Proliferation Of Esophageal Squamous Cell Carcinoma Research Articles

The abnormal expression of circ-ARAP2 promotes ESCC progression through regulating miR-761/FOXM1 axis-mediated stemness and the endothelial–mesenchymal transition

Circular RNAs (circRNAs) belong to a novel class of noncoding RNA that gained more attention in human cancer pathogenesis. The role of circRNA in esophageal squamous cell carcinoma (ESCC) is largely unclear. Present investigation was to characterize new circRNAs regulating ESCC progression and explore the regulatory mechanisms in ESCC. In this study, circRNAs differentially expressed in ESCC and adjacent normal tissues were characterized via high-throughput sequencing. Then the differentially expressed circRNA between ESCC and adjacent normal tissues were investigated using Rt-qPCR. The role of circ-ARAP2 expression on tumor progression were detected in both in vivo and in vitro. Luciferase reporter assays were used to identify the relationships among circ-ARAP2, microRNA (miR)-761 and the cell cycle regulator Forkhead Box M1 (FOXM1). The result of the expression profile analyses regarding human circRNAs in ESCC demonstrated that circ-ARAP2 was up-regulated significantly in both ESCC tissues and cell lines. Downregulation circ-ARAP2 suppressed ESCC proliferation, tumor growth and metastasis in both in vivo and in vitro. The data also suggested that miR-761 and FOXM1 were circ-ARAP2 downstream targets which were confirmed through luciferase reporter analysis. Overexpression of FOXM1 or inhibiting miR-761 restored ESCC cell proliferation and invasion ability after silencing circ-ARAP2. The study also found that circ-ARAP2 influenced the endothelial–mesenchymal transition (EMT) and cancer stem cells differently by regulating miR-761/FOXM1. In one word, the results demonstrated that abnormal circ-ARAP2 expression promoted ESCC progression by regulating miR-761/FOXM1 axis-mediated stemness and EMT.

CircLONP2 Accelerates Esophageal Squamous Cell Carcinoma Progression via Direct MiR-27b-3p-ZEB1 Axis.

Circular RNAs (circRNAs) are important mediators in esophageal squamous cell carcinoma (ESCC) carcinogenesis. We aim to explore the functions and mechanisms of circLONP2 in ESCC progression. The circLONP2 level was evaluated in ESCC samples and cell lines. The role and mechanisms of circLONP2 in ESCC proliferation and migration were demonstrated in vitro. We found that circLONP2 was upregulated in human ESCC and predicts poor overall survival (OS) and disease-free survival (DFS). CircLONP2 promotes ESCC aggressiveness by directly interacting with miR-27b-3p, thus upregulating the expression levels of its target gene ZEB1 by suppressing miR-27b-3p activity. Therefore, we demonstrated that circLONP2/miR-27b-3p/ZEB1 axis promotes ESCC metastasis via regulating epithelial-to-mesenchymal transition (EMT)-related proteins. CircLONP2 may serve as an oncogenic circRNA and as a prognostic biomarker in ESCC progression.

Establishment of a risk model by integrating hypoxia genes in predicting prognosis of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) has a dismal prognosis, and hypoxia plays a key role in metastasis and proliferation of ESCC. Thus, we aimed to develop a hypoxia-based gene signature to assist in the treatment decisions and prognosis. We performed consensus clustering analysis on samples from GSE53625 dataset from the Gene Expression Omnibus (GEO) database and used weighted gene co-expression network analysis to filter out candidate modules, which were then intersected with differentially expressed genes from clustered subgroups to obtain hypoxia-related genes (HRGs). After that, the aforementioned genes were used to construct risk score models and validated in The Cancer Genome Atlas (TCGA) database and Cox regression analysis were used to construct a nomogram. Immunohistochemical was used to detect protein expression levels of relevant genes. Moreover,the relationship between risk scores and tumor microenvironment was explored. A hypoxia risk model containing six genes (PNPLA1, CARD18, IL-18, SLC37A2, ADAMTS18, and FAM83C) was constructed by screening key HRGs. Poorer prognosis in the high-risk group than in the low-risk group. And Cox regression analysis showed that risk score was an independent prognostic factor. The nomogram based on risk scores could well predict 1-, 3-, and 5-year survival. P53, Wnt, and hypoxia signaling pathways may be some regulatory mechanisms of hypoxia associated with the tumor microenvironment. In addition, we confirmed the high expression of BGN and low expression of IL-18 in ESCC tissues. Our study determined the prognostic value of a 6-hypoxia gene signature and a prognostic model, providing potential prognostic predictors and therapeutic targets for ESCC.

