Metastasis Of Esophageal Cancer Research Articles

The promoting effects of Grin2d expression in tumorigenesis and the aggressiveness of esophageal cancer.

Grin2d is an ionotropic NMDA receptor, a subunit of glutamate-dependent, and a facilitator of cellular calcium influx in neuronal tissue. In this study, we found that Grin2d expression was higher in esophageal cancer than in normal mucosa at both the mRNA and protein level using RT-PCR, bioinformatics analysis, and western blotting (p<0.05). Grin2d mRNA expression was positively correlated with old age, white race, heavy weight, distal location, adenocarcinoma, cancer with Barrett's lesion, or high-grade columnar dysplasia (p<0.05). The differential genes associated with Grin2d mRNA were involved in fat digestion and absorption, cholesterol metabolism, lipid transfer, lipoproteins, synaptic membranes, and ABC transporters (p<0.05). The Grin2d-related genes were classified into the following categories: metabolism of glycerolipids, galactose, and O-glycan, cell adhesion binding, actin binding, cadherin binding, the Hippo signaling pathway, cell-cell junctions, desmosomes, DNA-transcription activator binding, and skin development and differentiation (p<0.05). Grin2d immunoreactivity was positively correlated with distal metastasis and unfavorable overall survival in esophageal cancer (p<0.05). Grin2d overexpression promoted proliferation, migration, and invasion in esophageal cancer cells but blocked apoptosis (p<0.05) and increased the expression of PI3K, Akt and p-mTOR. Grin2d knockout caused the opposite effects. These findings indicated that upregulated Grin2d expression played an important role in esophageal carcinogenesis via the PI3K/Akt/mTOR pathway and might be a biological marker for aggressive tumor behavior and poor prognosis. Its silencing might represent a targeted therapy approach against esophageal cancer.

Noninvasive prediction of metastasis in esophageal cancer using ensemble-based feature selection

Noninvasive prediction of metastasis in esophageal cancer using ensemble-based feature selection

Nomogram based on multimodal magnetic resonance combined with B7-H3mRNA for preoperative lymph node prediction in esophagus cancer.

Accurate preoperative prediction of lymph node metastasis (LNM) in esophageal cancer (EC) patients is of crucial clinical significance for treatment planning and prognosis. To develop a clinical radiomics nomogram that can predict the preoperative lymph node (LN) status in EC patients. A total of 32 EC patients confirmed by clinical pathology (who underwent surgical treatment) were included. Real-time fluorescent quantitative reverse transcription-polymerase chain reaction was used to detect the expression of B7-H3 mRNA in EC tissue obtained during preoperative gastroscopy, and its correlation with LNM was analyzed. Radiomics features were extracted from multi-modal magnetic resonance imaging of EC using Pyradiomics in Python. Feature extraction, data dimensionality reduction, and feature selection were performed using XGBoost model and leave-one-out cross-validation. Multivariable logistic regression analysis was used to establish the prediction model, which included radiomics features, LN status from computed tomography (CT) reports, and B7-H3 mRNA expression, represented by a radiomics nomogram. Receiver operating characteristic area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the predictive performance and clinical application value of the model. The relative expression of B7-H3 mRNA in EC patients with LNM was higher than in those without metastasis, and the difference was statistically significant (P < 0.05). The AUC value in the receiver operating characteristic (ROC) curve was 0.718 (95%CI: 0.528-0.907), with a sensitivity of 0.733 and specificity of 0.706, indicating good diagnostic performance. The individualized clinical prediction nomogram included radiomics features, LN status from CT reports, and B7-H3 mRNA expression. The ROC curve demonstrated good diagnostic value, with an AUC value of 0.765 (95%CI: 0.598-0.931), sensitivity of 0.800, and specificity of 0.706. DCA indicated the practical value of the radiomics nomogram in clinical practice. This study developed a radiomics nomogram that includes radiomics features, LN status from CT reports, and B7-H3 mRNA expression, enabling convenient preoperative individualized prediction of LNM in EC patients.

