Oseltamivir enhances 5-FU sensitivity in esophageal squamous carcinoma with high SPNS1.

Sphingolipid transporter 1 (SPNS1) is a significant differentially expressed gene (DEGs) in esophageal squamous cell carcinoma (ESCC). According to 3 pairs clinic cohorts, transcriptomic (155 pairs of ESCC samples and GSE53624, and proteomic data from PXD021701 including 124 ESCC samples) we found that SPNS1 was significantly higher in ESCC tissues compared to adjacent normal esophagus tissues. ESCC patients with high SPNS1 had a significantly poorer clinical prognosis than those with low SPNS1. Knockdown of SPNS1 significantly inhibited the proliferation, migration, and invasion abilities of ESCC cells, while promoting apoptosis. And overexpression of SPNS1 exhibited opposite functions. Furthermore, ESCC cells became more sensitive to 5-fluorouracil (5-FU) when SPNS1 was knocked down. Transcriptome sequencing revealed that NEU1 was one significant DEG affected by SPNS1 and positively correlated with SPNS1 expression. Oseltamivir phosphate (OP), one NEU1 inhibitor, markedly reversed 5-FU resistance, migration, and proliferation induced by high expression of SPNS1 both in vivo and in vitro. Our findings indicated that SPNS1 might promote the progression of ESCC by upregulating NEU1 expression and influencing chemotherapy sensitivity. These results provide new perceptions into potential therapeutic targets for ESCC treatment. The present study aimed to investigate the role and underlying mechanism of SPNS1 in ESCC.

The HIF-1/ BNIP3 pathway mediates mitophagy to inhibit the pyroptosis of fibroblast-like synoviocytes in rheumatoid arthritis.

BACKGROUND: Synovial hypoxia, a critical pathological characteristic of rheumatoid arthritis (RA), significantly contributes to synovitis and synovial hyperplasia. In response to hypoxic conditions, fibroblast-like synoviocytes (FLS) undergo adaptive changes involving gene expression modulation, with hypoxia-inducible factors (HIF) playing a pivotal role. The regulation of BCL2/adenovirus e1B 19 kDa protein interacting protein 3 (BNIP3) and nucleotide-binding oligomerization segment-like receptor family 3 (NLRP3) expression has been demonstrated to be regulated by HIF-1. The objective of this study was to examine the molecular mechanism that contributes to the aberrant activation of FLS in response to hypoxia. Specifically, the interaction between BNIP3-mediated mitophagy and NLRP3-mediated pyroptosis was conjointly highlighted. METHODS: The research methodology employed Western blot and immunohistochemistry techniques to identify the occurrence of mitophagy in synovial tissue affected by RA. Additionally, the levels of mitophagy under hypoxic conditions were assessed using Western blot, immunofluorescence, quantitative polymerase chain reaction (qPCR), and CUT&Tag assays. Pyroptosis was observed through electron microscopy, fluorescence microscopy, and Western blot analysis. Furthermore, the quantity of reactive oxygen species (ROS) was measured. The silencing of HIF-1α and BNIP3 was achieved through the transfection of short hairpin RNA (shRNA) into cells. RESULTS: In the present study, a noteworthy increase in the expression of BNIP3 and LC3B was observed in the synovial tissue of patients with RA. Upon exposure to hypoxia, FLS of RA exhibited BNIP3-mediated mitophagy and NLRP3 inflammasome-mediated pyroptosis. It appears that hypoxia regulates the expression of BNIP3 and NLRP3 through the transcription factor HIF-1. Additionally, the activation of mitophagy has been observed to effectively inhibit hypoxia-induced pyroptosis by reducing the intracellular levels of ROS. CONCLUSION: In summary, the activation of FLS in RA patients under hypoxic conditions involves both BNIP3-mediated mitophagy and NLRP3 inflammasome-mediated pyroptosis. Additionally, mitophagy can suppress hypoxia-induced FLS pyroptosis by eliminating ROS and inhibiting the HIF-1α/NLRP3 pathway.

A pan-cancer analysis of prognostic significance and immunological role of lysosomal-associated membrane protein 3.

