Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer.

Phospholipase C epsilon 1 (PLCE1) is a well-established susceptibility gene for esophageal squamous cell carcinoma (ESCC). Identification of the underlying mechanism(s) regulated by PLCE1 could lead to a better understanding of ESCC tumorigenesis. In this study, we found that PLCE1 enhances tumor progression by regulating the replicative helicase MCM7 via two pathways. PLCE1 activated PKCα-mediated phosphorylation of E2F1, which led to the transcriptional activation of MCM7 and miR-106b-5p. The increased expression of miR-106b-5p, located in intron 13 of MCM7, suppressed autophagy and apoptosis by targeting Beclin-1 and RBL2, respectively. Moreover, MCM7 cooperated with the miR-106b-25 cluster to promote PLCE1-dependent cell-cycle progression both in vivo and in vitro. In addition, PLCE1 potentiated the phosphorylation of MCM7 at six threonine residues by the atypical kinase RIOK2, which promoted MCM complex assembly, chromatin loading, and cell-cycle progression. Inhibition of PLCE1 or RIOK2 hampered MCM7-mediated DNA replication, resulting in G1-S arrest. Furthermore, MCM7 overexpression in ESCC correlated with poor patient survival. Overall, these findings provide insights into the role of PLCE1 as an oncogenic regulator, a promising prognostic biomarker, and a potential therapeutic target in ESCC. SIGNIFICANCE: PLCE1 promotes tumor progression in ESCC by activating PKCα-mediated phosphorylation of E2F1 to upregulate MCM7 and miR-106b-5p expression and by potentiating MCM7 phosphorylation by RIOK2.

Adult's Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: A case report.

Adult's Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis is a rare and life-threatening condition characterized by atypical initial symptoms and rapid disease progression. To facilitate early diagnosis and prompt treatment, it is imperative to implement early multidisciplinary intervention and prioritize pathogen detection, as these measures significantly contribute to enhancing patient prognosis.

Primary lipoblastic nerve sheath tumor in an inguinal lymph node mimicking metastatic tumor: a case report and literature review.

Lipoblastic nerve sheath tumors of soft tissue are characterized as schwannoma tumors that exhibit adipose tissue and lipoblast-like cells with signet-ring morphology. They have been documented to arise in various anatomic locations, including the thigh, groin, shoulder, and retroperitoneum. However, to our knowledge, this tumor has not been previously reported as a lymph node primary. We present herein the first case of a benign primary lipoblastic nerve sheath tumor arising in an inguinal lymph node in a 69-year-old man. Microscopic examination revealed a multinodular tumor comprising fascicles of spindle cells, as well as adipocytic and lipoblast-like signet-ring cell component in the context of schwannoma. Despite the presence of some bizarre cells with nuclear atypia, no obvious mitotic activity or necrosis was observed. Immunohistochemical analysis showed strong and diffuse expression of S-100, SOX10, CD56, and NSE in the spindle cells as well as in the signet-ring lipoblast-like cells and the mature adipocytes. Sequencing analysis of the neoplasm identified six non-synonymous single nucleotide variant genes, specifically NF1, BRAF, ECE1, AMPD3, CRYAB, and NPHS1, as well as four nonsense mutation genes including MRE11A, CEP290, OTOA, and ALOXE3. The patient remained alive and well with no evidence of recurrence over a period of ten-year follow-up.

SLC43A2 and NFκB signaling pathway regulate methionine/cystine restriction-induced ferroptosis in esophageal squamous cell carcinoma via a feedback loop.