The antagonistic effect of FTO on METTL14 promotes AKT3 m6A demethylation and the progression of esophageal cancer

BackgroundAs the most abundant modification in eukaryotic messenger RNAs (mRNAs), N6-methyladenosine (m6A) plays vital roles in many biological processes.MethodsMethylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen for m6A targets in esophageal cancer cells and patients. The role of m6A RNA methylase in esophageal cancer was also analyzed using bioinformatics. In vitro and in vivo experiments were used to analyze gene expression and function. CCK-8, colony formation, cell apoptosis and immunofluorescence staining assays were performed to evaluate the proliferation, migration and invasion of esophageal cancer cells, respectively. Western blot analysis, RNA stability, RIP and luciferase reporter assays were performed to elucidate the underlying mechanism involved.ResultsWe found that the m6A demethylase FTO was significantly upregulated in esophageal cancer cell lines and patient tissues. In vivo and in vitro assays demonstrated that FTO was involved in the proliferation and apoptosis of esophageal cancer cells. Moreover, we found that the m6A methyltransferase METTL14 negatively regulates FTO function in esophageal cancer progression. FTO alone is not related to the prognosis of esophageal cancer, and its function is antagonized by METTL14. By using transcriptome-wide m6A-seq and RNA-seq assays, we revealed that AKT3 is a downstream target of FTO and acts in concert to regulate the tumorigenesis and metastasis of esophageal cancer. Taken together, these findings provide insight into m6A-mediated tumorigenesis in esophageal cancer and could lead to the design of new therapeutic strategies.

The Role of Long Noncoding RNAs (lncRNAs) in Esophageal Cancer Therapy Resistance and Metastasis.

Esophageal cancer (EC) is one of the most aggressive gastrointestinal cancers. Despite improvements in therapies, the survival rate of patients with EC remains low. Metastasis accounts for up to 90% of cancer-related deaths, and resistance to anti-neoplastic therapeutics is also a main cause of poor survival. Thus, metastasis and drug resistance are undoubtedly the two main challenges in cancer treatment. Among the different categories of noncoding RNAs, lncRNAs have historically drawn less attention. However, lncRNAs have gradually become a research hotspot, and increasing research has demonstrated that lncRNAs participate in the tumorigenesis of multiple types of cancer, including EC. Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides in length that play important roles in epigenetics, transcription regulation, and posttranscriptional processing. In this review, we elucidated the role of lncRNAs in the metastasis and drug resistance of EC and discussed their potential clinical applications and related limitations. With a better understanding of the underlying mechanisms of lncRNAs, we can identify therapeutic targets for EC in the future.

Cysteine protease inhibitor S promotes lymph node metastasis of esophageal cancer cells via VEGF-MAPK/ERK-MMP9/2 pathway.

Cysteine protease inhibitor S (CST4) plays a pivotal role in the regulation of growth, invasion, and metastasis of a variety of malignancies. However, the potential mechanism behind how CST4 contributes to CST4 in lymph node metastasis (LNM) and tumor-associated lymphangiogenesis of esophageal cancer (EC) cells has not been elucidated previously. Short hairpin RNA technique was utilized to upregulate the CST4 gene expression. Different experiments, including the tubule formation assay and immunofluorescence, were conducted to observe the cellular behavior. Enzyme-linked immunosorbent assay (ELISA) and Western blot analyses were employed to determine the expression levels of relevant proteins. In our study, we discovered that high expression of CST4 in EC cells had multiple effects. It stimulated cell proliferation, invasion, and migration and caused epithelial-mesenchymal transition (EMT). Moreover, it also inhibited the apoptosis of EC cells and caused them to stagnate in the G2/M phase. High expression of CST4 promoted the secretion of lymphangiogenic markers (TGFβ1, VEGF, VEGF-C/D) in EC cells. In addition, high expression of CST4 in EC cells not only enhanced the proliferation and migration of HLECs, but also stimulated the lumen formation and F-actin expression and rearrangement of HLECs. The elevated expression of CST4 also facilitated the secretion of p-ERK1/2, MMP9, and MMP-2 in HLECs. However, various tumor-promoting effects of high expression of CST4 on HLECs could be inhibited by VEGF inhibitors in EC cells. Overall, our findings indicate that CST4 plays a significant role in the accumulation, migration, and EMT of EC cells. CST4 can activate the VEGF-MAPK/ERK-MMP9/2 signaling axis to promote LNM and lymphangiogenesis in EC.

