Poor Prognosis In Esophageal Squamous Cell Carcinoma Research Articles

Identification and Characterization of Copy Number-Associated Driver Genes in Esophageal Squamous Cell Carcinoma.

Background Esophageal squamous cell carcinoma (ESCC) is a leading malignancy with both high incidence and mortality worldwide. However, the molecular mechanisms of the poor prognosis in ESCC are still unclear. Methods We conducted differential expression analysis between ESCC and normal tissues and between ESCC samples with and without CNAs in a given gene. Overrepresentation enrichment and gene set enrichment analyses were used to identify the oncogenic pathways and abnormal transcription factors (TFs). The survival analysis was employed to identify the genes associated with overall survival. Results In this study, we aimed to identify and interpret the driver genes triggered by the copy number alterations (CNAs), including CCND1, TEAD4, EIF4EBP1, EGFR, FGFR3, and FZD6. Furthermore, we identified oncogenic pathways, including RTK-RAS, WNT, PI3K, Hippo, and cell cycle, and key TFs including TEAD4, a transcription factor in the Hippo signaling pathway, and LEF1 in the WNT signaling pathway. Furthermore, we observed that upregulations of FGFR3 and EIF4EBP1 were significantly associated with shorter overall survival in ESCC. Conclusion In conclusion, the driver genes triggered by CNAs not only exhibited critical functionality but also were clinically relevant in ESCC, which greatly improved our understanding of the molecular mechanisms in ESCC.

Upregulation of cervical carcinoma expressed PCNA regulatory long non-coding RNA promotes esophageal squamous cell carcinoma progression.

Cervical carcinoma expressed PCNA regulatory long non-coding (lnc)RNA (CCEPR) has recently been reported to play oncogenic roles in some common types of human cancer. However, the clinical significance of CCEPR mRNA expression levels in esophageal squamous cell carcinoma (ESCC) and the exact function of CCEPR in regulating the malignant phenotypes of ESCC cells have not been previously investigated. In the present study, CCEPR mRNA expression level was upregulated in ESCC tissues and cell lines, and overexpression of CCEPR was associated with advanced TNM stage, lymph node metastasis, and poor prognosis in ESCC. In vitro experiments showed that silencing CCEPR mRNA expression levels significantly suppressed the proliferation, migration, and invasion of ESCC cells, while inducing ESCC cell apoptosis. Furthermore, inhibition of CCEPR decreased the protein expression levels of matrix metalloproteinase (MMP)2 and MMP9 and inhibited epithelial-mesenchymal transition in ESCC cells. In conclusion, the results showed that CCEPR plays an oncogenic role in ESCC and suggests that CCEPR could be used as a potential therapeutic target for ESCC treatment.

SUMOylation of HSP27 regulates PKM2 to promote esophageal squamous cell carcinoma progression

A previous proteomic screening of differentially expressed biomarkers between Kazakh patients with esophageal squamous cell carcinoma (ESCC) and normal adjacent tissues demonstrated that heat shock protein 27 (HSP27) and pyruvate kinase isoenzyme M2 (PKM2) were both highly expressed in ESCC samples compared with normal controls. However, the regulatory association between HSP27 and PKM2 in ESCC remains elusive. In the present study, immunohistochemistry and immunoblotting were adopted to examine the expression of HSP27, PKM2 and other relevant biomarkers involved in epithelial-to-mesenchymal transition in clinical tissue samples. The interactions between proteins were detected by co-immunoprecipitation (Co-IP) assay and further confirmed by immunofluorescence assay. The growth and motility of ESCC cells were examined by MTT, Transwell and wound healing assays. Overexpression of HSP27 was found to be significantly associated with T-cell classification, lymph node metastasis and poor prognosis in ESCC. In addition, HSP27 expression was significantly correlated with PKM2 expression in ESCC specimens. Functionally, knockdown of HSP27 inhibited the growth and motility of ESCC cells. Moreover, HSP27 was found to directly interact with small ubiquitin-related modified protein 2/3 (SUMO2/3) in ESCC cell lines, as evidenced by Co-IP and laser confocal imaging. In addition, downregulation of HSP27 was shown to decrease PKM2 and E-cadherin expression. Knockdown of SUMO2/3 was observed to reduce the expression of HSP27, PKM2 and EMT-related biomarkers. The results of the present study indicated that the SUMOylation of HSP27 enhances the proliferation, invasion and migration of ESCC cells via PKM2.

