Human Esophageal Squamous Cell Carcinoma Tissues Research Articles

Effect of PLCE1-driven aerobic glycolysis through ENO1 modulation on immune evasion in esophageal squamous cell carcinoma (ESCC).

e16016 Background: Our prior investigations have demonstrated that PLCE1 actively promotes tumorigenesis, angiogenesis, and cell cycle progression in ESCC. However, the precise role of PLCE1 in glycolysis and its influence on the tumor immune microenvironment (TIME) remain elusive. Methods: To elucidate potential pathways regulated by PLCE1, we applied Affymetrix GeneChip, Affymetrix ClariomD Array, and IP-MS techniques to identify molecules interacting with PLCE1. Subsequently, we validated the involement of PLCE1 in glycolysis through assessments of glycolytic product production in both in vivo and in vitro assays. The underlying mechanisms by which PLCE1 influences glycolysis were further probed through a combination of IP assays, tumor growth experiments, and ubiquitination assays. Next, we conducted multi-color immunofluorescence staining to examine the infiltration of immune cells in human ESCC tissues. We utilized a transgenic PLCE1-/- C57BL/6 mice model to investigate the immune cell distribution in TIME. Results: PLCE1 emerges as a pivotal regulator in glycolytic processes within ESCC cell lines. Knockdown of PLCE1 instigates a notable attenuation of glycolysis, achieved through the modulation of ENO1 expression, a key enzyme in glycolysis. This effect was also observed in vivo. We have elucidated a novel pathway in which PLCE1 orchestrates a reduction in the expression of FBXW7, an E3 ubiquitin ligase, thereby attenuating FBXW7-mediated ubiquitination of ENO1 and fostering ENO1 stability. Based on mutations identified through sequencing of ESCC tissue and drawing from previous studies, we have pinpointed the specific interacting sites between FBXW7 and ENO1. Substrate phosphorylation is necessary for the recognition of FBXW7. We unveil a mechanism wherein PLCE1 interacts with CDK2 to augment ENO1 phosphorylation, potentiating FBXW7 recognition. Nonetheless, CDK2-mediated ENO1 phosphorylation fails to elicit FBXW7-mediated ubiquitination due to limited FBXW7 expression in ESCC. Elevated tumor glycolysis induced by PLCE1 via ENO1 engenders heightened lactate production, thereby dampening cytokine production and CD8+ T cell activation. In human ESCC tissues, a diminished CD8+ T cell population is observed proximal to PLCE1+ENO1+ tumor cells, concomitant with an augmented accumulation of exhausted CD8+ PD1+ T cells in their vicinity. In an ESCC murine model, a more robust infiltration and cytokine production, coupled with diminished PD-1 expression on both CD4+ and CD8+ T cells, is noted in the PLCE1-/- genotype. This effect was particularly prominent upon ENO1 inhibitor administration. Conclusions: Our investigation elucidates that PLCE1 orchestrates the glycolytic pathway in ESCC by upregulating the expression of ENO1, consequently hindering the infiltration and activation of CD8+ T cells, thus fostering an immunosuppressive TIME.

Nur77-IRF1 axis inhibits esophageal squamous cell carcinoma growth and improves anti-PD-1 treatment efficacy

The nuclear receptor Nur77 plays paradoxical roles in numerous cancers. However, whether Nur77 inhibits esophageal squamous cell carcinoma (ESCC) growth and affects immunological responses against ESCC has not been determined. The functional role of Nur77 in ESCC was investigated in this study using human ESCC cell lines, quantitative real-time polymerase chain reaction (PCR), cell proliferation and colony formation assays, flow cytometry analysis, western blotting and animal models. The target gene controlled by Nur77 was verified using dual-luciferase reporter assays, chromatin immunoprecipitation analysis and functional rescue experiments. To examine the clinical importance of Nur77, 72 human primary ESCC tissues were subjected to immunohistochemistry. Taken together, these findings showed that, both in vitro and in vivo, Nur77 dramatically reduced ESCC cell growth and triggered apoptosis. Nur77 directly interacts with the interferon regulatory factor 1 (IRF1) promoter to inhibit its activity in ESCC. Pharmacological induction of Nur77 using cytosporone B (CsnB) inhibited ESCC cell proliferation and promoted apoptosis both in vitro and in vivo. Furthermore, CsnB increased CD8+ T-cell infiltration and cytotoxicity to inhibit the formation of ESCC tumors in an immunocompetent mouse model. In ESCC tissues, Nur77 expression was downregulated, and IRF1 expression was increased; moreover, their expression levels were negatively related. IRF1 and Nur77 were strongly correlated with overall survival. These findings suggested that Nur77 targets and regulates the IRF1/PD-L1 axis to serve as a tumor suppressor in ESCC.Graphical abstract of the regulatory mechanism of Nur77 overexpression downregulates IRF1 in the inhibition of ESCC progression and enhance anti-PD-1 therapy efficacy.