Studies have indicated dietary restriction of methionine/cystine provided a therapeutic benefit in diseases such as cancer. However, the molecular and cellular mechanisms that underlie the interaction between methionine/cystine restriction (MCR) and effects on esophageal squamous cell carcinoma (ESCC) have remained elusive. Here, we discovered the dietary restriction of methionine/cystine has a large effect on cellular methionine metabolism as assayed in a ECA109 derived xenograft model. RNA-seq and enrichment analysis suggested the blocked tumor progression was affected by ferroptosis, together with the NFκB signaling pathway activation in ESCC. Consistently, GSH content and GPX4 expression were downregulated by MCR both in vivo and in vitro. The contents of Fe2+ and MDA were negatively correlated with supplementary methionine in a dose-dependent way. Mechanistically, MCR and silent of SLC43A2, a methionine transporter, diminished phosphorylation of IKKα/ß and p65. Blocked NFκB signaling pathway further decreased the expression of SLC43A2 and GPX4 in both mRNA and protein level, which in turn downregulated the methionine intake and stimulated ferroptosis, respectively. ESCC progression was inhibited by enhanced ferroptosis and apoptosis and impaired cell proliferation. In this study, we proposed a novel feedback regulation mechanism underlie the correlation between dietary restriction of methionine/cystine and ESCC progression. MCR blocked cancer progression via stimulating ferroptosis through the positive feedback loop between SLC43A2 and NFκB signaling pathways. Our results provided the theoretical basis and new targets for ferroptosis-based clinical antitumor treatments for ESCC patients.

Vitamin D receptor prevents tumour development by regulating the Wnt/ß-catenin signalling pathway in human colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a common disease threatening human lives worldwide, and vitamin D receptor (VDR) contributes protective roles in this disease. However, the molecular mechanisms underlying VDR protection in CRC progression require further investigation. METHODS: In this study, we statistically analyzed the relationship between VDR expression and CRC development in patients and detected invasion and apoptosis in CRC cells with VDR overexpression and interference. We also detected the expression of key genes involved in Wnt/ß-catenin signalling (ß-catenin, lymphoid enhancer factor (LEF)-1 and cyclin D1) in SW480 cells and nude mice injected with VDR-overexpressing SW480 cells and observed tumour development. Additionally, we performed Co-immunoprecipitation (Co-IP) and glutathione-S-transferase (GST) pull-down assays to identify the protein interactions of VDR with ß-catenin, dual luciferase (LUC) and chromatin immunoprecipitation (ChIP) to detect the activation of LEF-1 by VDR. RESULTS: The VDR level was closely related to the development and prognosis of CRC patients. VDR overexpression inhibited invasion but promoted apoptosis in cancer cells. ß-catenin shRNA contributed oppositely to cancer cell activity with VDR shRNA. Additionally, VDR interacted with ß-catenin at the protein level and blocked its nuclear accumulation. VDR regulated the expression of ß-catenin, cyclin D1 and LEF-1 and directly activated LEF-1 transcription in vitro. Furthermore, nude mice injected with VDR-overexpressing SW480 cells revealed suppression of tumour growth and decreased expression of ß-catenin, cyclin D1 and LEF-1. CONCLUSIONS: This study indicated that VDR protected against CRC disease in humans by inhibiting Wnt/ß-catenin signalling to control cancer cell invasion and apoptosis, providing new evidence to explore VDR biomarkers or agonists for CRC patient diagnosis and treatment.

Decreased vitamin D receptor protein expression is associated with progression and poor prognosis of colorectal cancer patients.

This study aimed to investigate vitamin D receptor (VDR) expression levels and evaluate their clinical significance in patients with colorectal cancer (CRC). VDR protein expression was validated by immunohistochemistry in 188 CRC tissues and 134 normal colorectal tissues. The associations between VDR expression and clinicopathologic characteristics, including prognostic outcomes, were analyzed. VDR expression in normal colorectal tissue was higher than that in CRC (83.6% versus 34.6%, P = 4.489 × 10-20) and generated moderate diagnostic performance for CRC detection (AUC = 0.88, sensitivity = 0.87, specificity = 0.84). Low VDR expression was associated with invasion depth (P = 0.001) and poor survival in CRC (P = 0.031). Univariate Cox analysis demonstrated VDR expression (P = 0.036) was a significant prognostic predictor for survival in patients with CRC. Low VDR expression could be a valuable diagnostic and prognostic biomarker for CRC patients. Targeting VDR may offer a potential therapeutic strategy for blocking CRC.

Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy.