MicroRNA-429 inhibits the proliferation and migration of esophageal squamous cell carcinoma cells by targeting RAB23 through the NF-κB pathway.

Esophageal squamous cell carcinoma (ESCC) is the main type of esophageal cancer and is a devastating malignancy. Recent research shows that microRNA-429 (miR-429) has a role in suppressing cell proliferation, cell cycle and promoting apoptosis in many cancers. This study aims to explore the great role of miR-429 in esophageal squamous cell carcinoma. The mRNA and protein levels of miR-429 and genes were calculated by using Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) and Western blot. We applied Cell Counting Kit-8 (CCK-8) and transwell assays to measure the proliferative and migratory abilities. Meanwhile, the Kaplan-Meier method was used to calculate the overall survival of esophageal squamous cell carcinoma patients. MiR-429 was downregulated while RAB23 was upregulated in ESCC tissues and cell lines, and downregulation of miR-429 predicted poor prognosis in ESCC. RAB23 was found to be a direct target gene of miR-429 and its expression was regulated by miR-429 in ESCC. Moreover, miR-429 inhibited the proliferation through nuclear factor-kappa B (NF-κB) pathway and inhibited cell migration-mediated epithelial-mesenchymal transition (EMT) in TE-2 cells. In addition, overexpression of miR-429 suppressed tumor growth of ESCC in vivo. MiR-429 inhibited the proliferation through the RAB23/NF-κB pathway and the migration-mediated EMT in ESCC. The newly identified miR-429/RAB23 axis provides novel insight into the pathogenesis of ESCC.

High expression of IGBP1 correlates with poor prognosis in esophageal squamous cell carcinoma.

Immunoglobulin binding protein 1 (IGBP1) is an important signal transduction regulator that mediates various functions. However, its expression profile, role, and clinical significance in cancers are uncertain. The purpose of this study was to determine the expression profile and the prognostic significance of IGBP1 in esophageal squamous cell carcinoma (ESCC). Polymerase chain reaction assay, western blotting, and immunohistochemistry (IHC) assay were performed to examine IGBP1 expression in ESCC tissues and matched adjacent non-cancerous tissues. Moreover, IHC was used to evaluate IGBP1 expression in archived 190 paraffin-embedded ESCC specimens. Statistical analyses were applied to evaluate the prognostic value and the correlations between IGBP1 expression and the clinical parameters. We found that the messenger RNA and protein levels of IGBP1 were up-regulated in the ESCC tissues compared with their adjacent non-cancerous tissues. High expression of IGBP1 in ESCC patients was positively associated with T classification (P=0.013) and vital status (P=0.03). The ESCC patients with higher IGBP1expression had a shorter survival time than those with lower IGBP1 expression. Importantly, multivariate analysis demonstrated that the expression of IGBP1 was an independent prognostic factor for ESCC (P< 0.05). We provide the first evidence that increased IGBP1 expression correlates with poor prognosis of ESCC, and that IGBP1 may be a tumor promoter of ESCC, which provide a promising prognostic biomarker and therapeutic target for ESCC.

Stromal interaction molecule 1 promotes tumor growth in Esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a disease with poor prognosis which urgently is in need of effective prognostic marker. To discover novel prognostic protein marker for ESCC, we applied a high-throughput monoclonal antibody microarray to compare tumor and adjacent non-tumor tissues from ESCC patients. Antibody #ESmAb270 was consistent higher expressed in tumors and it was identified via mass spectrometry to be stromal interaction molecule 1 (STIM1). STIM1 H scores in tumor tissues were significantly up-regulated in esophageal tumor tissues compared to non-tumor tissues in 105 ESCC patients. We also observed that high STIM1 expression was correlated with advanced tumor grade and poor prognosis of ESCC. In addition, attenuation of STIM1 by siRNA or chemical inhibitors significantly inhibited cell viability and migration of ESCC cells. Evidence from high-throughput monoclonal antibody microarray, IHC microarray with associated survival data and functional analysis show that STIM1 is an unfavorable prognostic biomarker in ESCC.

Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer.

Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the clinical importance of LOX expression and its epigenetic regulation in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Using a database of 284 ESCCs, we examined LOX expression and its prognostic characteristics. The functional role of LOX was assessed by in vitro growth, migration, and invasion assays. The relationship between LOX expression, global DNA hypomethylation (ie, LINE‐1 methylation), and LOX promoter methylation was evaluated by using mRNA expression arrays and pyrosequencing technology. High LOX expression cases had a significantly shorter overall survival and cancer‐specific survival (log‐rank, P < .001). The prognostic effect of LOX expression was not significantly modified by other clinical variables. Silencing and enzymatic inhibition of LOX suppressed growth and reduced the invasion and migration ability of ESCC cell lines along with the downregulation of AKT and MMP2. An integrated gene analysis in tissues and cell lines revealed that LOX was the most highly upregulated gene in LINE‐1 hypomethylated tumors. In vitro, LOX expression was upregulated following DNA demethylation. LOX promoter methylation was not associated with LOX expression. Conclusively LOX expression was associated with poor prognosis in ESCC and was regulated epigenetically by genome‐wide hypomethylation. It could serve as a prognostic biomarker in ESCC patients, and therapeutically targeting LOX could reverse the progression of esophageal cancer.

Expression and prognostic significance of long noncoding RNA AK001796 in esophageal squamous cell carcinoma.

Previous study has reported that long noncoding RNA AK001796 (AK001796) functions as a tumor promoter in esophageal squamous cell carcinoma (ESCC). However, its clinical in ESCC patients remains largely unclear. The purpose of the present study was to evaluate the prognostic value of AK001796 in ESCC patients. The expression levels of AK001796 in ESCC tissues and matched normal tissues were detected by RT-PCR. Association between AK001796 levels and clinicopathological factors was also analyzed by chi-square test. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and log-rank test. The predictors for OS and DFS were assessed by univariate analysis and multivariate analysis using Cox's proportional hazards model. We found that AK001796 was elevated in human ESCC samples compared with the adjacent normal tissues (p<0.01), and the high level of AK001796 expression was significantly correlated with lymph node metastasis (p=0.032) and advanced UICC stage (p=0.016). Interestingly, Kaplan-Meier analysis indicated that patients with high AK001796 expression had a significantly lower OS (p=0.010) and DFS (p=0.001). Moreover, we showed that AK001796 was an independent poor prognostic factor for OS and DFS in ESCC patients through univariate and multivariate analysis. Our data provide important evidence that AK001796 may be a useful biomarker of advanced progression and poor prognosis of ESCC.

Contribution of dysregulated circRNA_100876 to proliferation and metastasis of esophageal squamous cell carcinoma.

PurposeAccumulating evidence demonstrates that circRNAs regulate diverse cellular processes and cancer progression. However, it remains unclear whether circRNAs play any functional role in esophageal squamous cell carcinoma (ESCC).Materials and methodsThe significance of circRNA_100876 in ESCC was analyzed by studying circRNA_100876 expression in ESCC tissues and the association between circRNA_100876 expression and clinicopathologic parameters. The biological effects of circRNA_100876 knockdown by lentivirus-mediated siRNAs on cell proliferation, cell cycle, apoptosis, and migration were investigated in vitro and in vivo.ResultsCircRNA_100876 expression was upregulated (P<0.05) and was negatively correlated with survival outcome (P<0.05) in ESCC. Inhibition of proliferation, migration, invasion, and epithelial–mesenchymal transition progression was confirmed after circRNA_100876 depletion.ConclusionDysregulation of circRNA_100876 expression leads to poor prognosis in ESCC by accelerating cell proliferation and metastasis.

Long noncoding RNA LINC01296 is associated with poor prognosis in ESCC and promotes ESCC cell proliferation, migration and invasion.

Recent studies have reported that long intergenic non-protein-coding RNA 1296 (LINC01296) regulates the tumorigenesis and the progression of several tumors, but the role of LINC01296 in esophageal squamous cell carcinoma (ESCC) remains unclear. The purpose of this study was to examine the expression, function, and clinical significance of LINC01296 in ESCC. Expression of LINC01296 was analyzed in 221 ESCC tissues and three ESCC cell lines by Real-time quantitative RT-PCR. The correlation between LINC01296 levels and other clinical features, disease-free survival (DFS), and overall survival (OS) was analyzed statistically. The function of LINC01296 on cell proliferation, migration, and invasion was confirmed in vitro through MTT assay and transwell assay. We found that LINC01296 was upregulated in ESCC cell lines and cancerous tissues, as compared with normal esophagus cells and adjacent normal tissue samples. High LINC01296 expression was significantly correlated with differentiation grade (p=0.000), lymph nodes metastasis (p=0.002), distant metastasis (p=0.002), and TNM stage (p = 0.015). Moreover, ESCC patients with high LINC01296 expression experienced shorter OS and DFS (p=0.0009 and p=0.0005, respectively). In addition, univariate and multivariate analysis showed that LINC01296 expression was an independent predictor for both OS and DFS in ESCC. Functionally, the results of in vitro assay indicated that down-regulation of LINC01296 significantly suppressed ESCC cells proliferation, migration, and invasion, suggesting that LINC01296 contributed to tumorigenesis of ESCC. Our findings indicate that LINC01296 exerts a role in promoting the development of human ESCC. Up-regulation of LINC01296 could be considered as a predictor for diagnosis and prognosis of ESCC patients.