AURKA knockdown inhibits esophageal squamous cell carcinoma progression through ferroptosis

Aurora kinase A, as a pro-carcinogenic in gastric cancer and glioma kinase, is enhanced in several human tumors. However, it's regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, this study aimed to investigate the expression status, functional roles, and molecular mechanisms of AURKA in ESCC development. AURKA expression was analyzed by the screening of the GEO database and detected using an immunohistochemical method. The biological function of AURKA on ESCC was evaluated in vitro and in vivo. Western blot assay, malondialdehyde (MDA), iron, and glutathione (GSH) kits were utilized to assess changes in ferroptosis. Database analysis results showed that AURKA was a differential gene in ESCC and was highly expressed in human ESCC tissues. Functionally, AURKA knockdown decreased ESCC cell proliferation, invasion, and metastasis both in vitro and in vivo. Moreover, when AURKA was knockdown, cells were more correctly blocked in the G2/M phase, and the ferroptosis-related MDA and Fe increased, whereas the GSH reduced. Consistently, Glutathione peroxidase 4 (GPX4) and solute carrier family 7a member 11 (SLC7A11) expression were downregulated by AURKA knockdown. However, ferroptosis inhibitor partially restore ESCC cell proliferation, invasion, and metastasis caused by AURKA knockdown. AURKA knockdown enhances ferroptosis and acts against cancer progression in ESCC. AURKA acts as a tumor-promoting gene and may serve as potential target for ESCC treatment.

RSK4 promotes the macrophage recruitment and M2 polarization in esophageal squamous cell carcinoma

High infiltration of tumor-associated macrophages (TAMs) participates in host immunity and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Ribosomal s6 kinase 4 (RSK4) has been shown to be aberrantly overexpressed in ESCC. The role of RSK4 in cytokine secretion and its impact on macrophage recruitment and M2 polarization remains unclear. Therefore, a thorough understanding of RSK4 is needed to expand our knowledge of its therapeutic potential. Herein, RSK4 expression in human ESCC tissues and a xenograft mouse model was positively correlated with high infiltration of M0 and M2 macrophages which is positively associated with unfavorable overall survival outcomes and treatment resistance in patients with ESCC. In vitro experiments revealed that RSK4 derived from ESCC cells promoted macrophage recruitment and M2 polarization by enhancingsoluble intercellular adhesion molecule-1 (sICAM-1) secretion via direct and indirect STAT3 phosphorylation. Furthermore, RSK4-induced macrophages enhanced tumor proliferation, migration, and invasion by secreting C-C motif chemokine ligand 22 (CCL22). We further showed that patients with elevated CD68 and CD206 expression had unfavorable overall survival. Collectively, these results demonstrate that RSK4 promotes the macrophage recruitment and M2 polarization by regulating the STAT3/ICAM-1 axis in ESCC, influencing tumor progression primarily in a CCL22-dependent manner. These data also offer valuable insights for developing novel agents for the treatment of ESCC.

IFI16 Induced by Direct Interaction between Esophageal Squamous Cell Carcinomas and Macrophages Promotes Tumor Progression via Secretion of IL-1α.

