Dexrazoxane inhibits the growth of esophageal squamous cell carcinoma by attenuating SDCBP/MDA-9/syntenin-mediated EGFR-PI3K-Akt pathway activation.

Syndecan-binding protein (SDCBP) was reported to stimulate the advancement of esophageal squamous cell carcinoma (ESCC) and could potentially be a target for ESCC treatment. There is a growing corpus of research on the anti-tumor effects of iron chelators; however, very few studies have addressed the involvement of dexrazoxane in cancer. In this study, structure-based virtual screening was employed to select drugs targeting SDCBP from the Food and Drug Administration (FDA)-approved drug databases. The sepharose 4B beads pull-down assay revealed that dexrazoxane targeted SDCBP by interacting with its PDZ1 domain. Additionally, dexrazoxane inhibited ESCC cell proliferation and anchorage-independent colony formation via SDCBP. ESCC cell apoptosis and G2 phase arrest were induced as measured by the flow cytometry assay. Subsequent research revealed that dexrazoxane attenuated the binding ability between SDCBP and EGFR in an immunoprecipitation assay. Furthermore, dexrazoxane impaired EGFR membrane localization and inactivated the EGFR/PI3K/Akt pathway. In vivo, xenograft mouse experiments indicated that dexrazoxane suppressed ESCC tumor growth. These data indicate that dexrazoxane might be established as a potential anti-cancer agent in ESCC by targeting SDCBP.

Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target.

Transducin beta-like 1X-related protein 1 (TBL1XR1) was discovered two decades ago and was implicated as part of the nuclear transcription corepressor complex. Over the past 20 years, the emerging oncogenic function of TBL1XR1 in cancer development has been discovered. Recent studies have highlighted that the genetic aberrations of TBL1XR1 in cancers, especially in hematologic tumors, are closely associated with tumorigenesis. In solid tumors, TBL1XR1 is proposed to be a promising prognostic biomarker due to the correlation between abnormal expression and clinicopathological parameters. Post-transcriptional and post-translational modification are responsible for the expression and function of TBL1XR1 in cancer. TBL1XR1 exerts its functional role in various processes that involves cell cycle and apoptosis, cell proliferation, resistance to chemotherapy and radiotherapy, cell migration and invasion, stemness and angiogenesis. Multitude of cancer-related signaling cascades like Wnt-ß-catenin, PI3K/AKT, ERK, VEGF, NF-κB, STAT3 and gonadal hormone signaling pathways are tightly modulated by TBL1XR1. This review provided a comprehensive overview of TBL1XR1 in tumorigenesis, shedding new light on TBL1XR1 as a promising diagnostic biomarker and druggable target in cancer.

FSTL1: A double-edged sword in cancer development.

Flolistatin-related protein 1 (FSTL1), a secreted glycoprotein that is involved in many physiological functions, has attracted much interest and has been implicated in a wide range of diseases, including heart diseases and inflammatory diseases. In recent years, the involvement of FSTL1 in cancer progression has been implicated and researched. FSTL1 plays a contradictory role in cancer, depending on the cancer type as well as the contents of the tumor microenvironment. As reviewed here, the structure and distribution of FSTL1 are first introduced. Subsequently, the expression and clinical significance of FSTL1 in various types of cancer as a tumor enhancer or inhibitor are addressed. Furthermore, we discuss the functional role of FSTL1 in various processes that involve tumor cell proliferation, metastasis, immune responses, stemness, cell apoptosis, and resistance to chemotherapy. FSTL1 expression is tightly controlled in cancer, and a multitude of cancer-related signaling cascades like TGF-ß/BMP/Smad signaling, AKT, NF-κB, and Wnt-ß-catenin signaling pathways are modulated by FSTL1. Finally, FSTL1 as a therapeutic target using monoclonal antibodies is stated. Herein, we review recent findings showing the double-edged characteristics and mechanisms of FSTL1 in cancer and elaborate on the current understanding of therapeutic approaches targeting FSTL1.

DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90ß.