DNMT1-mediated epigenetic suppression of FBXO32 expression promoting cyclin dependent kinase 9 (CDK9) survival and esophageal cancer cell growth

ABSTRACT Esophageal cancer (EC) is a common and serious form of cancer, and while DNA methyltransferase-1 (DNMT1) promotes DNA methylation and carcinogenesis, the role of F-box protein 32 (FBXO32) in EC and its regulation by DNMT1-mediated methylation is still unclear. FBXO32 expression was examined in EC cells with high DNMT1 expression using GSE163735 dataset. RT-qPCR assessed FBXO32 expression in normal and EC cells, and impact of higher FBXO32 expression on cell proliferation, migration, and invasion was evaluated, along with EMT-related proteins. The xenograft model established by injecting EC cells transfected with FBXO32 was used to evaluate tumor growth, apoptosis, and tumor cells proliferation and metastasis. Chromatin immunoprecipitation (ChIP) assay was employed to study the interaction between DNMT1 and FBXO32. HitPredict, co-immunoprecipitation (Co-IP), and Glutathione-S-transferase (GST) pulldown assay analyzed the interaction between FBXO32 and cyclin dependent kinase 9 (CDK9). Finally, the ubiquitination assay identified CDK9 ubiquitination, and its half-life was measured using cycloheximide and confirmed through western blotting. DNMT1 negatively correlated with FBXO32 expression in esophageal cells. High FBXO32 expression was associated with better overall survival in patients. Knockdown of DNMT1 in EC cells increased FBXO32 expression and suppressed malignant phenotypes. FBXO32 repressed EC tumor growth and metastasis in mice. Enrichment of DNMT1 in FBXO32 promoter region led to increased DNA methylation and reduced transcription. Mechanistically, FBXO32 degraded CDK9 through promoting its ubiquitination.

Progress in correlation between lymph node metastasis and prognosis of esophageal cancer

The status of lymph node metastasis is an important parameter affecting the survival of patients with esophageal carcinoma, which is primarily determined by histological type and the depth of invasion. However, affected by pathological features, heterogeneity and individual differences of tumors, the present staging system of lymph node in esophageal carcinoma has not been unified, the rule of lymph node metastasis remains unclear, and the extent of lymphadenectomy is still controversial. Current lymph node staging system for esophageal carcinoma may be not effective enough, which may lead to inaccurate assessment of the stage and affect the clinicians' choice of treatment modalities, or even affect the conclusions of clinical trials. Therefore, it is essential to optimize the current lymph node staging system for esophageal carcinoma to guide the surgery-based multidisciplinary treatment, and effectively to evaluate the therapeutic effects and predict patients' prognosis.

FOXO3a-regulated arginine metabolic plasticity adaptively promotes esophageal cancer proliferation and metastasis.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with a poor prognosis due to a lack of early detection. Indeed, the mechanisms underlying ESCC progression remain unclear. Here, we discovered that abnormal arginine metabolism contributes to ESCC progression. Based on transcriptomic and metabolomic analyses, we found that argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) levels were increased in primary tumor tissues but decreased in lymph-metastatic tumor tissues. Intriguingly, FOXO3a was inversely correlated with ASS1 and ASL in primary and metastatic tumor tissues, suggesting that FOXO3a dissimilarly regulates ASS1 and ASL at different stages of ESCC. Silencing ASS1/ASL inhibited primary tumor growth and promoted metastasis. Conversely, overexpression of ASS1/ASL or increased arginine supply promoted tumor proliferation but suppressed metastasis. In addition, FOXO3a activation inhibited primary tumor growth by repressing ASS1 and ASL transcription, whereas inactivation of FOXO3a impeded metastasis by releasing ASS1 and ASL transcription. Together, the finding sheds light on metastatic reprogramming in ESCC.