Tumor-associated macrophages (TAMs), one of the major components of the tumor microenvironment, contribute to the progression of esophageal squamous cell carcinoma (ESCC). We previously established a direct co-culture system of human ESCC cells and macrophages and reported the promotion of malignant phenotypes, such as survival, growth, and migration, in ESCC cells. These findings suggested that direct interactions between cancer cells and macrophages contribute to the malignancy of ESCC, but its underlying mechanisms remain unclear. In this study, we compared the expression levels of the interferon-induced genes between mono- and co-cultured ESCC cells using a cDNA microarray and found that interferon-inducible protein 16 (IFI16) was most significantly upregulated in co-cultured ESCC cells. IFI16 knockdown suppressed malignant phenotypes and also decreased the secretion of interleukin-1α (IL-1α) from ESCC cells. Additionally, recombinant IL-1α enhanced malignant phenotypes of ESCC cells through the Erk and NF-κB signaling. Immunohistochemistry revealed that high IFI16 expression in human ESCC tissues tended to be associated with disease-free survival and was significantly associated with tumor depth, lymph node metastasis, and macrophage infiltration. The results of this study reveal that IFI16 is involved in ESCC progression via IL-1α and imply the potential of IFI16 as a novel prognostic factor for ESCC.

Association between circ_0004365 and cisplatin resistance in esophageal squamous cell carcinoma.

Cisplatin is one of the most predominant drugs for the chemotherapy of esophageal squamous cell carcinoma (ESCC); however, the underlying resistance mechanisms are still almost unknown. The present study performed RNA sequencing of human circular RNA (circRNA) in TE11 cells and cisplatin-resistant TE11 cells (TE11R). The expression profiles determined using CIRCexplorer2 revealed that the expression of circ_0004365, mapped on the Semaphorin 3C gene, was significantly greater in TE11R compared with in TE11. In reverse transcription-quantitative PCR, circ_0004365 expression was observed in human ESCC and non-tumor tissues and was significantly upregulated in ESCC tumor tissues after chemotherapy. Circ_0004365 expression was significantly upregulated in patients with poor pathological response (P=0.02). Furthermore, patients with advanced pT stage showed an upregulation in circ_0004365 expression after chemotherapy (P=0.02). The MTT assay revealed that knockdown of circ_0003465 in TE11 significantly decreased resistance to cisplatin. In conclusion, the present study suggested that circ_0004365 was associated with cisplatin resistance in ESCC and can be used as both a novel biomarker and a therapeutic target.

Hypoxia-responsive lncRNA G077640 promotes ESCC tumorigenesis via the H2AX-HIF1α-glycolysis axis.

Long noncoding RNAs (lncRNAs) contribute to esophageal squamous cell carcinoma (ESCC) progression, but the underlying mechanisms remain elusive. In this study, we verified a hitherto uncharacterized hypoxia-responsive lncRNA, G077640, which is upregulated in human ESCC cells and tissues, supporting the proliferation and migration of ESCC cells. Mechanistically, G077640 prevented hypoxia-inducible factor-1α (HIF1α) from being degraded by directly interacting with histone H2AX and further modulated the interaction of HIF1α and H2AX. In addition, G077640 reprogrammed glycolytic metabolism by regulating the expression of glucose transporter 4 (GLUT4), hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1) for ESCC proliferation and migration. Clinically, G077640 was associated with poor prognosis in ESCC patients. Taken together, our findings identified a hypoxia-responsive lncRNA that contributes to ESCC cells proliferation and migration, and targeting G077640 and its pathway might be a potential therapeutic strategy for ESCC.

CCT4 knockdown enhances the sensitivity of cisplatin by inhibiting glycolysis in human esophageal squamous cell carcinomas.

Esophageal squamous cell carcinoma (ESCC) is a common human malignancy characterized by late-stage diagnosis, metastasis, and poor prognosis. Cisplatin (DDP)-based chemotherapy has been the most predominant treatment for patients with ESCC. However, the high rate of DDP resistance and toxicity seriously hinder its clinical application. Then, the optimized strategy and mechanisms for ESCC to enhance DDP sensitivity are in great demand. Accumulating evidence have shown that chaperone proteins are closely related to the tumorigenesis and drug resistance of cancers. Chaperonin containing TCP1 complex 4 (CCT4) is a recent identified member of the family. However, its expression and function in ESCC have not been well illustrated. In this study, we found that CCT4 was highly expressed in human ESCC tissues and cell lines, and closely related to the poor prognosis. Moreover, CCT4 silence raised oxidative stress and inhibited glycolysis of ESCC cells, which significantly inhibited cell proliferation and migration, promoted apoptosis and caused cell cycle arrest in ESCC cells. Interestingly, CCT4 knockdown enhanced the sensitivity of KYSE150 cells to DDP by regulating AMPK/AKT/Nrf2 signaling pathway and inhibiting glycolysis ability. Taken together, our results indicate that targeting CCT4 may be a therapeutic target in ESCC patients, which provides a theoretical basis to enhance the sensitivity of DDP in ESCC.