The molecular and pathogenic mechanisms of esophageal squamous cell carcinoma (ESCC) development are still unclear, which hinders the development of effective treatments. In this study, we report that DUSP4 is highly expressed in human ESCC and is negatively correlated with patient prognosis. Knockdown of DUSP4 suppresses cell proliferation and patient-derived xenograft (PDX)-derived organoid (PDXO) growth and inhibits cell-derived xenograft (CDX) development. Mechanistically, DUSP4 directly binds to heat shock protein isoform ß (HSP90ß) and promotes the ATPase activity of HSP90ß by dephosphorylating HSP90ß on T214 and Y216. These dephosphorylation sites are critical for the stability of JAK1/2-STAT3 signaling and p-STAT3 (Y705) nucleus translocation. In vivo, Dusp4 knockout in mice significantly inhibits 4-nitrochinoline-oxide-induced esophageal tumorigenesis. Moreover, DUSP4 lentivirus or treatment with HSP90ß inhibitor (NVP-BEP800) significantly impedes PDX tumor growth and inactivates the JAK1/2-STAT3 signaling pathway. These data provide insight into the role of the DUSP4-HSP90ß-JAK1/2-STAT3 axis in ESCC progression and describe a strategy for ESCC treatment.

miR-132-3p promotes heat stimulation-induced esophageal squamous cell carcinoma tumorigenesis by targeting KCNK2.

Epidemiological evidence supports that consumption of high-temperature food and beverages is an important risk factor for esophageal squamous cell carcinoma (ESCC); however, the underlying mechanism still remains unclear. Here, we established a series of animal models and found that drinking 65°C water can promote esophageal tumor progression from preneoplastic lesions to ESCC. RNA sequencing data showed that miR-132-3p was highly expressed in the heat stimulation group compared with controls. Further study verified that miR-132-3p were upregulated in human premalignant lesion tissues of the esophagus, ESCC tissues, and cells. Overexpression of miR-132-3p could promote ESCC cell proliferation and colony formation, whereas knockdown of miR-132-3p could inhibit ESCC progression in vitro and in vivo. Importantly, dual-luciferase reporter assays showed that miR-132-3p could bind with the 3'-untranslated region of KCNK2 and inhibit KCNK2 gene expression. Knockdown or overexpression of KCNK2 could promote or suppress ESCC progression in vitro. These data suggest that heat stimulation can promote ESCC progression and miR-132-3p mediated this process by directly targeting KCNK2.

Bioinformatics and experimental validation of an AURKA/TPX2 axis as a potential target in esophageal squamous cell carcinoma.

Aurora kinase A (AURKA), a serine/threonine kinase that regulates mitotic processes, has garnered significant interest given its association with the development of several types of cancer. In the present study, it was shown that AURKA expression was significantly upregulated in esophageal squamous cell carcinoma (ESCC) and could serve as a diagnostic and prognostic indicator based on data obtained from The Cancer Genome Atlas (TCGA) and immunohistochemical analysis. In addition, AURKA was functionally associated with ESCC cell proliferation and colony formation in vitro and knockdown of AURKA inhibited ESCC tumor growth in vivo. Both bioinformatics analysis and pull­down assays demonstrated that TPX2 interacted with AURKA, and their expression was correlated. AURKA cooperated with TPX2 to regulate ESCC progression via the PI3K/Akt pathway. Furthermore, AURKA or TPX2 expression levels were negatively associated with the infiltration of cytotoxic cells, CD8+ T cells and mast cells, but positively associated with Th2 cells. The present study provided a relatively comprehensive understanding of the oncogenic roles of AURKA in ESCC based on data obtained from TCGA combined with experimental analysis.

Construction of the Interaction Network of Hub Genes in the Progression of Barrett's Esophagus to Esophageal Adenocarcinoma.

Introduction: Esophageal adenocarcinoma (EAC) is one of the histologic types of esophageal cancer with a poor prognosis. The majority of EAC originate from Barrett's esophagus (BE). There are few studies focusing on the dynamic progression of BE to EAC. Methods: R software was used to analyze differentially expressed genes (DEGs) based on RNA-seq data of 94 normal esophageal squamous epithelial (NE) tissues, 113 BE tissues and 147 EAC tissues. The overlapping genes of DEGs between BE and EAC were analyzed by Venn diagram tool. The hub genes were selected by Cytoscape software based on the protein-protein interaction network of the overlapping genes using STRING database. The functional analysis of hub genes was performed by R software and the protein expression was identified by immunohistochemistry. Results: In the present study, we found a large degree of genetic similarity between BE and EAC, and further identified seven hub genes (including COL1A1, TGFBI, MMP1, COL4A1, NID2, MMP12, CXCL1) which were all progressively upregulated in the progression of NE-BE-EAC. We have preliminarily uncovered the probable molecular mechanisms of these hub genes in disease development and constructed the ceRNA regulatory network of hub genes. More importantly, we explored the possibility of hub genes as biomarkers in the disease progression of NE-BE-EAC. For example, TGFBI can be used as biomarkers to predict the prognosis of EAC patients. COL1A1, NID2 and COL4A1 can be used as biomarkers to predict the response to immune checkpoint blockade (ICB) therapy. We also constructed a disease progression risk model for NE-BE-EAC based on CXCL1, MMP1 and TGFBI. Finally, the results of drug sensitivity analysis based on hub genes showed that drugs such as PI3K inhibitor TGX221, bleomycin, PKC inhibitor Midostaurin, Bcr-Abl inhibitor Dasatinib, HSP90 inhibitor 17-AAG, and Docetaxel may be potential candidates to inhibit the progression of BE to EAC. Conclusion: This study is based on a large number of clinical samples with high credibility, which is useful for revealing the probable carcinogenic mechanism of BE to EAC and developing new clinical treatment strategies.