Lysosomal dysfunction can drive carcinogenesis. Lysosomal-associated membrane protein 3 (LAMP3), is a member of the Lysosome Associated Membrane Proteins and is involved in the malignant phenotype such as tumour metastasis and drug resistance, while the mechanisms that regulate the malignant progression of tumour remain vague. Our study aims to provide a more systematic and comprehensive understanding of the role of LAMP3 in the progression of various cancers by various databases.We explored the role of LAMP3 in pan-cancer using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Multiple online web platforms and software were used for data analysis, including HPA, TIMER, TISIDB, GEPIA, UALCAN, Kaplan-Meier plotter, DAVID and TIGER. The immunohistochemistry was used to quantify the LAMP3 and PD-L1 expression levels in cancer.High LAMP3 expression was found in most cancers and differentially expressed across molecular and immune subtypes. The expression of LAMP3 was involved in the immune-associated processes of Antigen processing and presentation, Th17 cell differentiation, Th1 and Th2 cell differentiation, and the immune-associated pathways of T cell receptor and B cell receptor signalling pathways in most cancers. It also correlated with genetic markers of immunomodulators in various cancers. LAMP3 and PD-L1 expression in BRCA and HNSC tissues was higher than that in corresponding adjacent normal tissues by immunohistochemistry. There is a significant correlation between the expression of LAMP3 and PD-L1.Our study elucidates that LAMP3 has different expression patterns and genetic alteration patterns in different tumours. It is a potential biomarker for immune-related cancer diagnosis, prognosis and efficacy prediction.

TSTA3 overexpression promotes malignant characteristics in LUSC by regulating LAMP2-mediated autophagy and tumor microenvironment.

BACKGROUND: TSTA3 gene encoding GDP-L-fucose synthase has recently been proved to be closely related to the prognosis of patients with various tumors. However, its role in lung cancer is still unclear. The purpose of this study is to explore the expression level, prognostic effect, potential function and mechanism of TSTA3 in lung cancer. METHODS: Based on TCGA database, Kaplan-Meier and COX regression was used to analyze the relationship between TSTA3 expression and prognosis of lung cancer patients. Immunohistochemistry was used to determine the TSTA3 protein expression in lung cancer and normal tissues. The function of TSTA3 in lung squamous cell carcinoma (LUSC) cell was determined by CCK8, colony formation, transwell assay in vitro and subcutaneous xenografts in vivo. Transcriptome analysis, Lyso-Tracker Red staining and rescue experiment were used to explore the possible underlying mechanism. RESULTS: The expression of TSTA3 was significantly increased in lung cancer, especially in LUSC, and was significantly correlated with the malignant characteristics of LUSC. COX regression analysis showed that the high expression of TSTA3 was an independent prognostic factor in LUSC patients. This was also confirmed by immunohistochemical staining. Compared with the control group, the proliferation, colony formation, invasion and migration ability of LUSC cells with TSTA3 overexpression was enhanced. Similarly, the ability of cell proliferation, colony formation, invasion and migration were weakened after transient knockdown of TSTA3. In vivo experiment showed that compared with control group, TSTA3 overexpression significantly promoted the growth of tumor and shortened survival time. In addition, transcriptome sequencing analysis showed that the differentially expressed genes between TSTA3 overexpression and control group was mainly concentrated in the lysosome pathway. Further study found that TSTA3 might affect the proliferation, invasion and migration of LUSC by regulating the expression of lysosome-associated membrane protein 2 (LAMP2) in LUSC. CONCLUSION: The expression level of TSTA3 in LUSC is significantly higher than that in normal tissues. High expression of TSTA3 is associated with poor prognosis of LUSC patients. TSTA3 may affect the proliferation, invasion and migration of LUSC by regulating LAMP2.

Low-dose ethanol consumption inhibits neutrophil extracellular traps formation to alleviate rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Ethanol consumption has been reported to reduce morbidity in RA patients, but the mechanism behind it remains unclear. Our results showed that Muribaculaceae was predominant in the gut microbiota of mice after ethanol treatment, and the levels of microbiota metabolite acetate were increased. Acetate reduced arthritis severity in collagen-induced arthritis (CIA) mice, which was associated with a decrease in the articular neutrophils and the myeloperoxidase-deoxyribonucleic acid complex in serum. Meanwhile, in vitro experiments confirmed that acetate affected neutrophil activity by acting on G-protein-coupled receptor 43, which reduced endoplasmic reticulum stress in neutrophils and inhibited neutrophil extracellular traps formation. Furthermore, exogenous acetate reversed CIA mice with exacerbated gut microbial disruption, further confirming that the effect of gut microbial metabolite acetate on neutrophils in vivo is crucial for the immune regulation. Our findings illuminate the metabolic and cellular mechanisms of the gut-joint axis in the regulation of autoimmune arthritis, and may offer alternative avenues to replicate or induce the joint-protective benefits of ethanol without associated detrimental effects.