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignant diseases. Multiple studies with large clinic-based cohorts have revealed that variations of phospholipase C epsilon 1 (PLCE1) correlate with esophageal cancer susceptibility. However, the causative role of PLCE1 in ESCC has remained elusive. Here, we observed that hypomethylation-mediated upregulation of PLCE1 expression was implicated in esophageal carcinogenesis and poor prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and promoted p53 ubiquitination, whereas it increased the half-life of mouse double minute 2 homolog (MDM2) and inhibited its ubiquitination, leading to MDM2 stabilization. Mechanistically, the function of PLCE1 correlated with its direct binding to both p53 and MDM2, which promoted MDM2-dependent ubiquitination of p53 and subsequent degradation in vitro. Consequently, knockdown of PLCE1 combined with transfection of a recombinant adenoviral vector encoding wild-type p53 resulted in significantly increased levels of autophagy and apoptosis of esophageal cancer in vivo. Clinically, the upregulation of PLCE1 and mutant p53 protein predicted poor overall survival of patients with ESCC, and PLCE1 was positively correlated with p53 in ESCC cohorts. Collectively, this work identified an essential role for PLCE1- and MDM2-mediated ubiquitination and degradation of p53 in inhibiting ESCC autophagy and indicates that targeting the PLCE1-MDM2-p53 axis may provide a novel therapeutic approach for ESCC. SIGNIFICANCE: These findings identify hypomethylation-mediated activation of PLCE1 as a potential oncogene that blocks cellular autophagy of esophageal carcinoma by facilitating the MDM2-dependent ubiquitination of p53 and subsequent degradation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2175/F1.large.jpg.

Loss of c-Cbl expression correlates with de-differentiation status and lymphatic metastasis in gastric cancer.

CONTEXT: C-Cbl is an important negative regulator of the cell signaling that acts as an adaptor protein and E3 ubiquitin ligase. The role of c-Cbl in development and regulation of human cancer has aroused intensive attention. AIMS: In this study, we aimed to assess the correlation between the expression of c-Cbl and clinicopathological parameters and explored the role of c-Cbl in the development and progression of GC. SETTINGS AND DESIGN: This is a Pilot study. METHODS AND MATERIALS: In total, 84 tissue samples including 44 gastric cancers (GC) and 40 matched adjacent normal tissues were collected after surgery. Then tissue microarray (TMA) and immunohistochemistry (IHC) technology were combined to detect the protein expression of c-Cbl. STATISTICAL ANALYSIS USED: Statistical analysis was performed using SPSS 22.0 (IBM Corporation, Armonk, NY, USA). RESULTS: We have studied the correlation between c-Cbl expression and clinicopathological parameters. Our study showed that c-Cbl has a low expression in 61.4% (27/44) of GC tissues, and the incidence of cases was significantly higher than that in adjacent normal tissues (P < 0.0001). In addition, the correlation between c-Cbl expression and gastric carcinoma subtype (P = 0.027), histological type (P = 0.033), Borrmann classification (P = 0.009), histological differentiation (P = 0.0005), lymph node metastasis (P = 0.007), and intravascular tumor thrombus (P = 0.036) has also been revealed. CONCLUSIONS: Our results show that c-Cbl is down-regulated in GC tissues compared with normal gastric tissue, which may play an important role in the development and progression of GC.

Integrative genomics analysis of hub genes and their relationship with prognosis and signaling pathways in esophageal squamous cell carcinoma.