Regional differences and threshold effects of labor transfer affecting the technical efficiency of China's agricultural industry: A case study of the apple industry.

Apples, as a typical agricultural product with high added value, play a significant role in increasing farmers' income and promoting regional economic growth. They have become one of the main ways for farmers to develop agricultural and sideline products in China's Loess Plateau and Bohai Rim region. Based on panel data for provinces from 2007 to 2020, this study used stochastic frontier analysis to calculate the technical efficiency of apple production in China's major apple-producing areas and then introduced urbanization rate as the threshold variable. Based on the quantity, quality, and structure of the rural labor force, the threshold model was used to empirically analyze the effect of labor transfer at different stages of urbanization on industrial technical efficiency in the main apple-producing areas. The results showed that labor transfer had an obvious negative effect on apple production. The labor transfer at the national level has had an obvious negative impact on the output of the apple industry, and the impact of labor transfer on the technical efficiency of China's apple industry is significantly different; that is, the impact of labor outflow on the technical efficiency of apple production is different in different regions. In some areas, the technical efficiency of production in the main apple-producing areas can be significantly improved. Finally, the proportion of the labor force showed significant differences in its effect on technical efficiency in different stages of urbanization.

Identification of key genes and pathways related to cancer-associated fibroblasts in chemoresistance of ovarian cancer cells based on GEO and TCGA databases.

BACKGROUND: Studies have revealed the implications of cancer-associated fibroblasts (CAFs) in tumor progression, metastasis, and treatment resistance. Here, in silico analyses were performed to reveal the key genes and pathways by which CAFs affected chemoresistance in ovarian cancer. METHODS: Candidate genes were obtained from the intersected differentially expressed genes in ovarian cancer, ovarian cancer chemoresistance, and ovarian CAF-related microarrays and chemoresistance-related genes from GeneCards databases. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis were employed to identify the pathways engaged in ovarian cancer chemoresistance and ovarian CAF-related pathways. The top genes with high Degree in the protein-protein interaction network were intersected with the top genes enriched in the key pathways, followed by correlation analyses between key genes and chemotherapeutic response. The expression profiles of key genes were obtained from Human Protein Atlas database and TCGA-ovarian cancer data. RESULTS: p53, cell cycle, PI3K-Akt, and MAPK pathways were the key pathways related to the implication of CAFs in ovarian cancer chemoresistance. 276 candidate genes differentially expressed in CAFs were associated with ovarian cancer chemoresistance. MYC, IGF1, HRAS, CCND1, AKT1, RAC1, KDR, FGF2, FAS, and EGFR were enriched in the key chemoresistance-related ways. Furthermore, MYC, EGFR, CCND1 exhibited close association with chemotherapeutic response to platinum and showed a high expression in ovarian cancer tissues and platinum-resistant ovarian cancer cells. CONCLUSION: The study suggests the key genes (MYC, EGFR, and CCND1) and pathways (p53, cell cycle, PI3K-Akt, and MAPK) responsible for the effect of CAFs on ovarian cancer chemoresistance.

PI3K/Akt/mTOR Signaling Pathway: Role in Esophageal Squamous Cell Carcinoma, Regulatory Mechanisms and Opportunities for Targeted Therapy.

