties. However, it showed that most varieties possess favorable alleles of Waxy (Wx) and ALKALI DEGENERATION (ALK), which are able to enhance the eating and cooking qualities. Moreover, only about one fifth of all varieties harbors favorable the allele of fragrance gene Betainealdehyde dehydrogenase (BADH2). Together, these results give an overall view of the genetic constitution of the target traits, which provide useful information for future genetic improvement in breeding practices.

Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer.

5'-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway and has been reported to suppress tumorigenesis. The MTAP gene is located at 9p21, a chromosome region often deleted in breast cancer (BC). However, the clinical and biological significance of MTAP in BC is still unclear. Here, we reported that MTAP was frequently downregulated in 41% (35/85) of primary BCs and 89% (8/9) of BC cell lines. Low expression of MTAP was significantly correlated with a poor survival of BC patients (P=0.0334). Functional studies showed that MTAP was able to suppress both in vitro and in vivo tumorigenic ability of BC cells, including migration, invasion, angiogenesis, tumor growth and metastasis in nude mice with orthotopic xenograft tumor of BC. Mechanistically, we found that downregulation of MTAP could increase the polyamine levels by activating ornithine decarboxylase (ODC). By treating the MTAP-repressing BC cells with specific ODC inhibitor Difluoromethylornithine (DFMO) or treating the MTAP-overexpressing BC cells with additional putrescine, metastasis-promoting or -suppressing phenotype of these MTAP-manipulated cells was significantly reversed, respectively. Taken together, our data suggested that MTAP has a critical metastasis-suppressive role by tightly regulating ODC activity in BC cells, which may serve as a prominent novel therapeutic target for advanced breast cancer treatment.

MAPK10 Expression as a Prognostic Marker of the Immunosuppressive Tumor Microenvironment in Human Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains a devastating malignancy worldwide due to lack of effective therapy. The immune-rich contexture of HCC tumor microenvironment (TME) makes this tumor an appealing target for immune-based therapies; however, the immunosuppressive TME is still a major challenge for more efficient immunotherapy in HCC. Using bioinformatics analysis based on the TCGA database, here we found that MAPK10 is frequently down-regulated in HCC tumors and significantly correlates with poor survival of HCC patients. HCC patients with low MAPK10 expression have lower expression scores of tumor infiltration lymphocytes (TILs) and stromal cells in the TME and increased scores of tumor cells than those with high MAPK10 expression. Further transcriptomic analyses revealed that the immune activity in the TME of HCC was markedly reduced in the low-MAPK10 group of HCC patients compared to the high-MAPK10 group. Additionally, we identified 495 differentially expressed immune-associated genes (DIGs), with 482 genes down-regulated and 13 genes up-regulated in parallel with the decrease of MAPK10 expression. GO enrichment and KEGG pathway analyses indicated that the biological functions of these DIGs included cell chemotaxis, leukocyte migration and positive regulation of the response to cytokine-cytokine receptor interaction, T cell receptor activation and MAPK signaling pathway. Protein-protein interaction (PPI) analyses of the 495 DIGs revealed five potential downstream hub genes of MAPK10, including SYK, CBL, VAV1, LCK, and CD3G. Several hub genes such as SYK, LCK, and VAV1 could respond to the immunological costimulatory signaling mediated by the transmembrane protein ICAM1, which was identified as a down-regulated DIG associated with low-MAPK10 expression. Moreover, ectopic overexpression or knock-down of MAPK10 could up-regulate or down-regulate ICAM1 expression via phosphorylation of c-jun at Ser63 in HCC cell lines, respectively. Collectively, our results demonstrated that MAPK10 down-regulation likely contributes to the immunosuppressive TME of HCC, and this gene might serve as a potential immunotherapeutic target and a prognostic factor for HCC patients.

miR-421 promotes the viability of A549 lung cancer cells by targeting forkhead box O1.