Targeting the SOX2/PARP1 complex to intervene in the growth of esophageal squamous cell carcinoma

Elevated SOX2 protein levels are closely correlated with the increased incidence of esophageal squamous cell carcinoma (ESCC). However, establishing effective target measures for ESCC treatments continue to be researched. It has been previously proposed that SOX2 represents a potential therapeutic target for ESCC. Here, we found that the enzyme Poly(ADP-Ribose) polymerase 1 (PARP1) enriched in ESCCs interact with SOX2. Inhibition of PARP1 with 3-aminobenzamide (3-ABA) or shRNA knockdown reduced the proliferation of ESCCs, accompanied by decreased protein levels of SOX2. RNA sequencing demonstrated that PARP1 inhibition affected multiple signaling pathways involved in cancer cell proliferation. Additionally, 3-ABA synergistically suppressed the growth of ESCC cells when combined with cisplatin, and metformin potentiated the suppressive effect of 3-ABA on ESCC cell growth. Together these findings suggest that targeting SOX2 binding partner PARP1 provides a possible avenue to treat patients with high levels of SOX2.

LncRNA TMPO-AS1 promotes esophageal squamous cell carcinoma progression by forming biomolecular condensates with FUS and p300 to regulate TMPO transcription

Esophageal squamous cell carcinoma (ESCC) is one of the most life- and health-threatening malignant diseases worldwide, especially in China. Long noncoding RNAs (lncRNAs) have emerged as important regulators of tumorigenesis and tumor progression. However, the roles and mechanisms of lncRNAs in ESCC require further exploration. Here, in combination with a small interfering RNA (siRNA) library targeting specific lncRNAs, we performed MTS and Transwell assays to screen functional lncRNAs that were overexpressed in ESCC. TMPO-AS1 expression was significantly upregulated in ESCC tumor samples, with higher TMPO-AS1 expression positively correlated with shorter overall survival times. In vitro and in vivo functional experiments revealed that TMPO-AS1 promotes the proliferation and metastasis of ESCC cells. Mechanistically, TMPO-AS1 bound to fused in sarcoma (FUS) and recruited p300 to the TMPO promoter, forming biomolecular condensates in situ to activate TMPO transcription in cis by increasing the acetylation of histone H3 lysine 27 (H3K27ac). Targeting TMPO-AS1 led to impaired ESCC tumor growth in a patient-derived xenograft (PDX) model. We found that TMPO-AS1 is required for cell proliferation and metastasis in ESCC by promoting the expression of TMPO, and both TMPO-AS1 and TMPO might be potential biomarkers and therapeutic targets in ESCC.

FOXM1 Promotes Malignant Proliferation of Esophageal Squamous Cell Carcinoma Through Transcriptional Activating CDC6.

Forkhead box M1 (FOXM1) is a proliferative transcription factor and plays a vital role in many cancers. However, the function and molecular mechanism of FOXM1 in esophageal squamous cell carcinoma (ESCC) remain poorly understood. Hence, we aim to clarify the molecular basis of FOXM1-mediated ESCC progression. In this study, bioinformatics analysis showed that FOXM1 was mainly involved in key signal pathways, including cell proliferation, cell cycle, and homologous recombination in ESCC, and predicted that CDC6 might be a potential regulatory target gene of FOXM1. The results revealed that FOXM1 and CDC6 were significantly overexpressed in ESCC tissue and cell line, and their expression was positively correlated. Further studies showed that FOXM1 directly transcriptionally activated CDC6 by binding to its promoter region in ESCC cells. Moreover, FOXM1 mediated ESCC cell proliferation by regulating CDC6 expression, which may be related to promoting G1-S phase transition of cell cycle. Taken together, FOXM1-CDC6 axis mediates ESCC malignant proliferation and may serve as a potential biological target for ESCC treatment.