Esophageal squamous cell carcinoma (ESCC), is the most common type of esophageal cancer worldwide, mainly occurring in the Asian esophageal cancer belt, including northern China, Iran, and parts of Africa. Phosphatidlinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is one of the most important cellular signaling pathways, which plays a crucial role in the regulation of cell growth, differentiation, migration, metabolism and proliferation. In addition, mutations in some molecules of PI3K/Akt/mTOR pathway are closely associated with survival and prognosis in ESCC patients. A large number of studies have found that there are many molecules in ESCC that can regulate the PI3K/Akt/mTOR pathway. Overexpression of these molecules often causes aberrant activation of PI3K/Akt/mTOR pathway. Currently, several effective PI3K/Akt/mTOR pathway inhibitors have been developed, which can play anticancer roles either alone or in combination with other inhibitors. This review mainly introduces the general situation of ESCC, the composition and function of PI3K/Akt/mTOR pathway, and regulatory factors that interact with PI3K/Akt/mTOR signaling pathway. Meanwhile, mutations and inhibitors of PI3K/Akt/mTOR pathway in ESCC are also elucidated.

Bioinspiration of the vein structure of dragonfly wings on its flight characteristics.

Dragonflies have excellent flight characteristics, which are inextricably related to the characteristics of their wings. Their wings not only support a variety of loads during flight but also maintain high-efficiency flight characteristics. In this study, the forewing of a dragonfly (Pantala flavescens (Fabricius)) was used as a research object to explore the microstructure of the surface, cross section, and the vein distribution. Three-dimensional models of three different structures of the forewing vein, including an oval-shaped hollow tube, a circular hollow tube, and a circular solid tube, were established. Fluid dynamics analysis of these three forewing models under different angles of attack during gliding was carried out by FLUENT software, and subsequently, the influence of the dragonfly forewing vein structure on its flight characteristics was analyzed. The numerical simulation results indicated that the vein structure has a considerable influence on the lift, drag, and lift-drag ratio of the P. flavescens forewing. It was indicated that among the tested models, the forewing model with oval-shaped hollow tubular veins has better flight efficiency and aerodynamic characteristics. The results of this study may provide the basis for a novel bionic concept of flapping wing microaircraft design.

CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating ß-catenin/ MEK-ERK signaling pathway.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for CRC patients. Here, we found that CDK15 was highly expressed in human CRC and negatively correlated with patient prognosis and overall survival in tissue microarray. Knockdown of CDK15 suppressed cell proliferation and anchorage-independent growth of CRC cells and inhibited tumor growth in cell line-derived xenograft (CDX) model. Importantly, knockout of CDK15 in mice retarded AOM/DSS-induced tumorigenesis and CDK15 silencing by lentivirus significantly suppressed tumor progression in patient-derived xenograft (PDX) model. Mechanistically, CDK15 could bind PAK4 and phosphorylate PAK4 at S291 site. Phosphorylation of PAK4 at the S291 residue promoted cell proliferation and anchorage-independent growth through ß-catenin/c-Myc, MEK/ERK signaling pathway in CRC. Moreover, inhibition of PAK4 reversed the tumorigenic function of CDK15 in CRC cells and pharmacological targeting PAK4 suppressed tumor growth in PDX models. Thus, our data reveal the pivotal role of CDK15 in CRC progression and demonstrate CDK15 promotes CRC tumorigenesis by phosphorylating PAK4. Hence, the CDK15-PAK4 axis may serve as a novel therapeutic target for CRC.

BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression.

The low survival rate of esophageal squamous cell carcinoma patients is primarily attributed to technical limitations and a lack of insight regarding the molecular mechanisms contributing to its progression. Alterations in epigenetic modulators are critical to cancer development and prognosis. BRD4, a chromatin reader protein, plays an essential role in regulating oncogene expression. Here, we investigated the contributing role of BRD4 and its related mechanisms in the context of ESCC tumor progression. Our observations showed that BRD4 transcript and protein expression levels are significantly increased in ESCC patient tissues. Genetic or pharmacological inhibition of BRD4 suppressed ESCC cell proliferation in vitro and in vivo. Proteomic and transcriptomic analyses were subsequently used to deduce the potential targets of BRD4. Mechanistic studies showed that RCC2 is a downstream target of BRD4. Inhibition of either BRD4 or RCC2 resulted in decreased ESCC cell proliferation. The BRD4-TP73 interaction facilitated the binding of BRD4 complex to the promoter region of RCC2, and subsequently modulated RCC2 transcription. Furthermore, targeting BRD4 with inhibitors significantly decreased tumor volume in ESCC PDX models, indicating that BRD4 expression may contribute to tumor progression. Collectively, these findings suggest that BRD4 inhibition could be a promising strategy to treat ESCC by downregulating RCC2.