LncRNA SNHG16 predicts poor prognosis in ESCC and promotes cell proliferation and invasion by regulating Wnt/β-catenin signaling pathway.

Increasing evidence indicated that small nucleolar RNA host gene 16 (SNHG16) acted as a key regulator in the proliferation and metastasis of several cancers, including esophageal squamous cell carcinoma (ESCC). In this research, we aimed to explore biological functions, clinical significance and the underlying molecular mechanisms of SNHG16 in ESCC. qRT-PCR was performed to examine the expression of SNHG16 in ESCC cell lines and clinical ESCC tissue samples. The association of SNHG16 expression with clinicopathological factors and prognosis was statistically analyzed. Cell Counting Kit-8, flow cytometry, and transwell invasion assays were performed to determine the effect of SNHG16 in the regulation of biological behaviors of ESCC cells. Luciferase assay and Western blot were performed to determine the activation of Wnt/β-catenin signaling pathway RESULTS: We observed that SNHG16 expression levels were significantly upregulated in ESCC tissues and cell lines compared with the corresponding normal tissues and normal esophageal cell line, respectively. In addition, increased expression of SNHG16 were strongly linked to tumor stage (p = 0.019), lymph nodes metastasis (p = 0.007) and clinical stage (p = 0.026). Kaplan-Meier assay showed that the survival time of patients with high SNHG16 expression was significantly shorter than those with low SNHG16 expression (p = 0.0017). Univariate and multivariate analyses showed that high SNHG16 expression in ESCC was an independent predictor of poor survival. Loss-of-function experiments revealed that knockdown of SNHG16 suppressed proliferation and invasion and induced apoptosis of ESCC cells. Mechanistically, Wnt/β-catenin signaling pathways were actively modulated by SNHG16 in ESCC cells. Our findings reveal that SNHG16 plays an important role in ESCC proliferation/metastasis via modulating Wnt/β-catenin signaling pathways and could represent a novel biomarker for predicting poor survival as well a promising therapeutic target.

INHBA upregulation correlates with poorer prognosis in patients with esophageal squamous cell carcinoma.

PurposeINHBA, which encodes a member of the TGF-beta superfamily of proteins, has been identified to play a critical role in different types of cancer. However, its clinical significance in esophageal squamous cell carcinoma (ESCC) has never been reported.Patients and methodsIn this study, we collected 239 ESCC paraffin-embedded specimens and measured the expression of INHBA with immunohistochemistry (IHC). The clinical and prognostic significance of INHBA expression was statistically analyzed. What is more, we conducted a meta-analysis to study the prognostic value of INHBA expression in multiple types of solid tumors.ResultsThe results showed that INHBA expression was observed predominantly in the cytoplasm of cells in the ESCC specimens. INHBA expression was closely correlated with N categories (P=0.026). Kaplan–Meier analysis showed that ESCC patients in the low INHBA expression subgroup had significantly better prognosis than those with high INHBA level. Subgroup analysis revealed that INHBA distinguished the disease-free survival (DFS) and overall survival (OS) when patients were stratified by TNM stage status and N status. Multivariate analysis results suggested that INHBA expression was an independent factor that affected OS (HR =1.679, P=0.022) and DFS (HR =1.715, P=0.017). In the meta-analysis, six papers with 1321 patients were included and patients with high INHBA level had worse prognosis than patients with low INHBA level (HR 2.50, 95% CI 1.75–3.57, P<0.0001).ConclusionHigh INHBA level predicts poor prognosis in ESCC and other solid tumors. More studies are required to elucidate the role of INHBA and its clinical application in cancer settings.