Long noncoding RNA GK-IT1 promotes esophageal squamous cell carcinoma by regulating MAPK1 phosphorylation.

Long noncoding RNAs (lncRNAs) are implicated in the oncogenesis and metastasis of multiple human cancers. Nonetheless, the precise molecular mechanisms underlying the oncogenic role of lncRNA in esophageal squamous cell carcinoma (ESCC) remains to be clarified. The expression of GK intronic transcript 1 (GK-IT1) was analyzed using ESCC RNA-seq data from The Cancer Genome Atlas database. Quantitative real-time PCR was used to measure the expression of GK-IT1 in ESCC clinical samples and cells. The correlation between GK-IT1 expression and clinicopathological variables was examined using chi-squared tests. Kaplan-Meier survival and Cox regression analyses were employed to generate the survival curve and assess the prognostic value of GK-IT1. Functional experiments were utilized to explore the role of GK-IT1 in promoting cell migration, invasion, proliferation, and suppressing apoptosis and autophagy in ESCC. To understand the mechanism, an RNA pulldown assay, RNA immunoprecipitation, agarose gel electrophoresis, immunofluorescence, and co-immunoprecipitation assays were used. In this study we identified an unreported lncRNA, termed GK-IT1 that was aberrantly overexpressed in ESCC tissues and cells. GK-IT1 was closely associated with advanced clinical stage, and it was an independent prognostic indicator of ESCC. Functional assays verified that GK-IT1 significantly promoted ESCC proliferation, invasion, and migration, and suppressed ESCC apoptosis and autophagy. Furthermore, tumorigenesis experiments in nude mice indicated that GK-IT1 promoted ESCC tumor growth and metastasis. Mechanistically, GK-IT1 competitively bound to mitogen-activated protein kinase 1 (MAPK1) to prevent the interaction between dual specificity phosphatase 6 (DUSP6) and MAPK1, thereby controlling the phosphorylation of MAPK1 and promoting ESCC progression. Our study revealed that GK-IT1 competed with DUSP6 to attenuate the interaction between DUSP6 and MAPK1, leading to activation of the ERK/MAPK pathway, thereby promoting progression of ESCC. Our research indicated that GK-IT1 served as a novel potential target for the diagnosis and treatment of ESCC.

Dihydromyricetin mediates epithelial mesenchymal transformation and regulates the proliferation and apoptosis of esophageal squamous cell carcinoma cells