MicroRNA (miR)-421 has been reported to serve various important roles in numerous types of cancer, including neuroblastoma and gastric cancer. However, to the best of our knowledge, few reports have determined the role of miR-421 in lung cancer. The aim of the current study was to analyze the expression levels of miR-421 in A549 lung cancer cells, to determine the target gene of miR-421, and to investigate the function and mechanism of miR-421 in cellular cytotoxicity. miR-421 expression levels were analyzed in A549 lung cancer cells using reverse transcription-quantitative PCR, a MTT assay was performed to determine the effect of miR-421 on A549 cell cytotoxicity and the protein expression levels of forkhead box O1 (FOXO1) were determined via western blotting. The target gene of miR-421 was predicted and verified using TargetScan and a dual-luciferase reporter assay, respectively. The results revealed that miR-421 expression levels were significantly upregulated in A549 lung cancer cell lines compared with the normal cells (P<0.01). Additionally, it was discovered that miR-421 promoted A549 cell viability (P<0.01) compared with A549 transfected with negative control. miR-421 was also identified to bind to the 3'-untranslated region of FOXO1. In A549 cells transfected with miR-421-mimics, the expression levels of phosphorylated (p)-AKT, p-glycogen synthase kinase-3ß, p-retinoblastoma and cyclin D1 were significantly upregulated (P<0.01), whereas the expression levels of FOXO1 and p21 were significantly downregulated (P<0.01) compared with the control group. In conclusion, the results of the present study suggested that miR-421 may promote the viability of A549 lung cancer cells by targeting FOXO1 and modulating cell cycle, indicating that targeting miR-421 and FOXO1 may represent future therapeutic strategies for the treatment of patients with lung cancer.

Nucleosome Assembly Protein 1-Like 3 Enhances Cisplatin Resistance of Ovarian Cancer Cell by Activating Transforming Growth Factor-Beta Pathway.

Chemotherapy resistance is one of the main reasons for tumor-related death. In particular, ovarian cancer patients often acquire drug resistance after chemotherapy. In this study, we found that the histone chaperone, nucleosome assembly protein 1-like 3 (NAP1L3), was significantly upregulated in tissues with cisplatin resistance compared with cisplatin-sensitive tissues. Patients with high NAP1L3 levels had poor prognosis, suggesting that NAP1L3 might regulate ovarian cancer resistance. Colony formation and terminal deoxynulceotidyl transferase nick-end-labeling (TUNEL) assays showed cells with high NAP1L3 had high cisplatin resistance, whereas cells with low NAP1L3 had poor cisplatin resistance. NAP1L3 overexpression significantly increased cisplatin resistance, whereas NAP1L3 knockdown significantly reduced cisplatin resistance, suggesting that NAP1L3 promoted cisplatin resistance. Mechanistically, gene set enrichment analysis and luciferase reporter assays showed that NAP1L3 regulated the transforming growth factor-beta (TGF-ß) pathway. NAP1L3 overexpression increased the phosphorylation and nuclear translocation of SMAD family member 2 (SMAD2) and SMAD3, confirming that NAP1L3 activated the TGF-ß pathway. Therefore, NAP1L3 might represent a novel target to overcome ovarian cancer chemoresistance.

LncRNA SNHG16 Promotes the Progression of Laryngeal Squamous Cell Carcinoma by Mediating miR-877-5p/FOXP4 Axis.

OBJECTIVE: Laryngeal cancer is a common malignant tumor in the ENT, of which laryngeal squamous cell carcinoma (LSCC) accounts for more than 90% of laryngeal cancer. The purpose of this study is to investigate the regulatory mechanism of lncRNA SNHG16 in LSCC. MATERIALS AND METHODS: Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure mRNA expression. Cell Counting Kit (CCK-8), Transwell and luciferase reporter assays, flow cytometric analysis and Western blot analysis were used to investigate the function of lncRNA SNHG16 in LSCC. RESULTS: SNHG16 expression was increased in LSCC tissues and cells. The abnormal expression of SNHG16 was associated with clinical stage and lymph node metastasis in LSCC patients. In addition, knockdown of SNHG16 restrained cell proliferation, migration and invasion in LSCC. More importantly, SNHG16 acted as a competitive endogenous RNA in LSCC and regulated FOXP4 expression by making miR-877-5p sponge. Further, SNHG16 promoted LSCC progression by interacting with miR-877-5p and FOXP4. CONCLUSION: LncRNA SNHG16 promotes the progression of LSCC by sponging miR-877-5p and upregulating FOXP4.