COQ10B Knockdown Modulates Cell Proliferation, Invasion, Migration, and Apoptosis in Esophageal Squamous Cell Carcinoma.

Objective Esophageal squamous-cell carcinoma (ESCC) is an aggressive malignant tumor, accounting for more than 90% of esophageal cancers. However, treatments such as surgical resection, radiotherapy, and chemotherapy are unable to achieve ideal clinical outcomes. The purpose of this study was to explore the effects of COQ10B on proliferation, apoptosis, migration, and invasion of esophageal squamous-cell carcinoma (ESCC) cells. Methods Quantitative real-time PCR (qRT-PCR) was used to detect the expression of COQ10B in ESCC and normal tissues and in ESCC cell lines (KYSE-150 and TE-1). MTT assay and flow cytometry were applied to investigate the effects of COQ10B shRNA lentivirus (LV-shCOQ10B) on ESCC cell proliferation and apoptosis, respectively. The effect of COQ10B silencing on ESCC cell migration and invasion was determined by wound healing assay and transwell invasion assay, respectively. Results The expression of COQ10B mRNA in ESCC tissues was higher than that in surrounding tissues. The decreased COQ10B level in KYSE-150 and TE-1 cells by LV-shCOQ10B could inhibit cell proliferation, promote cell apoptosis, and reduce the ability of invasion and migration (all P < 0.05). Conclusion COQ10B was highly expressed in human ESCC tissues. COQ10B silencing contributed to the inhibition of proliferation, invasion, and migration of ESCC cells and the promotion of cell apoptosis, suggesting COQ10B may be a potential molecular target for the diagnosis and treatment of ESCC.

MELK predicts poor prognosis and promotes metastasis in esophageal squamous cell carcinoma via activating the NF‑κB pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide with a low 5-year survival rate due to the lack of effective therapeutic strategies. Accumulating evidence has indicated that maternal embryonic leucine zipper kinase (MELK) is highly expressed in several tumors and associated with tumor development. However, the biological effects of MELK in ESCC remain unknown. In the present study, cell phenotypical experiments and animal metastasis assays were performed to detect the influence of MELK knockdown in vitro and in vivo. The potential molecular mechanism of MELK-mediated ESCC metastasis was further investigated by western blotting and immunofluorescence staining. The results revealed that the expression of MELK in human ESCC tissues was higher than that in adjacent normal tissues and was positively associated with the poor prognosis of patients. Reducing MELK expression resulted in growth inhibition and suppression of the invasive ability of ESCC cells in vitro and in vivo. MELK inhibition induced alterations of epithelial-mesenchymal transition-associated proteins. Mechanistically, MELK interacted with IκB kinase (IKK) and promoted the phosphorylation of IKK, by which MELK regulated activation of the NF-κB pathway. Collectively, the present study revealed the function and mechanism of MELK in the cell metastasis of ESCC, which may be a potential therapeutic target for ESCC.

Cystathionine-β-synthase (CBS)/H2S system promotes lymph node metastasis of esophageal squamous cell carcinoma (ESCC) by activating SIRT1.

Lymph node metastasis is a key factor of death and prognosis in patients with esophageal squamous cell carcinoma (ESCC). Previous studies have demonstrated that Cystathionine-β-synthase (CBS)/H2S system plays important roles in progression of various cancer. However, the function and mechanism of CBS/H2S system in lymph node metastasis of ESCC remains unclear. Here, we found that CBS was highly expressed in human ESCC tissues and closely associated with lymph node metastasis in ESCC patients. Functional studies demonstrated that CBS could significantly promote lymph node metastasis of ESCC tumor cells. In vitro, CBS knockdown inhibited tumor cell proliferation, migration and invasion, whereas CBS overexpression produced the opposite results. In vivo, downregulation of CBS distinctly inhibited ESCC tumor growth and lymphatic metastasis, as evidenced by the decreased size and weight of tumor and popliteal lymph node. Meanwhile, we also found high expression of CBS-induced ESCC angiogenesis and lymphangiogenesis in vitro and in vivo by upregulating VEGF, VEGF-C, and VEGF-D. Mechanistically, CBS up-regulated the expression of SIRT1 and thus interrupted the Notch1/Hes1 axis, which plays a crucial role in lymph node metastasis of ESCC. Moreover, it was demonstrated that H2S derived from CBS-activated SIRT1 via increasing the NAD+/NADH ratio and promoting the phosphorylation of SIRT1. In addition, H2S derived from CBS also enhanced SIRT1 protein stability. Taken together, these data show that the high expression of CBS/H2S system promotes ESCC lymph node metastasis via activating SIRT1 signaling pathway and CBS could serve as a potential therapeutic target for clinical intervention in ESCC.