Objective: To study the effects of dihydromyricetin (DMY) on the proliferation, apoptosis and epithelial mesenchymal transition (EMT) of esophageal squamous cell carcinoma (ESCC) cell KYSE150 and KYSE410. Methods: KYSE150 and KYSE410 cells were treated with different concentrations of DMY (0, 25, 50, 100, 150, 200 μmol/L) for 24 hours. The median inhibition concentration (IC50) values of KYSE150 and KYSE410 were detected by cell counting kit-8 (CCK-8) method. Then 0.5‰ dimethyl sulfoxide (DMSO) was used as control group, dihydromyricetin (DMY), dihydromyricetin and transforming growth factor-β1 (DMY+ TGF-β1), transforming growth factor-β1 (TGF-β1) were used as experimental group. Cell proliferation and apoptosis rates were measured by clonal formation and flow cytometry. Transwell invasion and wound healing assay were used to detect cell invasion and migration. The protein expression levels of Caspase-3, Caspase-9, Bcl-2, Bax, Smad2/3, phosphorylation-Smad2/3 (p-Smad2/3) and Vimentin were detected by western blot. Results: The IC50 values of DMY on KYSE410 and KYSE150 cells were 100.51 and 101.27 μmol/L. The clone formation numbers of KYSE150 and KYSE410 in DMY group [(0.53±0.03) and (0.31±0.03)] were lower than those in DMSO group [(1.00±0.10) and (1.00±0.05), P<0.05]. The apoptosis rates of KYSE150 and KYSE410 cells in DMY group [(1.84±0.22)% and (2.80±0.07)%] were higher than those in DMSO group [(1.00±0.18)% and (1.00±0.07)%, P<0.05]. The invasion numbers of KYSE150 and KYSE410 cells in DMY group [(0.42±0.03) and (0.29±0.05)] were lower than those in DMSO group [(1.00±0.08) and (1.00±0.05), P<0.05]. The migration rates of KYSE150 and KYSE410 cells in DMY group [(0.65±0.14)% and (0.40±0.17)%] were lower than those in DMSO group [(1.00±0.10)% and (1.00±0.08)%, P<0.05]. The clone formation numbers of KYSE150 and KYSE410 in TGF-β1 group [(1.01±0.08) and (0.99±0.25)] were higher than those in DMY+ TGF-β1 group [(0.73±0.10) and (0.58±0.05), P<0.05]. The apoptosis rates of KYSE150 and KYSE410 cells in TGF-β1 group [(0.81±0.14)% and (1.18±0.10)%] were lower than those in DMY+ TGF-β1 group [(1.38±0.22)% and (1.85±0.04)%, P<0.05]. The invasion numbers of KYSE150 and KYSE410 cells in TGF-β1 group [(1.19±0.11) and (1.39±0.11)] were higher than those in DMY+ TGF-β1 group [(0.93±0.09) and (0.93±0.05), P<0.05]. The migration rates of KYSE150 and KYSE410 cells in TGF-β1 group [(1.87±0.19)% and (1.32±0.04)%] were higher than those in DMY+ TGF-β1 group [(0.86±0.16)% and (0.77±0.12)%, P<0.05]. The protein expression levels of Bax, Caspase-3 and Caspase-9 in KYSE150 and KYSE410 cells in DMY group were higher than those in DMSO group, while the protein expression level of Bcl-2 was lower than that in DMSO group (P<0.05). The protein expression levels of p-Smad2/3, Smad2/3 and Vimentin in KYSE150 and KYSE410 cells in DMY group were lower than those in DMSO group (P<0.05). The protein expression levels of Bax, Caspase-3 and Caspase-9 in KYSE150 and KYSE410 cells in TGF-β1 group were lower than those in DMY+ TGF-β1 group, and the protein expression level of Bcl-2 was higher than that in DMY+ TGF-β1 group (P<0.05). The protein expression levels of Bax, Caspase-3 and Caspase-9 in KYSE150 and KYSE410 cells in DMY+ TGF-β1 group were lower than those in DMY group, and the protein expression level of Bcl-2 was higher than that in DMY group (P<0.05). The protein expression levels of p-Smad2/3, Smad2/3 and Vimentin in KYSE150 and KYSE410 cells in TGF-β1 group were higher than those in DMY+ TGF-β1 group (P<0.05). Conclusion: DMY can inhibit the proliferation and EMT of ESCC mediated by TGF-β1 and promote cell apoptosis.

CircFAM120B functions as a tumor suppressor in esophageal squamous cell carcinoma via the miR-661/PPM1L axis and the PKR/p38 MAPK/EMT pathway

Extensive changes of circRNA expression underscore their essential contributions to multiple hallmarks of cancers; however, their functions and mechanisms of action in esophageal squamous cell carcinoma (ESCC) remain undetermined. Here, we adopted a three-stage approach by first screening for significantly differentially expressed circRNAs in ESCC and performing an external validation study, followed by the functional analyses. The properties of circRNAs were evaluated using Sanger sequencing, RNase R digestion, actinomycin D treatment, subcellular localization analysis, and fluorescence in situ hybridization. Target transcripts were predicted using online tools and verified by dual-luciferase, RNA immunoprecipitation, qRT-PCR, and western blot. Biotin-labeled RNA-protein pull-down, mass spectrometry, and RNA immunoprecipitation were employed to identify proteins interacting with circRNAs. Gain- and loss-of-function experiments were performed to uncover the roles of circRNAs, their target genes, and binding proteins in the proliferation, metastasis, and invasion. We observed that circFAM120B (hsa_circ_0001666) was frequently downregulated in cancer tissues and patient plasma, and its expression level was related to overall survival in ESCC patients. Overexpression of circFAM120B inhibited the proliferation, metastasis, and invasion of ESCC while silencing it enhanced malignant phenotypes. Mechanistically, circFAM120B was predominantly located in the cytoplasm, guarantying its sponging for miR-661 to restore the expression of PPM1L, a tumor suppressor. We observed that circFAM120B could reduce the stability of RNA-dependent protein kinase (PKR) by promoting its ubiquitination-dependent degradation and subsequently regulating the p38 MAPK signaling pathway, resulting in the repression of EMTs in ESCC cells. Our findings suggest that circFAM120B is a promising biomarker of ESCC, which acts as a tumor suppressor via the circFAM120B/miR-661/PPM1L axis and PKR/p38 MAPK/EMT pathway, supporting its significance as a candidate therapeutic target.