Gastric tumorigenesis induced by combining Helicobacter pylori infection and chronic alcohol through IL-10 inhibition.

Helicobacter pylori infection and alcohol intake are independent risk factors in gastric carcinogenesis; however, until now, the combined effect of H. pylori infection and alcohol consumption and the specific mechanism is still problematic. Here, we developed a series of mouse models that progress from chronic gastritis to gastric cancer, induced by infecting H. pylori combined with chronic alcohol consumption and then determining the molecular mechanism of the progression by flow cytometry, western blotting, qPCR, Mito Traker assay in the gastric cancer and T-cell lines. Interleukin-10 (IL-10) knockout mice was used to determine whether IL-10 deficiency directly contributes to H. pylori and alcohol induced gastric tumorigenesis. Alcohol consumption, together with H. pylori infection, causes gastric cancer; IL-10 downregulation and mitochondrial metabolic dysfunction in CD8+ cells are also involved. IL-10 knockout accelerates tumor development in mice with either H. pylori infection or alcohol induced gastric cancer or both. IL-10 inhibits glucose uptake and glycolysis and promotes oxidative phosphorylation with lactate inhibition. Consequently, in the absence of IL-10 signaling, CD8+ cells accumulate damaged mitochondria in a mouse model of gastric cancer induced with the combination of alcohol plus H. pylori infection, and this results in mitochondrial dysfunction and production of IL-1ß. IL-1ß promotes H. pylori infection and reduces NKX6.3 gene expression, resulting in increased cancer cell survival and proliferation. Gastric cancer can be induced by the combination of H. pylori infection and chronic alcohol consumption through IL-10 inhibition induced CD8+ cells dysfunction and NKX6.3 suppression.

miR-17-3p promotes the proliferation of multiple myeloma cells by downregulating P21 expression through LMLN inhibition.

Multiple myeloma (MM), a hematological malignancy, has a poor prognosis and requires an invasive procedure. Reports have implicated miRNAs in the diagnosis, treatment and prognosis of hematological malignancies. In our study, we evaluated the expression profiles of miR-17-3p in plasma and bone marrow mononuclear cells of monoclonal gammopathy of undetermined significance (MGUS) and MM patients and healthy subjects. The results showed that the plasma and mononuclear cell expression levels of miR-17-3p in MM patients were higher than those in MGUS patients and normal controls. In addition, the expression of miR-17-3p was positively correlated with diagnostic indexes, such as marrow plasma cell abundance and serum M protein level, and positively correlated with the International Staging System stage of the disease. Receiver operating characteristic curve analysis suggested that miR-17-3p might be a diagnostic index of MM. Moreover, miR-17-3p regulated cell proliferation, apoptosis and the cell cycle through P21 in MM cell lines and promoted MM tumor growth in vivo. Furthermore, we predicted and verified LMLN as a functional downstream target gene of miR-17-3p. Negatively regulated by miR-17-3p, LMLN inhibits MM cell growth, exerting a tumor suppressive function through P21. Taken together, our data identify miR-17-3p as a promising diagnostic biomarker for MM in the clinic and unveil a new miR-17-3p-LMLN-P21 axis in MM progression.

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy.

Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

SDCBP/MDA-9/syntenin phosphorylation by AURKA promotes esophageal squamous cell carcinoma progression through the EGFR-PI3K-Akt signaling pathway.

SDCBP is an adapter protein containing two tandem PDZ domains mediating cell adhesion. The role and underlying molecular mechanism of SDCBP in ESCC remain obscure. Here, we report that SDCBP is frequently overexpressed in ESCC tissues and cells compared to normal controls and that its overexpression is correlated with late clinical stage and predicts poor prognosis in ESCC patients. Functionally, high expression of SDCBP is positively related to ESCC progression both in vitro and in vivo. Furthermore, mechanistic studies show that SDCBP activates the EGFR-PI3K-Akt signaling pathway by binding to EGFR and preventing EGFR internalization. Moreover, we provide evidence that AURKA binds to SDCBP and phosphorylates it at the Ser131 and Thr200 sites to inhibit ubiquitination-mediated SDCBP degradation. More importantly, the sites at which AURKA phosphorylates SDCBP are crucial for the EGFR signaling-mediated oncogenic function of SDCBP. Taken together, we propose that SDCBP phosphorylation by AURKA prevents SDCBP degradation and promotes ESCC tumor growth through the EGFR-PI3K-Akt signaling pathway. Our findings unveil a new AURKA-SDCBP-EGFR axis that is involved in ESCC progression and provide a promising therapeutic target for ESCC treatment in the clinic.