Construction and validation of a risk-scoring model to predict lymph node metastasis in T1b-T2 esophageal cancer.

Lymph node status is an important factor in determining preoperative treatment strategies for stage T1b-T2 esophageal cancer (EC). Thus, the aim of this study was to investigate the risk factors for lymph node metastasis (LNM) in T1b-T2 EC and to establish and validate a risk-scoring model to guide the selection of optimal treatment options. Patients who underwent upfront surgery for pT1b-T2 EC between January 2016 and December 2022 were analyzed. On the basis of the independent risk factors determined by multivariate logistic regression analysis, a risk-scoring model for the prediction of LNM was constructed and then validated. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminant ability of the model. The incidence of LNM was 33.5% (214/638) in our cohort, 33.4% (169/506) in the primary cohort and 34.1% (45/132) in the validation cohort. Multivariate analysis confirmed that primary site, tumor grade, tumor size, depth, and lymphovascular invasion were independent risk factors for LNM (all P < 0.05), and patients were grouped based on these factors. A 7-point risk-scoring model based on these variables had good predictive accuracy in both the primary cohort (AUC, 0.749; 95% confidence interval 0.709-0.786) and the validation cohort (AUC, 0.738; 95% confidence interval 0.655-0.811). A novel risk-scoring model for lymph node metastasis was established to guide the optimal treatment of patients with T1b-T2 EC.

Location-based prediction model for Crohn’s disease regarding a novel serological marker, anti-chitinase 3-like 1 autoantibodies

Esophageal cancer (EC) has a high incidence and mortality rate and is emerging as one of the most common health problems globally. Owing to the lack of sensitive detection methods, uncontrollable rapid metastasis, and pervasive treatment resistance, EC is often diagnosed in advanced stages and is susceptible to local recurrence. Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis, progression, and therapeutic resistance of EC. Considering the critical role of exosomes in tumor pathogenesis, this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance. Here, we summarized the relevant signaling pathways involved in these processes. In addition, we discussed the potential clinical applications of exosomes for the early diagnosis, prognosis, and treatment of EC.

Global burden of inflammatory bowel disease 1990-2019: A systematic examination of the disease burden and twenty-year forecast

Esophageal cancer (EC) has a high incidence and mortality rate and is emerging as one of the most common health problems globally. Owing to the lack of sensitive detection methods, uncontrollable rapid metastasis, and pervasive treatment resistance, EC is often diagnosed in advanced stages and is susceptible to local recurrence. Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis, progression, and therapeutic resistance of EC. Considering the critical role of exosomes in tumor pathogenesis, this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance. Here, we summarized the relevant signaling pathways involved in these processes. In addition, we discussed the potential clinical applications of exosomes for the early diagnosis, prognosis, and treatment of EC.

Time series analysis-based seasonal autoregressive fractionally integrated moving average to estimate hepatitis B and C epidemics in China