RETRACTED ARTICLE: Down-regulation of kappa opioid receptor promotes ESCC proliferation, invasion and metastasis via the PDK1-AKT signaling pathway

BackgroundAs a class of the opioid receptors, the kappa opioid receptor (KOR) has been verified to be a potential biomarker and therapeutic target for human malignant tumors. However, a thorough understanding of whether KOR affects progression of esophageal squamous cell carcinoma (ESCC) is still lacking. This study focused on exploring the effect of knocking down KOR in ESCC and its underlying mechanism.MethodsBioinformatics analysis was used to compare the different expression level of OPRK1 (KOR gene) in tumor and adjacent normal tissues, and predict the relationship between KOR expression and overall survival. RNA-sequence analysis was performed to detect the altered functions and mechanisms after down regulating KOR. The in vitro and in vivo assays were used to detect the effects of down-regulated KOR on cell proliferation, migration and invasion. Substrate gel zymography and 3D cell culture assays were used to find the effect of KOR knockdown on the degradation of extracellular matrix (ECM), and immunefluorescence was performed to detect the altered cytoskeleton. Western blotting and immunohistochemistry were used to explore the underlying mechanism pathway.ResultsBioinformatics analysis revealed that the expression of OPRK1 was lower in tumor tissue than that in adjacent normal tissues, and lowered expression of KOR was associated with poorer overall survival. The in vitro assays demonstrated that down-regulation of KOR enhanced ESCC proliferation, metastasis and invasion. Western blotting revealed that down-regulation of KOR could activate PDK1-AKT signaling pathway, which actively regulated the cancer progression. Down-regulation of KOR enhanced the formation of invadopodia, secretion of matrix metalloproteinase-2 (MMP2) and rearrangement of cytoskeleton, which were positively related with the invasion of ESCC. KOR knockdown enhanced the tumor invasion and elevated the AKT phosphorylation in nude mice. The AKT kinase inhibition could reverse the effect of down-regulation of KOR.ConclusionKOR might act as a tumor suppressor in ESCC and down-regulation of KOR could enhance the ESCC tumor phenotype.Graphical abstract8saryVZK7ypoVwSXab2T6mVideo

GPx8 regulates apoptosis and autophagy in esophageal squamous cell carcinoma through the IRE1/JNK pathway

Glutathione peroxidase 8 (GPx8) belongs to a family of enzymes that have a critical role in controlling levels of reactive oxygen species (ROS). GPX family members have been associated with several cancers. Here, we examined the role of GPx8 in esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining and western blot analysis were used to study the clinical significance of GPx8 in ESCC tissue. GPx8 was further evaluated in cells by MTT assay and colony formation. RT-PCR, western blot, immunofluorescence staining, TUNEL assay, TEM, and flow cytometry were used to assess the molecular mechanism underlying endoplasmic reticulum (ER) stress associated with GPx8 in ESCC cells. Xenografted tumor growth was used to assess the in vivo role of GPx8. We found that GPx8 was overexpressed in both ESCC cell lines and tumor tissue. GPx8 knockdown significantly suppressed ESCC proliferation and induced autophagy and apoptosis in ESCC cell lines, whereas GPx8 overexpression led to increased proliferation and inhibition of apoptosis. GPx8-mediated inhibition of apoptosis was associated with the ER stress pathway through inositol-requiring enzyme 1 (IRE1) and Jun N-terminal kinase (JNK). Knockdown of GPx8 in xenograft models of ESCC resulted in a significant reduction in tumor weight and volume, which was further reduced with IRE1 or JNK inhibitors. Our study suggests that GPx8 regulates apoptosis and autophagy in ESCC through the IRE1/JNK pathway in response to ER stress. Targeting this pathway might be a potential therapeutic strategy for ESCC.