BAFF Promotes FLS Activation Through BAFFR-Mediated Non-canonical NF-κB Pathway and the Effects of CP-25.

B cell activating factor (BAFF) has been shown to play a key role in regulating B cell function, but little is known about whether BAFF affects the function of fibroblast-like synoviocyte (FLS), an effector cell of rheumatoid arthritis (RA). CP-25, a new ester derivative of paeoniflorin, could alleviate the arthritis symptoms of collagen-induced arthritis (CIA) mice by inhibiting BAFF-mediated abnormal activation of B cells. In this study, we aimed to understand the mechanism by which BAFF activates FLS and the effect of CP-25 on FLS function. Therefore, the proliferation and migration abilities of FLS and key proteins on the non-canonical NF-κB pathway were examined. The results showed that compared with the FLS of normal rats/OA patients, the expression of BAFF-R, TRAF2, NIK, p-IKKα, P100, and P52 was higher in the FLS of AA rats/RA patients, while the expression of TRAF3 was lower. And, BAFF promotes FLS activation by activating the non-canonical NF-κB signaling pathway. Meanwhile, BAFFR-siRNA inhibited the proliferation of FLS and the activation of non-canonical NF-κB signaling in FLS induced by BAFF. Additionally, CP-25 could inhibit abnormal proliferation and migration of FLS by regulating non-canonical NF-κB signaling. We concluded that BAFF may act as an important role in facilitating the function of FLS through the BAFFR-mediated non-canonical NF-κB pathway, which would be useful for revealing the pathological mechanism of RA. And CP-25 may become a potential new drug for the treatment of RA, providing a scientific basis for the development of new drugs to treat RA.

FAT1 downregulation enhances stemness and cisplatin resistance in esophageal squamous cell carcinoma.

Primary or acquired drug resistance accounts for the failure of chemotherapy and cancer recurrence in esophageal squamous cell carcinoma (ESCC). However, the aberrant mechanisms driving drug resistance are not fully understood in ESCC. In our previous study, FAT Atypical Cadherin 1 (FAT1) was found to inhibit the epithelial-mesenchymal transition (EMT) process in ESCC. EMT plays a critical role in the development of drug resistance in multiple cancer types. Besides, it equips cancer cells with cancer stem cell (CSC)-like characters that also are associated with chemotherapy resistance. Whether FAT1 regulates the stemness or drug resistance of ESCC cells is worth being explored. Here we found that FAT1 was downregulated in ESCC spheres and negatively correlated with stemness-associated markers including ALDH1A1 and KLF4. Knocking down FAT1 enhanced the sphere-forming ability, resistance to cisplatin and drug efflux of ESCC cells. Additionally, FAT1 knockdown upregulated the expression of drug resistance-related gene ABCC3. Furtherly, we found FAT1 knockdown induced the translocation of ß-catenin into nucleus and enhanced its transcriptional activity. The result of ChIP showed that ß-catenin was enriched in ABCC3 promoter. Furthermore, ß-catenin promoted expression of ABCC3. In conclusion, FAT1 knockdown might enhance the stemness and ABCC3-related cisplatin resistance of ESCC cells via Wnt/ß-catenin signaling pathway. FAT1 and its downstream gene ABCC3 might be potential targets for overcoming chemoresistance in ESCC.

Cadmium inhibits apoptosis of human esophageal epithelial cells by upregulating CDK6.