BACKGROUND Hepatitis B (HB) and hepatitis C (HC) place the largest burden in China, and a goal of eliminating them as a major public health threat by 2030 has been set. Making more informed and accurate forecasts of their spread is essential for developing effective strategies, heightening the requirement for early warning to deal with such a major public health threat. AIM To monitor HB and HC epidemics by the design of a paradigmatic seasonal autoregressive fractionally integrated moving average (SARFIMA) for projections into 2030, and to compare the effectiveness with the seasonal autoregressive integrated moving average (SARIMA). METHODS Monthly HB and HC incidence cases in China were obtained from January 2004 to June 2023. Descriptive analysis and the Hodrick-Prescott method were employed to identify trends and seasonality. Two periods (from January 2004 to June 2022 and from January 2004 to December 2015, respectively) were used as the training sets to develop both models, while the remaining periods served as the test sets to evaluate the forecasting accuracy. RESULTS There were incidents of 23400874 HB cases and 3590867 HC cases from January 2004 to June 2023. Overall, HB remained steady [average annual percentage change (AAPC) = 0.44, 95% confidence interval (95%CI): -0.94-1.84] while HC was increasing (AAPC = 8.91, 95%CI: 6.98-10.88), and both had a peak in March and a trough in February. In the 12-step-ahead HB forecast, the mean absolute deviation (15211.94), root mean square error (18762.94), mean absolute percentage error (0.17), mean error rate (0.15), and root mean square percentage error (0.25) under the best SARFIMA (3, 0, 0) (0, 0.449, 2)12 were smaller than those under the best SARIMA (3, 0, 0) (0, 1, 2)12 (16867.71, 20775.12, 0.19, 0.17, and 0.27, respectively). Similar results were also observed for the 90-step-ahead HB, 12-step-ahead HC, and 90-step-ahead HC forecasts. The predicted HB incidents totaled 9865400 (95%CI: 7508093-12222709) cases and HC totaled 1659485 (95%CI: 856681-2462290) cases during 2023-2030. CONCLUSION Under current interventions, China faces enormous challenges to eliminate HB and HC epidemics by 2030, and effective strategies must be reinforced. The integration of SARFIMA into public health for the management of HB and HC epidemics can potentially result in more informed and efficient interventions, surpassing the capabilities of SARIMA.

Global burden of inflammatory bowel disease 1990-2019: A systematic examination of the disease burden and twenty-year forecast

BACKGROUND Inflammatory bowel disease (IBD) is an idiopathic intestinal disease with various levels and trends in different countries and regions. Understanding the current burden and trends of IBD in various geographical locations is essential to establish effective strategies for prevention and treatment. We report the average annual percentage change (AAPC) and estimated annual percentage change (EAPC) in age-standardized rates (ASR) of IBD in different regions based on the Global Burden of Disease (GBD) study from 1990-2019, and the relationships between IBD and the human development index (HDI) and socio-demographic index (SDI). The prevalence trends of IBD were predicted by gender from 2019-2039. AIM To comprehensively investigate IBD data, providing further insights into the management of this chronic disease. METHODS We collected the information on the incidence of IBD from the GBD study from 1990-2019 to calculate the AAPC and EAPC in ASR of IBD in different regions. The relationships between IBD, HDI, and SDI were analyzed. The Nordpred and Bayesian age-period-cohort models were used to predict the prevalence trends of IBD by gender from 2019-2039, and the reliability of the results was validated. Statistics of all the data in this study were performed using R software (version 4.2.1). RESULTS North America consistently had the highest IBD ASR, while Oceania consistently had the lowest. East Asia had the fastest average annual growth in ASR (2.54%), whereas Central Europe had the fastest decline (1.38%). Countries with a low age-standardized incidence rates in 1990 showed faster growth in IBD while there was no significant correlation in 2019. Additionally, IBD increased faster in countries with a low age-standardized death rates in 1990, whereas the opposite was true in 2019. Analysis of SDI and IBD ASR showed that countries with a high SDI generally had a higher IBD ASR. Finally, the projections showed a declining trend in the incidence of IBD from 2019-2039, but a gradual increase in the number of cases. CONCLUSION As the global population increases and ages, early monitoring and prevention of IBD is important to reduce the disease burden, especially in countries with a high incidence of IBD.

Role of exosomes in metastasis and therapeutic resistance in esophageal cancer

Esophageal cancer (EC) has a high incidence and mortality rate and is emerging as one of the most common health problems globally. Owing to the lack of sensitive detection methods, uncontrollable rapid metastasis, and pervasive treatment resistance, EC is often diagnosed in advanced stages and is susceptible to local recurrence. Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis, progression, and therapeutic resistance of EC. Considering the critical role of exosomes in tumor pathogenesis, this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance. Here, we summarized the relevant signaling pathways involved in these processes. In addition, we discussed the potential clinical applications of exosomes for the early diagnosis, prognosis, and treatment of EC.