The main purpose of the present study was to recognize the integrative genomics analysis of hub genes and their relationship with prognosis and signaling pathways in esophageal squamous cell carcinoma (ESCC). The mRNA gene expression profile data of GSE38129 were downloaded from the Gene Expression Omnibus database, which included 30 ESCC and 30 normal tissue samples. The differentially expressed genes (DEGs) between ESCC and normal samples were identified using the GEO2R tool. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify the functions and related pathways of the genes. The protein­protein interaction (PPI) network of these DEGs was constructed with the Search Tool for the Retrieval of Interacting Genes and visualized with a molecular complex detection plug­in via Cytoscape. The top five important modules were selected from the PPI network. A total of 928 DEGs, including ephrin­A1 (EFNA1), collagen type IV α1 (COL4A1),  C­X­C chemokine receptor 2 (CXCR2), adrenoreceptor ß2 (ADRB2), P2RY14, BUB1B, cyclin A2 (CCNA2), checkpoint kinase 1 (CHEK1), TTK, pituitary tumor transforming gene 1 (PTTG1) and COL5A1, including 498 upregulated genes, were mainly enriched in the 'cell cycle', 'DNA replication' and 'mitotic nuclear division', whereas 430 downregulated genes were enriched in 'oxidation­reduction process', 'xenobiotic metabolic process' and 'cell­cell adhesion'. The KEGG analysis revealed that 'ECM­receptor interaction', 'cell cycle' and 'p53 signaling pathway' were the most relevant pathways. According to the degree of connectivity and adjusted P­value, eight core genes were selected, among which those with the highest correlation were CHEK1, BUB1B, PTTG1, COL4A1 and CXCR2. Gene Expression Profiling Interactive Analysis in The Cancer Genome Atlas database for overall survival (OS) was applied among these genes and revealed that EFNA1 and COL4A1 were significantly associated with a short OS in 182 patients. Immunohistochemical results revealed that the expression of PTTG1 in esophageal carcinoma tissues was higher than that in normal tissues. Therefore, these genes may serve as crucial predictors for the prognosis of ESCC.

Cholesterol Induces Epithelial-to-Mesenchymal Transition of Prostate Cancer Cells by Suppressing Degradation of EGFR through APMAP.

Cholesterol increases the risk of aggressive prostate cancer and has emerged as a potential therapeutic target for prostate cancer. The functional roles of cholesterol in prostate cancer metastasis are not fully understood. Here, we found that cholesterol induces the epithelial-to-mesenchymal transition (EMT) through extracellular-regulated protein kinases 1/2 pathway activation, which is mediated by EGFR and adipocyte plasma membrane-associated protein (APMAP) accumulation in cholesterol-induced lipid rafts. Mechanistically, APMAP increases the interaction with EGFR substrate 15-related protein (EPS15R) to inhibit the endocytosis of EGFR by cholesterol, thus promoting cholesterol-induced EMT. Both the mRNA and protein levels of APMAP are upregulated in clinical prostate cancer samples. Together, these findings shed light onto an APMAP/EPS15R/EGFR axis that mediates cholesterol-induced EMT of prostate cancer cells. SIGNIFICANCE: This study delineates the molecular mechanisms by which cholesterol increases prostate cancer progression and demonstrates that the binding of cholesterol-induced APMAP with EPS15R inhibits EGFR internalization and activates ERK1/2 to promote EMT. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/12/3063/F1.large.jpg.

Loss of the Vitamin D Receptor in Human Breast Cancer Cells Promotes Epithelial to Mesenchymal Cell Transition and Skeletal Colonization.

Expression of the vitamin D receptor (VDR) is thought to be associated with neoplastic progression. However, the role of the VDR in breast cancer metastasis to bone and the molecular mechanisms underlying this process are unknown. Employing a rodent model (female Balb/c nu/nu mice) of systemic metastasis, we here demonstrate that knockdown of the VDR strongly increases the metastatic potential of MDA-MB-231 human breast cancer cells to bone, resulting in significantly greater skeletal tumor burden. Ablation of VDR expression promotes cancer cell mobility (migration) and invasiveness, thereby facilitating skeletal colonization. Mechanistically, these changes in tumor cell behavior are attributable to shifts in the expression of proteins involved in cell adhesion, proliferation, and cytoskeletal organization, patterns characteristic for epithelial-to-mesenchymal cell transition (EMT). In keeping with these experimental findings, analyses of human breast cancer specimens corroborated the association between VDR expression, EMT-typical changes in protein expression patterns, and clinical prognosis. Loss of the VDR in human breast cancer cells marks a critical point in oncogenesis by inducing EMT, promoting the dissemination of cancer cells, and facilitating the formation of tumor colonies in bone. © 2019 American Society for Bone and Mineral Research.

Comprehensive bioinformation analysis of methylated and differentially expressed genes in esophageal squamous cell carcinoma.