Clinicopathological and predictive significance of SIRT1 and peroxisome proliferator-activated receptor gamma in esophageal squamous cell carcinoma: The correlation with EGFR and Survivin

SIRT1 (silent mating type information regulation 2 homolog 1) is an enzyme that deacetylates proteins that contributes to cell survival and angiogenesis. Peroxisome proliferator-activated receptor Ƴ (PPAR Ƴ) is a member of the nuclear steroid hormone receptor superfamily and regulates cell apoptosis and proliferation. The functional roles of SIRT1 and PPAR Ƴ in tumor progression remain controversy. This study aims to investigate the roles of SIRT1 and PPAR Ƴ in esophageal squamous cell carcinoma (ESCC), as well as correlation with expression of EGFR and Survivin. Here, we analyzed the protein expression of SIRT1 and PPAR Ƴ in tumor microarray with ESCC and its associations with clinicopathological parameters and overall survival. Both SIRT1 and PPAR Ƴ were highly expressed in tumor tissues comparing with non-cancerous epithelium. High expression of SIRT1 was positively correlated with advanced TNM stage and poor outcome, while high expression of PPAR Ƴ was positively related with tumor grading, not with patients’ prognosis. In addition, the high expression of SIRT1 was positively correlated with overexpression of EGFR, not related with PPAR Ƴ or Survivin expression status. These data suggests SIRT1 may serve as a predictor of poor prognosis in ESCC, and its mediated tumor-promoting role might be associated with the overexpression of EGFR protein in ESCC.

NFkB hyperactivation causes invasion of esophageal squamous cell carcinoma with EGFR overexpression and p120-catenin down-regulation.

Four out of five patients diagnosed with esophageal squamous cell carcinoma (ESCC) will die within five years. This is primarily a result of the aggressive invasive potential of the disease. Our research is focused on the interplay between tumor suppressors and oncogenes in the invasive process. Specifically, EGFR and p120-catenin (p120ctn) are commonly dysregulated genes that are indicative of poor prognosis in ESCC. In a previous study we demonstrated that in our 3D organotypic culture model, only when EGFR overexpression is combined with p120ctn inactivation do the cells transform and invade – as opposed to either event alone. The purpose of this present study was to identify the components of the molecular pathways downstream of p120ctn and EGFR that lead to invasion. Using both human esophageal keratinocytes and human ESCC cells, we have identified NFkB as a central regulator of the invasive process downstream of p120ctn down-regulation and EGFR overexpression. Interestingly, we found that NFkB is hyperactivated in cells with EGFR overexpression and p120ctn inactivation than with either EGFR or p120ctn alone. Inhibition of this NFkB hyperactivation results in complete loss of invasion, suggesting that NFkB signaling is necessary for invasion in this aggressive cell type. Furthermore, we have identified RhoA and Rho-kinase as upstream regulators of NFkB in this process. We believe the cooperation of p120ctn down-regulation and EGFR overexpression is not only important in the aggressive mechanisms of ESCC but could be broadly applicable to many other cancer types in which p120ctn and EGFR are involved.

LncRNA and mRNA integration network reconstruction reveals novel key regulators in esophageal squamous-cell carcinoma

Many experimental and computational studies have identified key protein coding genes in initiation and progression of esophageal squamous cell carcinoma (ESCC). However, the number of researches that tried to reveal the role of long non-coding RNAs (lncRNAs) in ESCC has been limited. LncRNAs are one of the important regulators of cancers which are transcribed dominantly in the genome and in various conditions. The main goal of this study was to use a systems biology approach to predict novel lncRNAs as well as protein coding genes associated with ESCC and assess their prognostic values. By using microarray expression data for mRNAs and lncRNAs from a large number of ESCC patients, we utilized “Weighted Gene Co-expression Network Analysis” (WGCNA) method to make a big coding-non-coding gene co-expression network, and discovered important functional modules. Gene set enrichment and pathway analysis revealed major biological processes and pathways involved in these modules. After selecting some protein coding genes involved in biological processes and pathways related to cancer, we used “LncTar”, a computational tool to predict potential interactions between these genes and lncRNAs. By combining interaction results with Pearson correlations, we introduced some novel lncRNAs with putative key regulatory roles in the network. Survival analysis with Kaplan-Meier estimator and Log-rank test statistic confirmed that most of the introduced genes are associated with poor prognosis in ESCC. Overall, our study reveals novel protein coding genes and lncRNAs associated with ESCC, along with their predicted interactions. Based on the promising results of survival analysis, these genes can be used as good estimators of patients' survival, or even can be analyzed further as new potential signatures or targets for the therapy of ESCC disease.