Oxethazaine inhibits esophageal squamous cell carcinoma proliferation and metastasis by targeting aurora kinase A

Esophageal squamous cell carcinoma (ESCC), a malignant neoplasm with high incidence, is a severe global public health threat. The current modalities used for treating ESCC include surgery, chemotherapy, and radiotherapy. Although ESCC management and treatment strategies have improved over the last decade, the overall 5-year survival rate remains <20%. Therefore, the identification of novel therapeutic strategies that can increase ESCC patient survival rates is urgently needed. Oxethazaine, an amino-amide anesthetic agent, is mainly prescribed in combination with antacids to relieve esophagitis, dyspepsia, and other gastric disorders. In the present study, we found that oxethazaine inhibited the proliferation and migration of esophageal cancer cells. According to the results of in vitro screening and binding assays, oxethazaine binds directly to AURKA, suppresses AURKA activity, and inhibits the downstream effectors of AURKA. Notably, we found that oxethazaine suppressed tumor growth in three patient-derived esophageal xenograft mouse models and tumor metastasis in vivo. Our findings suggest that oxethazaine can inhibit ESCC proliferation and metastasis in vitro and in vivo by targeting AURKA.

METTL3 Facilitates Tumor Progression by COL12A1/MAPK Signaling Pathway in Esophageal Squamous Cell Carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common aggressive tumors in the world. m6A modification has been implicated to play an important role in many biological progressions. METTL3 as the main methyltransferase has been found in many cancers, including ESCC. Here, we investigated the underlying mechanism of METTL3 in the development of ESCC.Methods: Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) and western blot were used to detect METTL3 expression. To evaluate the function of METTL3, MTS, colony formation, scratch wound healing assay, and transwell and invasion assays were performed. To find out the downstream target of METTL3, mRNA sequencing (mRNA-seq) was conducted. GO and KEGG functional enrichment analyses were carried out to predict possible biological processes and signaling pathways. qRT-PCR and western blot were performed to identify the expression of COL12A1 and the phosphorylation status of RAF, MRK and ERK. Cotransfection of small interfering RNA (for METTL3 silence) with plasmid (for overexpression of COL12A1) and the following gain- and loss-of-function experiments were performed to detect the target gene function of COL12A1 in progression of ESCC mediated by METTL3.Results: Using TCGA database, higher METTL3 expression was found in ESCC tissues. Moreover, we found that METTL3 was significantly increased in ESCC patient tissues compared with normal tissues and correlated with poor prognosis. The expression of METTL3 in ESCC cell lines was assessed. The gain- and loss-of-function indicates that METTL3 promotes cell proliferation, migration and invasion. Additionally, we confirmed that METTL3 can promote the expression of COL12A1 and upregulate the phosphorylation of RAF, MER and ERK, and moreover COL12A1 can restrain siMETTL3-mediated inhibition of proliferation, migration and invasion in ESCC.Conclusion: Our study revealed that METTL3 may have an oncogenic role, facilitating the ESCC progression and metastasis by COL12A1/MAPK signaling pathway.

Circular RNA hsa_circ_0003823 promotes the Tumor Progression, Metastasis and Apatinib Resistance of Esophageal Squamous Cell Carcinoma by miR-607/CRISP3 Axis.

Background: Circular RNAs (CircRNAs) have attracted a growing interest of research in cancer. The regulatory roles and mechanisms of circRNAs in progression, metastasis and drug resistance of esophageal squamous cell carcinoma (ESCC) needed to be clarified. Our previous study revealed the crucial role of Apatinib in ESCC therapy. However, the correlation between circRNAs and Apatinib resistance remained unclear.Methods: 3 pairs of tumor and paracancerous tissues of ESCC patients were used for RNA sequencing. Western blot analysis, RNA immunoprecipitation (RIP), dual-luciferase reporter assays, apoptosis and animal assays were conducted to confirm the roles and specific mechanisms of hsa_circ_0003823 as well as the effects of it on Apatinib sensitivity in ESCC.Results: Our results revealed that hsa_circ_0003823 was highly expressed in ESCC and associated with poor prognosis. Further results indicated that hsa_circ_0003823 promoted proliferation and metastasis ability of ESCC. In the section of mechanism experiments, hsa_circ_0003823 regulated CRISP3 by targeting microRNA-607 (miR-607) to promote progression of ESCC. Besides, we found that silencing hsa_circ_0003823 improved Apatinib sensitivity. hsa_circ_0003823 resulted in Apatinib resistance by miR-607/CRISP3 axis.Conclusions: In this study, we elucidated the function of hsa_circ_0003823 and its role in promoting tumor progression, metastasis and Apatinib resistance of ESCC through miR-607/CRISP3 axis.