Differentially methylated genes (DMGs) play a crucial role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). This study aimed to ascertain aberrant DMGs and pathways by comprehensive bioinformatics analysis. We downloaded the gene expression microarray of GSE51287 from the Gene Expression Omnibus (GEO). Aberrant DMGs were obtained using the GEO2R tool. Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were performed on selected genes by using the Database for Annotation Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed with the Retrieval of Interacting Genes (STRING) and visualized in Cytoscape. Then, the modules in the PPI networks were analyzed with Molecular Complex Detection, and the hub genes derived from the PPI networks were verified by using the Cancer Genome Atlas. A total of 271 DMGs, including 173 hypermethylated genes, were enriched in the biological processes of peptidyl-tyrosine phosphorylation, positive regulation of transcription from RNA polymerase II promoters, and autophosphorylation. Pathway analysis enrichment revealed cancer, PI3K-Akt, and Ras signaling pathways, and 98 hypomethylated genes were enriched in the biological processes of the immune response, extracellular matrix disassembly, and macrophage differentiation. Pathway enrichment showed rheumatoid arthritis, cytokine-cytokine receptor interaction, and toxoplasmosis. Furthermore, bioinformatics analysis indicated feasible aberrant DMGs and pathways in ESCC. The results provided valuable information on the pathogenesis of ESCC. The significant DMGs may provide novel insights into their potential predictive and prognostic value as methylation-based biomarkers for the precise diagnosis and treatment of ESCC.

Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-κB signaling pathway and VEGF-C/ Bcl-2 expression.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Neovascularization during tumorigenesis supplies oxygen and nutrients to proliferative tumor cells, and serves as a conduit for migration. Targeting oncogenes involved in angiogenesis is needed to treat organ-confined and locally advanced ESCC. Although the phospholipase C epsilon-1 (PLCE1) gene was originally identified as a susceptibility gene for ESCC, how PLCE1 is involved in ESCC is unclear. METHODS: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to measure the methylation status of the PLCE1 promoter region. To validate the underlying mechanism for PLCE1 in constitutive activation of the NF-κB signaling pathway, we performed studies using in vitro and in vivo assays and samples from 368 formalin-fixed esophageal cancer tissues and 215 normal tissues with IHC using tissue microarrays and the Cancer Genome Atlas dataset. RESULTS: We report that hypomethylation-associated up-regulation of PLCE1 expression was correlated with tumor angiogenesis and poor prognosis in ESCC cohorts. PLCE1 can activate NF-κB through phosphoinositide-phospholipase C-ε (PI-PLCε) signaling pathway. Furthermore, PLCE1 can bind p65 and IκBα proteins, promoting IκBα-S32 and p65-S536 phosphorylation. Consequently, phosphorylated IκBα promotes nuclear translocation of p50/p65 and p65, as a transcription factor, can bind vascular endothelial growth factor-C and bcl-2 promoters, enhancing angiogenesis and inhibiting apoptosis in vitro. Moreover, xenograft tumors in nude mice proved that PLCE1 can induce angiogenesis, inhibit apoptosis, and increase tumor aggressiveness via the NF-κB signaling pathway in vivo. CONCLUSIONS: Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLCε-NF-κB signaling pathway and VEGF-C/Bcl-2 expression, but also suggest that modulation of PLCE1 by epigenetic modification or a selective inhibitor may be a promising therapeutic approach for the treatment of ESCC.

Three-gene immunohistochemical panel predicts progression and unfavorable prognosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly invasive disease with a poor long-term survival rate. Although there has been progress in understanding the pathogenesis of ESCC, there are currently no molecular biomarkers that are used in routine clinical practices to determine prognosis. Therefore, the aim of this study was to determine a small immunohistochemical panel that could predict the prognosis of patients with ESCC. Phospholipase C epsilon-1 (PLCE1), IKKα, IKBα, p65, and p53 were highly expressed in ESCC tissues. The high expression level of PLCE1, IKBα, and p53 showed a significant positive correlation with a short overall survival (P = .022, .009, and .024, respectively). This 3-biomarker panel (ie, PLCE1, IKBα, and p53) was found to be a predictor of ESCC, with a worse overall survival as each positive marker was added (hazard ratio, 1.553; 95% confidence interval, 1.166-2.067; P = .003). In another cohort (including 1922 esophageal endoscopic biopsy tissues), the lesions of 28 patients were aggravated. Three proteins (PLCE1, 12/28 [42.86%]; IKBα, 16/28 [57.14%]; p53, 16/28 [57.14%]) were immunoreactive in patients with progressive disease. Our study identified and validated that this immunohistochemical biomarker panel of 3 proteins, consisting of PLCE1, IKBα, and p53, is not only independently associated with an unfavorable outcome for ESCC patients but also able to predict disease progression to precancerous lesions.