Inhibition of BRD4 Suppresses the Growth of Esophageal Squamous Cell Carcinoma

Background Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on histones to facilitate the epigenetic regulation of many genes, and it plays a key role in many cancer types. Despite many prior reports that have explored the importance of BRD4 in oncogenesis and the regulation of epigenetic memory, its role in esophageal squamous cell carcinoma (ESCC) progression is poorly understood. Here, we investigated BRD4 expression in human ESCC tissues to understand how it regulates the biology of these tumor cells. Methods BRD4 expression in ESCC tissues was measured via immunohistochemical staining. BRD4 inhibition in the Eca-109 and KYSE-150 ESCC cell lines was conducted to explore its functional role in these tumor cells. Results BRD4 overexpression was observed in ESCC tissues and cells, and inhibiting the function of the gene impaired the proliferative, invasive, and migratory activity of these cells while promoting their apoptosis. Cyclin D1 and c-Myc expression were also suppressed by BRD4 inhibition, and the expression of key epithelial-mesenchymal transition markers including E-cadherin and Vimentin was markedly altered by such inhibition. Conclusions BRD4 plays key functional roles in the biology of ESCC, proposing that it could be a viable therapeutic target for treating this cancer type.

Long Non-Coding RNA OIP5-AS1 Inhibits the Proliferation and Migration of Esophageal Squamous Carcinoma Cells by Targeting FOXD1/miR-30a-5p Axis and the Effect of Micro- and Nano-Particles on Targeting Transfection System.

Esophageal cancer is one of the most common human malignancies and ranks sixth for global mortality; the major histological type is esophageal squamous cell carcinoma (ESCC). Here we assessed the effect of long non-coding (lnc) RNA OIP5-AS1 on the miR-30a-5p/Forkhead box protein D1 (FOXD1) axis in ESCC and investigated the underlying mechanism involving the ERK1/2 signaling pathway. lnc RNA OIP5-AS1 was highly expressed in human ESCC tissues and cells, targeted miR-30a-5p, and inhibited miR-30a-5p expression. Additionally, in human ESCC tissues, miR-30a-5p was poorly expressed, whereas FOXD1 mRNA and protein were highly expressed, with a negative correlation between miR-30a-5p and FOXD1 expression. miR-30a-5p targeted and inhibited FOXD1 expression. FOXD1 promoted the proliferation and invasion of ESCC and was related to the ERK1/2 signaling pathway; ERK1/2 inhibitors (LY-3214996) reversed the biological function of FOXD1. miR-30a-5p combined with FOXD1 regulated ERK1/2 expression and inhibited tumor growth in vivo. In this study, micro- and nano-particles were used as carriers to construct Nanocapsules carrying miR-30a-5p mimics and miR-30a-5p inhibitor through self-assembly method, so as to realize an efficient Nanocapsules delivery system of miR-30a-5p to esophageal cancer cells. It provides insights into targeted drug therapy and the development of micro- and nano-particles carriers.

MiR-4306 Suppresses Proliferation of Esophageal Squamous Cell Carcinoma Cell by Targeting SIX3.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and the primary cause of cancer-related mortality in China. micoRNA plays a vital role during tumor initiation and malignant progression. miR-4306 has been reported to negatively regulate aggressive cell phenotypes in triple-negative breast cancer (TNBC). Nevertheless, the function of miR-4306 in ESCC was still not clear. In this study, we detected miR-4306 expression by quantitative real-time reverse transcription-PCR (qRT-PCR) and found that miR-4306 expression was downregulated in human ESCC tissue samples and cell lines. Moreover, miR-4306 overexpression could restrain ESCC cell proliferation, migratory and invasive ability and epithelial-mesenchymal transition (EMT), promote cell apoptosis after treatment with or without cisplatin. In contrast, inhibiting the expression of miR-4306 showed the opposing results. Furthermore, we explored the molecular mechanism of effects of miR-4306 and found that miR-4306 inhibited the expression of SIX3 by interaction with SIX3 3'UTR in ESCC cells, and SIX3 overexpression significantly reversed the effect of miR-4306-mediated ESCC cells proliferation. The current study provided evidence of miR-4306 as a tumor suppression gene in ESCC.