Isobavachalcone exerts anti­proliferative and pro­apoptotic effects on human liver cancer cells by targeting the ERKs/RSK2 signaling pathway.

Aberrant activation of the extracellular signal­regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathway is frequently determined in various human tumor types, including liver cancer, and has been considered as a promising target for cancer chemoprevention and therapy. In the present study, using computer­aided virtual screening and molecular docking, isobavachalcone (IBC), a natural chalcone compound, was identified to be an ATP­competitive inhibitor targeting ERK1/2 and RSK2. Cell Counting Kit­8, EdU incorporation and colony formation assays were used to detect the effects of IBC on cell viability and proliferation, and the results demonstrated that IBC effectively inhibited the proliferation of liver cancer HepG2 and Hep3B cells, whereas it had no notable cytotoxic effect on immortal liver L02 cells. Flow cytometric analysis and western blotting further revealed that IBC caused significant levels of apoptosis on liver cancer cells via the caspase­dependent mitochondria pathway. The computer prediction was confirmed with pull­down and in vitro kinase assays, in which IBC directly bound with ERK1/2 and RSK2, and dose­dependently blocked RSK2 kinase activity in liver cancer cells. Treatment of HepG2 or Hep3B cells with IBC significantly attenuated epidermal growth factor­induced phosphorylation of RSK2 and resulted in the reduced activation of its downstream substrates including cAMP response element­binding protein, activating transcription factor 1, histone H3 and activating protein­1. Enforced RSK2 expression in L02 cells could increase the effect of IBC on suppressing cell growth. Conversely, knockdown of RSK2 reduced the inhibitory effect of IBC on HepG2 cell proliferation. Overall, the present data indicated that ERKs/RSK2 signaling serves a pivotal role in IBC­induced suppression of liver cancer cells and that IBC may be a potential therapeutic candidate for human cancer with elevated ERKs/RSK2 activity.

Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) occurs with the highest frequency in China, especially in the high-risk Northern Chinese. Recent studies have reported that SLC22A3 is significantly downregulated in non-tumor (NT) esophageal tissues from familial ESCC patients compared with those from sporadic ESCC. However, the mechanism of how SLC22A3 regulates familial ESCC remains unknown. In this study, post hoc genome-wide association studies (GWAS) in 496 cases with a family history of upper gastrointestinal tract cancers and 1056 controls were performed and the results revealed that SLC22A3 is a novel susceptibility gene for familial ESCC. Reduced expression of SLC22A3 in NT esophageal tissues from familial ESCC patients significantly correlates with its promoter hypermethylation. Moreover, case-control study of Chinese descendants from different risk areas of China revealed that the methylation of the SLC22A3 gene in peripheral blood leukocyte (PBL) DNA samples could be a risk factor for developing ESCC in this high-risk population. Functional studies showed that SLC22A3 is a novel antioxidant gene, and deregulation of SLC22A3 facilitates heat stress-induced oxidative DNA damage and formation of γ-H2AX foci in normal esophageal epithelial cells. Collectively, we show that epigenetic alterations of SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer.

miR-221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells.

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild-type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1.