Genome-wide screening for genomic aberrations in Kazakh patients with esophageal squamous cell cancer by comparative genomic hybridization.

Multiple chromosome aberrations are responsible for tumorigenesis of esophagus squamous cell carcinoma (ESCC). To characterize genetic alterations by comparative genomic hybridization (CGH) and their relation to ESCC, We enrolled 54 members with ESCC from Kazakh's patients. We found that the deletions of 3p (P = 0.032), 17p (P = 0.004), 22q (P = 0.000) and gains of 5p (P = 0.000), 11q (P = 0.000) were significantly correlated with the location of tumors. Losses of 1p (P = 0.005), 3p (P = 0.006), 22q (P = 0.024) and gains of 3q (P = 0.043), 8q (P = 0.038), 18q (P = 0.046) were also found more frequently in patients with larger diameter disease. The loss of 19q (P = 0.005) and gains of l3q (P = 0.045), 18p (P = 0.018) were significantly correlated with pathologic grade. The gain of 7p (P = 0.009) and deletion of 19q (P = 0.018) were seen more frequently in patients with Grade III-IV tumors. Chromosome amplifications in ESCC at 1q (P = 0.008), 7p (P = 0.008), 8q (P = 0.018) and deletions at 3p (P = 0.021), 11q (P = 0.002), 17p (P = 0.012) were related to lymph node metastasis; the gains of 1q (P = 0.026) and 6q (P = 0.017) and the loss of 11q (P = 0.001) were significant in different isoforms of HPV infection. We identified some chromosomes in which the genes were related to the tumorgenesis of ESCC, which may be a theme for future investigation.

Comprehensive bioinformation analysis of the miRNA of PLCE1 knockdown in esophageal squamous cell carcinoma.

Phospholipase C epsilon 1 (PLCE1) has been recognized as a novel susceptibility marker for esophageal squamous cell carcinoma (ESCC). The purpose of our study is to investigate its effect on the regulation of miRNA expression so as to translating the data into a novel strategy in control of ESCC. In this study, PLCE1 siRNA and vector-only plasmid were stably transfected into Eca109 and EC9706 cells and then subjected to miRNA array analysis, and quantitative real-time PCR was applied to validate miRNA array data. Then bioinformatic analyses, such as GO and pathway software, were conducted to obtain data on these differentially expressed miRNAs-targeted genes (DEGs) and clarify their function and pathway. The results showed that 36 miRNAs were found to be differentially expressed in PLCE1 siRNA-transfected cells compared with the control cells. In particular, 28 miRNAs were upregulated while 8 miRNAs were downregulated. Gene Ontology analysis showed that the function of the DEGs included cell cycle arrest, cell-matrix adhesion, apoptosis, etc. After this, the major pathways associated with the DEGs were regulation of actin cytoskeleton, TGF-beta signaling pathway, Notch signaling pathway and so on. Taken together, these results showed that the knockdown of PLCE1 may play a vital role in the control of ESCC. Further investigation will reveal and verify the function and pathway of the DEGs for the development of novel treatment strategy for the better control of ESCC.

A Genetic Variant in miR-124 Decreased the Susceptibility to Esophageal Squamous Cell Carcinoma in a Chinese Kazakh Population.