Cadmium (Cd) exposure in environment is associated with development of esophageal cancer. However, the mechanisms of Cd-induced carcinogenesis are still not been fully cleared, and the present study aimed to explore the possible etiological mechanism of Cd-induced esophageal cancer. Human esophageal epithelial cell lines (HET-1A and KYSE450) were treated with CdCl2 at 0.05 mg/l for 12, 24 h, and the then the apoptosis were detected using flow cytometry with annexin-V-FITC/PI staining. Results showed that apoptosis of treatment groups was significantly inhibited, and decreased reactive oxygen species (ROS) production played a key role in the inhibitory effects by upregulating Bcl-2 and downregulating Caspase-3/9. The relief of oxidative stress during Cd exposure was actively promoted by the increased nicotinamide adenine dinucleotide phosphoric acid and glutathione levels. To investigate the causes of enhanced intracellular antioxidant capacity, the activity of pyruvate kinase (PK), a key enzyme of glycolysis, was detected. Our results showed that PK activity was inhibited, suggesting that glycolysis process was blocked which promoted more intermediate metabolites of glycolysis to be used for reduced nicotinamide adenine dinucleotide phosphoric acid (NADPH) or other antioxidants synthesis. PK activity was closely correlated with phosphorylation of pyruvate kinase M2 (PKM2), and a highly negative correlation (correlation coefficients: -0.835, p < 0.05) between them was found. Western blotting showed the overphosphorylation of PKM2 in Cd-exposed cells, resulting from increased expression of cyclin-dependent kinases 6 (CDK6). These results suggested a possible mechanism of carcinogenic: Cd-induced upregulation of CDK6 in esophageal cell lines caused PKM2 overphosphorylation inhibiting PK activity, thereby shunting glucose-derived carbon into the pentose phosphate pathway and promoting the production of NADPH and reduced glutathione (GSH) to neutralize ROS, which finally results in the inhibited apoptosis.

Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients' outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients' outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.

Considering gemcitabine-based combination chemotherapy as a potential treatment for advanced oesophageal cancer: A meta-analysis of randomised trials.

BACKGROUND: Gemcitabine has been proved to be effective in many advanced cancer. However, almost all trials failed to demonstrate the response rate of gemcitabine-based combination schedules on oesophageal cancer (EC). METHODS: A systematic meta-analysis of randomised clinical trials (RCTs) was performed to investigate the efficacy of gemcitabine-based combination chemotherapy in EC treatment. Clinical trials were collected during the period ranging from January 2000 to November 2018 by searching different databases. Odds-ratios (ORs) of response rate (RR), disease control rate (DCR) and grade 3-4 toxicity rates (TRs) were extracted as presented in retrieved studies. RESULTS: Fourteen trials (1024 patients) were selected for the final analysis. The results showed that RR and DCR of gemcitabine-based combination chemotherapy demonstrated a significant advantage for non-gemcitabine therapy (OR for RR: 1.51; 95% CI: 1.16-1.96; P = .002; OR for DCR: 1.66; 95% CI: 1.19-2.32, P = .003). Toxicities of gemcitabine-based combination chemotherapy on gastrointestinal tract (OR, 0.39; 95% CI: 0.24-0.63, P = .0001) were less frequent compared to that of the non-gemcitabine therapy. CONCLUSION: The improvements of gemcitabine-based combination chemotherapy on RR, CDR and reduction of gastrointestinal tract, hepatic and renal for EC patients suggests that the combined chemotherapy based on gemcitabine could be a potential treatment options for advanced EC.

Decreased ZNF750 promotes angiogenesis in a paracrine manner via activating DANCR/miR-4707-3p/FOXC2 axis in esophageal squamous cell carcinoma.

ZNF750 is one novel significantly mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinically relevant and potential mechanisms have remained elusive. Using genomic sequencing of 612 ESCC patients, we analyzed the associations of ZNF750 mutations with clinicopathologic features and its prognostic value. We further investigated the function and underlying mechanism of ZNF750 in angiogenesis. The results showed ZNF750 mutations/deletions are significantly associated with malignant progression and poor prognosis of ESCC patients. Decreased ZNF750 in ESCC cells induces enhanced angiogenesis of human umbilical vein endothelial cells (HUVECs) and human arterial endothelial cells (HAECs), and the effect may be indirectly mediated by FOXC2. RNA-seq and ChIP shows lncRNA DANCR is a direct downstream target of ZNF750. Furtherly, knockdown ZNF750 evokes DANCR expression, which prevents miR-4707-3p to interact with FOXC2 as a microRNA sponge in a ceRNA manner, leading to enhanced FOXC2 signaling and angiogenesis. In contrast, ZNF750 expression reverses the effect. Our study reveals a novel mechanism of ZNF750, highlights a significance of ZNF750 as a metastatic and prognostic biomarker, and offers potential therapeutic targets for ESCC patients harboring ZNF750 mutations.

Novel ESCC-related gene ZNF750 as potential Prognostic biomarker and inhibits Epithelial-Mesenchymal Transition through directly depressing SNAI1 promoter in ESCC.