Preventive effect of oral nicorandil on contrast-induced nephropathy in patients with renal insufficiency undergoing elective cardiac catheterization.

This study aims to investigate the preventive effect of oral nicorandil on contrast-induced nephropathy (CIN) in patients with renal insufficiency undergoing elective cardiac catheterization. A total of 240 patients with an estimated glomerular filtration rate (eGFR) of 60 mL/min or less, who were undergoing elective cardiac catheterization, were randomly assigned to nicorandil group (n = 120, 10 mg nicorandil, three times daily from 2 days before to 3 days after procedure) or control group (n = 120, matching placebo as the same method). The primary endpoint was the incidence of CIN defined as 25 % increase in serum creatinine (SCr) from baseline or 44 µmol/L (0.5 mg/dL) increase in absolute value within 72 h after exposure to contrast medium. The secondary endpoints were: (1) the changes of SCr, Cystatin-C (Cys-C) and eGFR within 72 h; (2) major adverse events (MACE) occurring within 30 days. Baseline characteristics of the patients in the two groups were similar. The incidence of CIN was significantly lower in nicorandil group compared with control group (6.67 vs. 17.5 %, P = 0.017). Compared with the control group, nicorandil group tended to have a lower SCr and Cys-C levels as well as a higher eGFR at 48 h after the procedure (all P < 0.05). There was no difference about the incidence of MACE within 30 days between nicorandil group and control group (4.16 vs. 5.83 %, P = 0.767). Multivariate logistic analysis showed that nicorandil was an independent protective factor against CIN (OR = 0.260, 95 % CI = 0.1-0.676, P = 0.006). Therefore, we concluded that oral nicorandil was associated with a decline in the incidence of CIN in patients with renal insufficiency undergoing elective cardiac catheterization.

Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients.

CD4(+)FoxP3(+) regulatory T cells (Tregs) represent a major cellular mediator of cancer immune evasion. The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs is reported to identify the maximally suppressive Treg population in both mice and human. We therefore investigated the phenotype and function of TNFR2(+) Tregs present in the peripheral blood (PB) of 43 lung cancer patients. Further, the association of TNFR2 expression on Tregs with clinicopathological factors was analyzed. The results showed that in the PB of lung cancer patients, Tregs expressed markedly higher levels of TNFR2 than conventional T cells (Tconvs). Expression of TNFR2 appeared to correlate better than CD25(+) and CD127(-) with FoxP3 expression. PB TNFR2(+) Tregs in lung cancer patients were more proliferative and expressed higher levels of the immunosuppressive molecule CTLA-4, and consequently more potently suppressed IFNγ production by cocultured CD8 CTLs. More importantly, higher TNFR2 expression levels on Tregs were associated with lymphatic invasion, distant metastasis and more advanced clinical stage of lung cancer patients. Therefore, our study suggests that TNFR2(+) Tregs play a role in promoting tumor progressive metastasis and expression of TNFR2 by PB Tregs may prove to be a useful prognostic marker in lung cancer patients.

Matrix metalloproteinase 13: a potential intermediate between low expression of microRNA-125b and increasing metastatic potential of non-small cell lung cancer.

Recent findings have suggested that microRNAs may be involved in the regulation of metastasis in malignant cancers such as non-small cell lung cancer (NSCLC). This study aimed to determine the relationship between expression of miR-125b and matrix metalloproteinase 13 (encoded by MMP-13) and the metastatic potential of cancer cells in NSCLC. Expression levels of miR-125b transcripts and MMP-13 proteins were analyzed by quantitative real-time PCR and immunohistochemistry, respectively, in tumor tissues and adjacent nontumor tissues from 42 patients with NSCLC. The interaction between miR-125b and MMP-13 expression and the associations between miR-125b and clinicopathologic data were analyzed. MiR-125 b expression levels were decreased in NSCLC tumor tissue samples, which correlated with an increased incidence of lymph node metastases, increased pathologic stage, increased MMP-13 expression levels, and decreased early progression-free survival. Additionally, we have demonstrated that increased levels of miR-125b can directly downregulate MMP-13 protein expression and inhibit the invasive capabilities of cancer cells. Expression levels of miR-125b were negatively correlated with metastatic potential of NSCLC tumors, which may function through regulation of MMP-13.