Retraction.

Retraction: "Silence of HDAC6 suppressed esophageal squamous cell carcinoma proliferation and migration by disrupting chaperone function of HSP90," by Hua Tao, Yuan-Yuan Chen, Zong-Wen Sun, Hua-Lin Chen and Ming Chen, J Cell Biochem. 2018; 6623-6632: The above article, published online on 17 April 2018 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/jcb.26841), has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The retraction has been agreed after the authors asked to correct the article. An investigation revealed several flaws and inconsistencies between results presented and experimental methods described, thus the editors consider the conclusions of this article to be invalid.

Identification of KIF4A as a prognostic biomarker for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the most common and aggressive tumor worldwide, and the long-term survival of these patients remains poor. Three databases (GSE17351, GSE20347, and GSE100942) were obtained from Gene Expression Omnibus, and 193 differentially expressed genes including 56 upregulated and 137 downregulated genes were identified by paired test using limma R package. Then, functional enrichments by gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed these genes were mainly related protein digestion and absorption, and IL-17 signaling pathway. We then constructed a protein-protein interaction network and cytoHubba module to determine the six hub genes and overall survival analysis of the six hub genes were evaluated by UALCAN and GEPIA2 analysis. Ultimately, the experimental results confirmed the KIF4A was overexpressed in the ESCC tissues and cell lines compared with the normal esophageal mucosal tissues and was linked to poor prognosis. Moreover, we also revealed that KIF4A facilitates proliferation, cell cycle, migration, and invasion of ESCC in vivo and in vitro. Overall, these findings demonstrated that KIF4A could serve as diagnostic and prognostic biomarkers and may help facilitate therapeutic targets in ESCC patients.

COL11A1 promotes esophageal squamous cell carcinoma proliferation and metastasis and is inversely regulated by miR-335-5p.

BackgroundEsophagus squamous cell carcinoma (ESCC) is a sort of cancer that occurs in the esophageal epithelial tissue. This study performed integrated bioinformatics analysis of Gene Expression Omnibus (GEO) datasets GSE32424, GSE29968, and GSE130078. Collagen type XI alpha 1 (COL11A1) was identified as the hub gene in ESCC progression. The involvement of COL11A1 in ESCC development was next determined using in vitro functional tests.MethodsHub genes were identified through integrated bioinformatics analysis. The real-time reverse transcription-polymerase chain reaction was implemented for detecting the expression of COL11A1 mRNA in esophageal cancer cells. KYSE-30 cells were transfected using a vector encoding COL11A1. The proliferation of cells was determined using the Cell Counting Kit-8 (CCK-8) assay. Detection of the cell migration and invasion was made through making use of the transwell test. The development of ESCC cells in vivo was evaluated in naked mice. The interplay among COL11A1 and microRNA-335-5p (miR-335-5p) was discovered using a luciferase reporter experiment.ResultsIn vitro studies showed the upregulation of COL11A1 in ESCC cell lines obtained from ESCC patients and upregulation of COL11A1 was correlated with poor disease-free survival of ESCC patients, thereby implying an oncogenic involvement of COL11A1 in ESCC. Overexpression of COL11A1 enhanced the proliferation of ESCC cells, invasion, and migration; whereas COL11A1 knockdown impeded the proliferation of ESCC cells, invasion, and migration. Additionally, miRNA pathway analysis in combination with TargetScan’s online prediction and the luciferase reporter assay suggested miR-335-5p targeting and negatively regulating the COL11A1 3' untranslated region (3'UTR) within ESCC cells. MiR-335-5p overexpression diminished the development of ESCC cells. Additionally, co-expression of COL11A1 ameliorated the repressive influence of miR-335-5p overexpression on the growth and metastasis of ESCC cells.ConclusionsUsing comprehensive bioinformatics analysis, the current study identified COL11A1 as an oncogene in ESCC. The mechanistic studies indicated that COL11A1 promoted ESCC cell progression and that miR-335-5p negatively regulated the expression of COL11A1 in ESCC.