Inhibitory effect of miR-451 on proliferation of hepatic carcinoma HepG2 cells and its prospect in hepatic carcinoma diagnosis and prognosis / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To explore the mRNA molecular targets for diagnosis of hepatic carcionoma and to investigate their functional roles in proliferation and cell cycle of hepatic cancer cells. Methods: Based on the statistical analysis of miRNA expression data from 377 hepatic carcionoma samples and 37 adjacent non-cancerous samples in TCGAdatabase, a group of 33 differentially expressed miRNAs were identified.A further screen of these differentially expressed miRNAs was performed using the receiver operating characteristic curve (ROC curve) and Kaplan-Meier survival analysis; and with referring to the current publications, miR-451 was screened as the study subject. HepG2 cells were transfected with pLVX-shRNA2-miR-451 to over-express miR-451. The effect of miR-451 over-expression on the proliferation of HepG2 cell was determined by CCK-8 assay; while the effect on cell cycles was detected by flow cytometry. Results: The expression of miR-451 in the adjacent non-cancerous tissues was significantly lower than that in cancer tissues ([473.40±390.24] vs [1 990.47±2 118.04], P<0.05). MiR-451 could be used as an early diagnostic biomarker of hepatic carcionoma, with a high ROC value of 0.91 (sensitivity 0.89, specificity 0.87). The results of in vitro experiments showed that the proliferation of HepG2 cells was significantly decreased after miR-451 over-expression (48 h: [0.69±0.04] vs [1.08±0.05]; 72 h: [0.76±0.07] vs [1.52± 0.02]; all P<0.01), and a large number of cells were blocked in S phase(P<0.05). Conclusion: miR-451 has the potential to be used as a biomarker for hepatic carcionoma diagnosis and prognosis; moreover, it also exhibits the inhibitory effect on proliferation of hepatic cancer cells.

Functional PIN1 promoter polymorphisms associated with risk of nasopharyngeal carcinoma in Southern Chinese populations.

Our previous work reported the association between two single nucleotide polymorphisms (SNPs) in PIN1 promoter and nasopharyngeal carcinoma (NPC) risk with a small sample size in a low incidence area. This study investigated the association between the two SNPs and NPC risk in 733 patients and 895 controls from a high incidence area. The results indicated the genotype and allele frequencies of -842G > C and -667C > T were both significantly different between patients and controls even using the resampling statistics. The -842GC and -667TT genotypes showed a significantly increased risk of NPC (OR = 1.977, 95% CI = 1.339-2.919, P = 0.001 and OR = 1.438, 95% CI = 1.061-1.922, P = 0.019, respectively). Compared to the most common -842G-667C haplotype, -842G-667T haplotype and -842C-667C haplotype showed a significantly increased risk of NPC (OR = 1.215, 95% CI = 1.053-1.402, P = 0.008 and OR = 2.268, 95% CI = 1.530-3.362, P = 0.001, respectively). Further reporter gene expression suggested that variant -842C-667C and -842G-667T were associated with an enhanced transcriptional activity. In conclusion, our findings suggest that -842G > C and -667C > T in PIN1 promoter are associated with NPC risk; as well as the promoter activity is mediated by functional PIN1 variants.

Epigallocatechin-3-gallate Modulates MicroRNA Expression Profiles in Human Nasopharyngeal Carcinoma CNE2 Cells.

BACKGROUND: Epigallocatechin-3-gallate (EGCG) has exhibited antitumor properties in several types of cancers, including nasopharyngeal carcinoma (NPC), but the molecular mechanisms underlying this function remain incompletely understood. The aim of the present study was to characterize the global impact of EGCG on the expression of microRNAs (miRNAs) in NPC cells. METHODS: Using microarray analysis, the alterations of miRNA expression profiles were investigated in EGCG-treated CNE2 cells. Furthermore, the target genes and signaling pathways regulated by EGCG-specific miRNAs were identified using target prediction program and gene ontology analysis. RESULTS: A total of 14 miRNAs exhibited >2-fold expression changes in a dose-dependent manner after treatment with 20 µmol/L and 40 µmol/L EGCG. Totally 43, 49, and 52 target genes from these differentially expressed miRNAs were associated with the apoptosis, cell cycle regulation, and cell proliferation, respectively. A total of 66 signaling pathways, primarily involved in cancer development and lipid and glucose metabolism, were shown to be regulated by EGCG-specific miRNAs. CONCLUSION: EGCG induces considerable alterations of miRNA expression profiles in CNE2 cells, which provides mechanistic insights into cellular responses and antitumor activity mediated by EGCG.