Background: Cancer genomic studies have identified Zinc Finger Protein 750 (ZNF750) was a novel significantly mutated gene in esophageal squamous cell carcinoma (ESCC). This study was designed to determine the clinical value and molecular mechanisms of ZNF750 in the development of ESCC. Methods: Genomic data from 4 reported ESCC cohorts were used to analyze the mutation profile of ZNF750. Tissue microarrays were used to detect its expression in 308 ESCC samples. Furtherly, the effects of ZNF750 on proliferation, colony formation, migration and invasion were tested in ESCC cells. PCR-array, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay were used to explore the mechanism of ZNF750. Correlation of ZNF750 with its target genes was analyzed in TCGA data from various SCC types. Results: ZNF750 was frequently mutated in ESCC and the most common type was nonsense mutation. Its nucleus/cytoplasm ratio in ESCC was significantly lower than that in paired non-tumor tissues; it was an independent and potential predictor for survival in ESCC patients. Furtherly, ZNF750 knockdown significantly promoted proliferation, colony formation, migration and invasion in ESCC cells. PCR-array showed epithelial-to-mesenchymal transition (EMT) was the main biologic process affected by ZNF750. Moreover, ZNF750 directly bound to the promoter region of SNAI1 and depressed its activity. Decreased ZNF750 up-regulated SNAI1 expression and promoted EMT phenotype. SNAI1 knockdown partially reversed the malignant phenotype induced by ZNF750 knockdown. Further TCGA data analyses showed ZNF750 expression was positively correlated with E-cadherin and negatively correlated with SNAI1, N-cadherin and Vimentin in ESCC and other SCC samples. Conclusion: Our results suggest that ZNF750 may act as a tumor suppressor by directly repressing SNAI1 and inhibiting EMT process in ESCC and other types of SCC.

EP300 as an oncogene correlates with poor prognosis in esophageal squamous carcinoma.

E1A Binding Protein P300 (EP300) is one of the mutations of genes involved in histone modifications in esophageal squamous cell carcinoma (ESCC). However, its clinical relevance, potential function and mechanisms have remained elusive. Methods: Genomic sequencing datas from 325 esophageal squamous cell carcinoma (ESCC) cases were integrated and screened a series of frequently mutated histone modifier genes. EP300 was selected to further analyze its clinical significance, function and RNA-sequencing was performed to explore its potential mechanism. Results: Of 35 histone modifier genes, EP300 was not only a significantly mutated gene but also a frequently mutated gene with a mutation frequency of more than 10% in ESCC. EP300 mutation was associated with tumor grade, pathological T stage and lymph node metastasis, predicting a shorter cumulative survival status. Immunohistochemical analysis showed that EP300 expression was significantly higher in ESCC tumor tissues, and the expression levels were associated with poor survival of ESCC patients. Moreover, we found that EP300 knockdown led to inhibition of cell proliferation, colony formation, migration and invasion. RNA-sequencing showed EP300 knockdown led to a significant change of genes expression associated with angiogenesis, hypoxia and epithelial-to-mesenchymal transition (EMT). Conclusions: Taken together, our study identified a novel role and mechanism of EP300 in ESCC and provided epigenetic therapeutic strategies for the treatment of ESCC.

High TSTA3 Expression as a Candidate Biomarker for Poor Prognosis of Patients With ESCC.

Esophageal squamous cell carcinoma is the sixth most lethal cancer worldwide and the fourth most lethal cancer in China. Tissue-specific transplantation antigen P35B codifies the enzyme GDP-d-mannose-4,6-dehydratase, which participates in the biosynthesis of GDP-l-fucose. GDP-l-fucose is an important substrate involved in the biosynthesis of many glycoproteins. Cancer cells are often accompanied by the changes in glycoprotein structure, which affects the adhesion, invasion, and metastasis of cells. It is not clear whether tissue-specific transplantation antigen P35B has any effect on the development of esophageal squamous cell carcinoma. We used an immunohistochemical method to assess the expression of tissue-specific transplantation antigen P35B in 104 esophageal squamous cell carcinoma samples. The results showed tissue-specific transplantation antigen P35B expression was associated with some clinical features in patients, such as age ( P = .017), clinical stage ( P = .010), and lymph node metastasis ( P = .043). Kaplan-Meier analysis and log-rank test showed that patients with esophageal squamous cell carcinoma having high tissue-specific transplantation antigen P35B expression had a worse prognosis compared to the patients with low expression ( P = .048). Multivariate Cox proportional hazards regression model showed that high expression of tissue-specific transplantation antigen P35B could predict poor prognosis for patients with esophageal squamous cell carcinoma independently. In conclusion, abnormal fucosylation might participate in the progress of esophageal squamous cell carcinoma and tissue-specific transplantation antigen P35B may serve as a novel biomarker for prognosis of patients with esophageal squamous cell carcinoma.