YAP/TEAD4-induced KIF4A contributes to the progression and worse prognosis of esophageal squamous cell carcinoma.

Aberrant expression of kinesin family member 4A (KIF4A), which is associated with tumor progression, has been reported in several types of cancer. However, its expression and the underlying molecular mechanisms regulating the transcription of KIF4A in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that high KIF4A expression was positively correlated with tumor stage and poor prognosis in ESCC patients. KIF4A silencing significantly inhibited the growth and migration of ESCC cells, arrested cell cycle, and induced apoptosis. Interestingly, KIF4A expression was positively related to the expression of YAP in human ESCC tissues. YAP knockdown or disrupting YAP/TEAD4 interaction by verteporfin repressed KIF4A expression. Also, KIF4A knockdown significantly inhibited the cell growth induced by YAP overexpression. Mechanistically, YAP activated KIF4A transcriptional expression by TEAD4-mediated direct binding to KIF4A promoter. Finally, KIF4A knockdown and verteporfin treatment synergistically inhibited tumor growth in xenograft models. Together, these results indicated that KIF4A, a novel target gene of YAP/TEAD4, may be a progression and prognostic biomarker of ESCC. Targeting drugs for KIF4A combined with YAP inhibitor may be a novel therapeutic strategy for ESCC.

KDM6B promotes ESCC cell proliferation and metastasis by facilitating C/EBP\u03b2 transcription

BackgroundAs an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression, KDM6B has been implicated in the development and malignant progression in various types of cancers. However, its potential roles in esophageal squamous cell carcinoma (ESCC) have not been explored.MethodsThe expression of KDM6B in human ESCC tissues and cell lines was examined using RT-qPCR, immunohistochemical staining and immunoblotting. The effects of KDM6B on the proliferation and metastasis of ESCC were examined using in vitro and in vivo functional tests. RNA-seq and ChIP-seq assay were used to demonstrate the molecular biological mechanism of KDM6B in ESCC.ResultsWe show that the expression level of KDM6B increased significantly in patients with lymph node metastasis. Furthermore, we confirmed that KDM6B knockdown reduces proliferation and metastasis of ESCC cells, while KDM6B overexpression has the opposite effects. Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFκB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPβ, leading to the promotion of C/EBPβ transcription. Besides, we show that GSK-J4, a chemical inhibitor of KDM6B, markedly inhibits proliferation and metastasis of ESCC cells.ConclusionsThe present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPβ depending on its H3K27 demethylase activity.

Up-regulation of SOCS4 promotes cell proliferation and migration in esophageal squamous cell carcinoma.

BackgroundSuppressors of cytokine signaling family member 4 (SOCS4) was shown to serve critical and multifaceted roles in the progression of numerous cancers, including hepatocellular carcinoma, thyroid cancer, breast cancer, and lung adenocarcinoma. While, the expression and the roles of SOCS4 in esophageal squamous cell carcinoma (ESCC) remain elusive. The current study is aimed to investigate the expression pattern and functions of SOCS4 in ESCC.MethodsThe relationship between SOCS4 and the clinicopathological features of ESCC was analyzed. SOCS4 expression in ESCC tissues was measured by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemical (IHC) staining. The roles of SOCS4 in modulating ESCC cell behaviors were examined using a series of assays, including cell proliferation assay, cell counting kit-8 (CCK-8) assay, cell cycle analysis, and wound-healing assay.ResultsIn human ESCC tissues, SOCS4 expression was up-regulated and correlated with tumor size and lymph node metastasis, however was not correlated with the overall survival (OS) of patients. SOCS4 silencing in ESCC cells resulted in the suppression of cell growth, which was related to the cell cycle. SOCS4 knockdown also inhibited nuclear factor-kappa B (NF-κB) signaling and decreased the migratory potential of ESCC cells.ConclusionsThese findings revealed that increased expression of SOCS4 in ESCC may promote the progression, proliferation, and migration by NF-κB signaling. Inhibition of SOCS4 may be a promising therapeutic strategy for ESCC.