FoXA2 promotes esophageal squamous cell carcinoma progression by ZEB2 activation

BackgroundIt has been reported that Forkhead transcription family member (FOXA2) regulates esophageal squamous cell carcinoma (ESCC) progression. However, the specific mechanism, by which FOXA2 promotes ESCC malignant progression, remains unclear.Materials and methodsQRT-PCR and western blotting were applied to measure FOXA2 expression in ESCC tissues, while CCK-8 assay and Transwell assays were used to investigate the effect of FOXA2 on ESCC. Luciferase reporter assay, followed by fast chromatin immunoprecipitation (ChIP) assay, was used to study the relationship between FOXA2 and ZEB2.ResultsFOXA2 was significantly increased in ESCC tissues, when compared to normal tissues. Moreover, high expression of FOXA2 was also found in ESCC cells. Knockdown of FOXA2 inhibited ESCC cell proliferation, invasion, and migration. Mechanically, FOXA2 was verified to regulate ZEB2 expression at transcription level. Moreover, ZEB2 reversed the inhibitory effect of FOXA2 on ESCC proliferation, invasion, and migration. The relationship between ZEB2 and FOXA2 in ESCC tissues was negative.ConclusionsThese results indicate that FOXA2 plays a critical role in ESCC progression and may become a potential candidate target for ESCC treatment.

Tegaserod Maleate Inhibits Esophageal Squamous Cell Carcinoma Proliferation by Suppressing the Peroxisome Pathway.

Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of esophageal cancer (EC). ESCC accounts for 90% of EC. Recurrence after primary treatment is the main reason for poor survival. Therefore, recurrence prevention is a promising strategy for extending the 5-year survival rate. Here, we found tegaserod maleate could inhibit ESCC proliferation both in vivo and in vitro. Proteomics analysis revealed that tegaserod maleate suppressed the peroxisome signaling pathway, in which the key molecules peroxisome membrane protein 11B (PEX11B) and peroxisome membrane protein 13 (PEX13) were downregulated. The immunofluorescence, catalase activity assay, and reactive oxygen species (ROS) confirmed that downregulation of these proteins was related to impaired peroxisome function. Furthermore, we found that PEX11B and PEX13 were highly expressed in ESCC, and knockout of PEX11B and PEX13 further demonstrated the antitumor effect of tegaserod maleate. Importantly, tegaserod maleate repressed ESCC tumor growth in a patient-derived xenograft (PDX) model in vivo. Our findings conclusively demonstrated that tegaserod maleate inhibits the proliferation of ESCC by suppressing the peroxisome pathway.

TPM3 mediates epithelial-mesenchymal transition in esophageal cancer via MMP2/MMP9.

BackgroundEsophageal cancer (EC) is a malignant tumor with high mortality. Correlations have been found between the expression level of tropomyosin 3 (TPM3) and the depth of tumor invasion, lymph node metastasis, and the 5-year survival rate. However, the specific mechanisms underlying EC remain unclear.MethodsStably transfected TPM3-overexpresing and TPM3-knockdown esophageal squamous cell carcinoma (ESCC) cell lines (ECa109 and EC9706) were constructed, and the association between TPM3 and the proliferation, invasion, and migration of ESCC was investigated using molecular biology methods. The associations between TPM3 and matrix metalloproteinase (MMP)2/9 or epithelial-mesenchymal transition (EMT)-related proteins were verified, and the potential tumor-promoting mechanism was explored by Gelatin Zymography Experiment.ResultsTPM3 was found to promote the proliferation, migration, and metastatic potential of ESCC in vivo and in vitro, and stimulate the expression of MMP2/9 and certain EMT markers other than E-cadherin. The replenishment of MMP2/9 restored the malignant behavior of ESCC caused by TPM3. A gelatinase assay showed that the expression of TPM3 was related to the activity of MMP9.ConclusionsTPM3 promoted proliferation, migration, and metastatic potential in EC cells. Additionally, TPM3 promoted the EMT process. This function may be achieved via the regulation the expression of MMP2/9.