AIMS: Esophageal squamous cell carcinoma (ESCC) is characterized by high prevalence and mortality worldwide, and it is very highly prevalent in China. ESCC is caused by various factors, including microRNAs (miRNAs) whose expression have been shown to play a major role in tumor generation. Single nucleotide polymorphisms (SNPs) in miRNAs could affect susceptibility to numerous cancers. This study aimed to evaluate the relationship between SNPs in miR-124 and ESCC risk in the Chinese Kazakh population. METHODS: A total of 239 Chinese Kazakh patients with ESCC and 227 healthy Chinese Kazakh individuals were recruited in this study. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to analyze the miR-124 rs531564 genotype. RESULTS: Allele G of the miR-124 rs531564 polymorphism significantly reduced the risk of ESCC in the Chinese Kazakh population [odds ratio (OR) = 0.711; 95% confidence interval (CI): 0.508-0.996; p = 0.047]. The dominant model indicated that the CG+GG genotypes were associated with significantly decreased ESCC risk compared to the CC genotype (adjusted OR = 0.586; 95% CI: 0.396-0.867; p = 0.007). Stratification analyses showed that compared with the CC genotype, the CG and CG+GG genotypes manifested reduced ESCC risks in the female group [CG vs. CC: OR = 0.472; 95% CI: 0.255-0.872; p = 0.016; (CG+GG) vs. CC: OR = 0.472; 95% CI: 0.255-0.872; p = 0.016] and the age group of <57 years old [CG vs. CC: OR = 0.456; 95% CI: 0.258-0.806; p = 0.006; (CG+GG) vs. CC: OR = 0.456; 95%CI: 0.258-0.806; p = 0.006]. The miR-124 rs531564 polymorphism showed no significant association with histological stage, lymph node metastasis, depth of invasion, or tumor/node/metastasis stage. CONCLUSIONS: Our findings are the first to be reported that the miR-124 rs531564 polymorphism decreased ESCC risk in the Chinese Kazakh population.

Clinicopathological significance of Bmi-1 overexpression in esophageal cancer: a meta-analysis.

AIM: The clinicopathological effects of Bmi-1 expression in esophageal cancer remain widely disputed. Our aim was to clarify this relationship. METHODS: Available studies were retrieved from diverse databases. Review Manager 5.3 and Stata 12.0 software were used to identify correlations between Bmi-1 expression and the clinicopathological features of esophageal cancer. RESULTS: From 16 studies, 1523 esophageal cancer patients were analyzed. Meta-analysis demonstrated that Bmi-1 overexpression was associated with differentiation (p = 0.03), tumor/node/metastasis stage (p = 0.02), depth of invasion (p = 0.0006) and lymph node metastasis (p = 0.008). CONCLUSION: The expression of Bmi-1 is associated with the progression and invasion of esophageal cancer.

MicroRNA-34a functions as a tumor suppressor by directly targeting oncogenic PLCE1 in Kazakh esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the frequent malignant tumors with poor prognosis worldwide. Identifying the prognostic biomarkers and potential mechanisms of such tumors has attracted increasing interest in esophageal cancer biology. Our previous study showed that phospholipase C elipson 1 (PLCE1) expression is up-regulated and associated with disease progression in esophageal carcinoma. MicroRNAs (miRNAs) play vital roles in regulating its target gene expression. However, studies on miRNA-regulated PLCE1 expression and its cellular function are still very few. We found that miR-34a is significantly expressed lower in ESCC tissues. We further showed that PLCE1 is a direct functional target gene of miR-34a, and the functional roles of miR-34a in ESCC cell lines in vitro were also determined through gain- and loss-of-function analyses. Results revealed that miR-34a functions as a tumor suppressor by inhibiting the proliferation, migration, and EMT phenotype, as well as promoting apoptosis of ESCC cell lines. Moreover, PLCE1 is overexpressed in ESCC tumors and promotes tumorigenicity in vivo and vitro. PLCE1 expression is negatively correlated with miR-34a profiles in ESCC tissues. Our data suggest that miR-34a exerts its anti-cancer function by suppressing PLCE1. The newly identified miR-34a/PLCE1 axis partially illustrates the molecular mechanism of ESCC metastasis and represents a new candidate therapeutic target for ESCC treatment.