Knockdown of TRIM15 inhibits the proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inactivation of the Wnt/β-catenin signaling pathway.

TRIM15 is a member of tripartite motif-containing protein (TRIM) protein family, which plays important roles in several cancers. The aim of the present study was to evaluate the role of TRIM15 in esophageal squamous cell carcinoma (ESCC). Our results showed that TRIM15 was upregulated in human ESCC tissues and cell lines. In vitro studies showed that knockdown of TRIM15 significantly inhibited the proliferation, migration, and invasion of ESCC cells. Knockdown of TRIM15 caused a significant increase in E-cadherin expression, as well as decreases in expression of N-cadherin and Vimentin proteins. Moreover, in vivo assay proved that tumor growth was suppressed by knockdown of TRIM15. Furthermore, the protein expression levels of β-catenin, C-myc, and CyclinD1 were markedly decreased in sh-TRIM15-infected ESCC cells. Additionally, treatment with LiCl reversed the inhibitory effects of TRIM15 knockdown on ESCC cells. In conclusion, these findings indicated that knockdown of TRIM15 blocked the growth and metastasis of ESCC in part through inhibiting the Wnt/β-catenin signaling pathway. Thus, TRIM15 might serve as a promising therapeutic target for ESCC.

Eomes promotes esophageal carcinoma progression by recruiting Treg cells through the CCL20-CCR6 pathway.

Eomesodermin (Eomes) is a T‐box transcription factor that drives the differentiation and function of cytotoxic lymphocytes. However, the underlying function and mechanism of Eomes in tumor cells remains elusive. Here, we studied the role of Eomes in human esophageal squamous cell carcinoma (ESCC). Using 2 human ESCC cell lines, we found that Eomes knockdown reduced esophageal cancer cell proliferation and that the esophageal cancer cell cycle was blocked in the G2/M phase. Mechanistically, we identified CCL20 as the main downstream target of Eomes. Furthermore, we found that CCL20 could chemoregulate regulatory T cells (Tregs) through their specific receptor CCR6, then promoting the proliferation of esophageal cancer cells. Eomes knockdown also delayed the growth of human ESCC xenografts in BALB/c nude mice. Importantly, in 133 human ESCC tissues, high Eomes levels were associated with poor clinical prognosis. Overall, our findings suggested that the Eomes‐CCL20‐CCR6 pathway plays a vital role in human ESCC progress. Therefore, targeting this pathway may represent a promising strategy for controlling human ESCC.

Matrix metalloproteinase-14 (MMP-14) downregulation inhibits esophageal squamous cell carcinoma cell migration, invasion, and proliferation.

BackgroundMatrix metalloproteinase‐14 (MMP‐14) is known to be a key regulator of oncogenesis and tumor progression. The present study was designed to assess the relationship between the downregulation of MMP‐14 and the in vitro proliferative, migratory, and invasive activity of esophageal squamous cell carcinoma (ESCC) cells.MethodsMMP‐14 expression in human ESCC and paracancerous normal esophageal tissue samples was evaluated via immunohistochemistry, and correlations between MMP‐14 staining and patient clinicopathological features were examined. In addition, siRNA was used to knockdown MMP‐14 in ESCC cells, and the proliferation and invasive activity of these cells were then evaluated via MTT and Transwell assays, respectively. Flow cytometry was additionally used to assess cell cycle progression, while Western blotting was employed to measure protein levels within these cells.ResultsESCC samples were found to exhibit MMP‐14 overexpression relative to paracancerous tissue samples, and this overexpression was positively correlated with tumor T classification (T1‐2 vs. T3; P < 0.05), N classification (negative vs. positive; P < 0.001), degree of differentiation (G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05) and clinical stage (I–IIA vs. IIB–III; P < 0.05). When MMP‐14 was knocked down in ESCC cells, this induced cell cycle arrest, impairing their proliferative and invasive activity.ConclusionsMMP‐14 is a key regulator of the proliferation and invasion of ESCC cells, making it a viable therapeutic target for the treatment of this cancer.