High expression of special AT-rich sequence binding protein-1 predicts esophageal squamous cell carcinoma relapse and poor prognosis.

Previous studies of the roles of special AT-rich sequence binding protein-1 (SATB1) in the development and progression of cancer have suggested that SATB1 promotes cancer cell metastasis. The aim of the present study is to evaluate the role of SATB1 in the progression and prognosis of esophageal squamous cell carcinoma (ESCC). ESCC tissues were collected from 102 patients and SATB1 mRNA expression was measured by reverse transcription-quantitative polymerase chain reaction. The association between expression of SATB1 mRNA with clinicopathological features and prognosis was assessed, and the prognosis of ESCC was evaluated using Kaplan-Meier survival curves. In the 102 ESCC tissues, SATB1 mRNA expression correlated with the clinical tumor node metastasis stage (P<0.05), but not with any other clinicopathological features (including age, gender, tumor differentiation grade, adjuvant radio/chemotherapy, or the consumption of alcohol and use of cigarettes) (P>0.05). The disease-free survival (DFS) and overall survival (OS) of patients with high SATB1 expression was decreased compared with those with low SATB1 expression. The present study indicated that SATB1 mRNA expression was associated with the postoperative recurrent and poor prognosis in ESCC. SATB1 may be a novel marker for predicting the recurrent and worse prognosis of ESCC.

Association of epithelial-mesenchymal transition with an immunosuppressive tumor microenvironment with elevated levels of PD-L1 in esophageal carcinoma.

e15585 Background: Programmed death-ligand 1 (PD-L1) plays a crucial role in the host immune system in cancer progression and is has become a new target for cancer therapy. PD-L1 gene promoter region contains a binding site of ZEB1, a transcription factor related to epithelial-mesenchymal transition (EMT). The purpose of this study is to clarify relationships between PD-L1, EMT and its clinical importance in esophageal squamous cell carcinoma (ESCC). Methods: We conducted preclinical studies using cell lines and clinical specimens. ZEB1, PD-L1 expression in TE8 cell line, demonstrating EMT phenotype, was determined following ZEB1 knockdown by siZEB1. TE5, 6 and 11 cell lines with non-EMT phenotype were also used for studies of TGF-β1-dependent EMT induction and ZEB1, PD-L1 expression. PD-L1 and ZEB1 expression at the tumor invasive front was examined in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy by immunohistochemistry and their expression and clinicopathological factors were compared. Results: A correlation was observed between PD-L1 and ZEB1 expression. In TE8 cells which express EMT character , siZEB1 suppressed PD-L1 and promoted E-cadherin mRNA and protein expression. In TE5, 6 and 11 cell lines which are not EMT phenotype, TGF-β1 induced EMT and surface expression of PD-L1. In cases of high PD-L1 expression at invasive front, greater depth of tumor invasion, EMT, less CD8 expression were significantly observed. High PD-L1 expression was also associated with worse overall and relapse-free survival. Conclusions: PD-L1 expression at the invasive front was related to ZEB1 expression, EMT and poor prognosis in ESCC. We suggest that cooperative mechanism between tumor immune avoidance and EMT contributes to tumor malignancy. Whether or not ZEB1-PD-L1 signal pathway could be a target in treatment for ESCC requires further investigations.

Correlations of ALDH2 rs671 and C12orf30 rs4767364 polymorphisms with increased risk and prognosis of esophageal squamous cell carcinoma in the Kazak and Han populations in Xinjiang province.

Genetic polymorphisms in ALDH2 and C12orf30 genes have been reported to increase the risk of developing esophageal squamous cell carcinoma (ESCC). This study aims to investigate the relationship between ALDH2 rs671 and c12orf30 rs4767364 polymorphisms in the chromosome 12q24 gene, and risk and prognosis of individuals developing esophageal cancer (ESCC) in Xinjiang Kazak and Han populations. The case group consisted of 127 ESCC patients. The control group comprised of 125 healthy individuals. Subjects that were recruited all come from Xinjiang province. TaqMan and the Hardy-Weinberg equilibrium were the main methods employed to detect and examine the distribution of genotypes of rs671 and rs4767364. The genotype frequencies of ALDH2 rs671 between the Kazak case and control groups were statistically significant, while no significant difference was observed between the Han case and control groups (P>.05). Moreover, ALDH2 rs671 (G>A) was associated with poor prognosis of ESCC in both Kazak and Han populations, and c12orf30 rs4767364 (A>G) was also connected with poor prognosis of ESCC in Kazak but not in Han population. In the chromosome 12q24 locus, ALDH2 rs671 (G>A) is related to the susceptibility to ESCC in Kazak populations, and it is also associated with poor prognosis of EC in Kazak and Han populations. Furthermore, c12orf30 rs4767364 (A>G) may be correlated with poor ESCC prognosis in Kazak population.