FAT1 inhibits cell migration and invasion by affecting cellular mechanical properties in esophageal squamous cell carcinoma.

FAT atypical cadherin 1 (FAT1) belongs to the cadherin superfamily and has been reported to regulate cell­cell adhesion and other cell behaviors, suggesting its pivotal roles in human cancers. We previously identified FAT1 as one of the significant mutant genes in esophageal squamous cell carcinoma (ESCC). In the present study, the knockdown of FAT1 expression in YSE2 and Colo680N cell lines was carried out by lentivirus, and we found that knockdown of FAT1 led to acceleration of cell migration and invasion. Furthermore, we detected the cell adhesive force and cell elasticity force by atomic force microscopy (AFM) and found that the suppression of endogenous expression of FAT1 led to a decrease in the cell adhesive force and increase in the cell elasticity force compared with the control groups. In conclusion, our study demonstrated that FAT1 altered cellular mechanical properties leading to deregulation of cell migration and invasion of ESCC, which may be a novel target for ESCC therapy.

FAT1 prevents epithelial mesenchymal transition (EMT) via MAPK/ERK signaling pathway in esophageal squamous cell cancer.

FAT1 regulates cell-cell adhesion, cell growth, cell migration, and actin dynamics as either oncogene or tumor suppressor in human cancers. We previously identified FAT1 was one of significant mutant genes in esophageal squamous cell carcinoma (ESCC). However, the function and underlying mechanism of FAT1 in ESCC have not been explored. In this study, we report that FAT1 expression was significantly lower in ESCC tumor tissues. Exogenous expression of FAT1 led to inhibition of cell proliferation and colony formation, as well as cell migration and invasion whereas FAT1 knockdown showed the opponent trends in vitro and in vivo. Moreover, FAT1 knockdown led to a statistically decrease of E-cadherin expression and a dramatically increase expression of N-cadherin, Vimentin, and Snail in a MAPK/ERK pathway-dependent manner. Meanwhile, over-expression of FAT1 resulted in the opposite trends. These alterations were abrogated in the presence of U0126, a MEK specific inhibitor. Collectively, our studies identified a novel role for FAT1 in inhibiting tumor growth and EMT occurrence in ESCC. We proposed that disruption of MAPK/ERK pathway by FAT1 contributes the EMT in ESCC and has important implications for understanding ESCC development.

The macro-evolutionary events in esophageal squamous cell carcinoma.

Understanding the evolutionary processes operative in cancer genome may provide insights into clinical outcome and drug-resistance. However, studies focus on genomic signatures, especially for macro-evolutionary events, in esophageal squamous cell carcinoma (ESCC) are limited. Here, we integrated published genomic sequencing data to investigate underlying evolutionary characteristics in ESCC. We found most of ESCC genomes were polyploidy with high genomic instability. Whole genome doubling that acts as one of mechanisms for polyploidy was predicted as a late event in the majority of ESCC genome. Moreover, loss of heterozygosity events were more likely to occur in chromosomes harboring tumor suppressor genes in ESCC. The 40% of neutral loss of heterozygosity events was not a result of genome doubling, suggesting an alternative mechanism for neutral loss of heterozygosity formation. Importantly, deconstruction of copy number alterations extending to telomere revealed that telomere-bounded copy number alterations play a critical role for amplification/deletion of oncogenes/suppressor genes. For well-known genes SOX2, PIK3CA and TERT, nearly all of their amplifications were telomere bounded, which was further confirmed in a Japanese ESCC cohort. Furthermore, we provide evidence that karyotype evolution was mostly punctuated in ESCC. Collectively, our data reveal the potential biological role of whole genome doubling, neutral loss of heterozygosity and telomere-bounded copy number alterations, and highlight mecro-evolution in ESCC tumorigenesis.