Prognostic Significance of KAI1/CD82 and its Relation Tod2-40 Labeled Lymphatic Vessel Invasion (LVI) and Lymphatic Vessel Density (LVD) in Esophageal Squamous Cell Carcinoma (ESCC)

Objectives: The KAI1/CD82 appears to inhibit multiple steps of cancer metastatic. D2-40 labeled LVI and LVD are also closely associated with cancer metastasis. We investigated the expression levels of KAI1/CD82, D2-40 labeled LVI and LVD and their correlation with clinicopathological factors in ESCC. Methods: Immunohistochemistry and Western Blot were used to detect KAI1/CD82 expression levels in the peritumoral tissue and ESCC. LVI and LVD detected by D2-40 immunohistochemical staining. The relationships between the KAI1/CD82 expression levels, LVI and LVD were analyzed. The prognosis of ESCC was analyzed by Kaplan-Meier survival analysis and Cox’s proportional hazards model. Results: KAI1/CD82 expression was markedly lower in ESCC than in the para-carcinoma tissue (P<0.05). Positive peritumoral LVI and high mean peritumoral LVD were positively correlated while KAI1/ CD82 expression was negatively correlated with tumor invasion, lymph node metastasis, and clinical stage. Kaplan-Meier analysis revealed that high mean peritumoral LVD and positive LVI was negatively correlated with overall survival (OS) and disease-free survival (DFS) time, while KAI1/CD82 expression was positively correlated with OS and DFS time. Low KAI1/CD82 expression, high mean peritumoral LVD, positive LVI was associated with a poor prognosis in ESCC. Multivariate Cox regression analysis indicated that the positive LVI and KAI1/CD82 positive expression were independent predictors for OS in ESCC. Positive LVI and high mean peritumoral LVD were independent predictors for DFS in ESCC Conclusions: KAI1/CD82 expression, LVI and LVD were significantly correlated with some clinicopathological factors of ESCC including lymph node metastasis, differentiation, and clinical stage. Combined detection of these factors may be of significant value in predicting the prognosis and metastasis in ESCC patients.

Increased expression of high-mobility group A2: A novel independent indicator of poor prognosis in patients with esophageal squamous cell carcinoma.

Although high-mobility group A2 (HMGA2) protein has been reported to participate in cancer progression and metastasis, its clinical relationship with tumor invasion, lymph node metastasis, and prognosis in esophageal squamous cell carcinoma (ESCC) remains unclear. The purpose of this study is to analyze the clinical and prognostic significance of HMGA2 in ESCC patients after curative resection. The expression of HMGA2 protein was evaluated by using immunohistochemistry in a tissue microarray (TMA) containing ESCC lesions and adjacent normal esophageal epithelial tissues from 96 patients who had undergone curative resection. TMA was constructed by Shanghai Biochip Co. Ltd., Shanghai, China. The relationship between HMGA2 expression and clinicopathological parameters and prognosis was further analyzed. HMGA2 expression was significantly higher in ESCC tissues compared with that of the adjacent noncancerous tissues (P < 0.001). High expression of HMGA2 was significantly related to tumor size, lymph node metastasis, and advanced tumor-node-metastasis stage (P < 0.05). Patients with low expression of HMGA2 had a better prognosis than those with high expression (χ2 = 5.069, P = 0.024). Univariate analysis showed that age (P = 0.041), depth of tumor invasion (P = 0.031), lymph node status (P = 0.001), and HMGA2 expression (P = 0.024) were correlated with prognosis. Multivariate analysis showed that HMGA2 expression (hazard ratio [HR]: 0.539; 95% confidence interval [95% CI]: 0.302-0.963, P = 0.037) and lymph node metastasis (HR: 0.504; 95% CI: 0.310-0.820, P = 0.006) were independent prognostic factors for overall survival. High HMGA2 expression was related to lymph node metastasis and poor prognosis in ESCC. Our results indicated that HMGA2 could act as a potential biomarker for prognosis evaluation of ESCC patients.