The association between histological subtypes and lymph node metastasis and prognosis in early esophageal cancer: a population-based study.

There is still a lack of high-level clinical evidence and uniform conclusions on whether there are differences in lymph node metastasis (LNM) and prognosis between early esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Patients with surgically resected, histologically diagnosed, pT1 EAC or ESCC in the Surveillance, Epidemiology and End Results registries database from 2004 to 2015 were included. Multivariable logistic regression, Cox regression, multivariate competing risk model, and propensity score matching were used to analyze association the histology and LNM or prognosis. A total of 570 early esophageal cancer patients were included. The LNM rates were 13.8% and 15.1% for EAC and ESCC ( P = 0.757), respectively. Multivariate logistic regression analysis showed no significant association between histological type and LNM (odds ratio [OR], 1.209; 95% CI, 0.538-2.715; P = 0.646). Moreover, the prognosis of early EAC and ESCC was shown to be comparable in both multivariate Cox regression (hazard ratio [HR], 1.483; 95% CI, 0.699-3.150; P = 0.305) and the multivariate competing risk model (subdistribution HR, 1.451; 95% CI, 0.628-3.354; P = 0.383). After propensity score matching, there were no significant differences between early EAC and ESCC in terms of LNM (10.6% vs.18.2%, P = 0.215), 5-year CSS (89.8% [95% CI, 81.0%-98.6%] vs. 79.1% [95% CI, 67.9%-90.3%], P = 0.102) and 5-year cumulative incidence of CSS (10.2% [95% CI, 1.4%-19.0%] vs. 79.1% [95% CI, 9.7%-32.1%], P = 0.124). The risk of LNM and prognosis of early ESCC and EAC are comparable, so the treatment choice for early esophageal cancer does not depend on the histologic type.

Outcome of selective neck dissection for cervical lymph node recurrence or residual lymph node metastasis of oesophageal cancer.

Outcome of selective neck dissection for cervical lymph node recurrence or residual lymph node metastasis of oesophageal cancer.

Prediction of lymph node metastasis in early esophageal cancer.

Given the poor prognosis of patients with lymph node metastasis, estimating the lymph node status in patients with early esophageal cancer is crucial. Indicators that could be used to predict lymph node metastasis in early esophageal cancer have been reported in many recent studies, but no recent studies have included a review of this subject. To review indicators predicting lymph node metastasis in early esophageal squamous cell carcinoma (ESCC) and early esophageal adenocarcinoma (EAC). We searched PubMed with "[early esophageal cancer (Title/Abstract)] and [lymph node (Title/Abstract)]" or "[early esophageal carcinoma (Title/Abstract)] and [lymph node (Title/Abstract)]" or "[superficial esophageal cancer (Title/Abstract)] and [lymph node (Title/Abstract)]." A total of 29 studies were eligible for analysis. Preoperative imaging (size), serum markers (microRNA-218), postoperative pathology and immunohistochemical analysis (depth of invasion, tumor size, differentiation grade, lymphovascular invasion, neural invasion, expression of PIM-1 < 30%) were predictive factors for lymph node metastasis in both early ESCC and EAC. Serum markers (thymidine kinase 1 ≥ 3.38 pmol/L; cytokeratin 19 fragment antigen 21-1 > 3.30 ng/mL; stathmin-1) and postoperative pathology and immunohistochemical analysis (overexpression of cortactin, mixed-lineage leukaemia 2, and stanniocalcin-1) were predictive for lymph node metastasis in early ESCC. Transcription of CD69, myeloid differentiation protein 88 and toll-like receptor 4 and low expression of olfactomedin 4 were predictive of lymph node metastasis in early EAC. A total of 6 comprehensive models for early ESCC, including logistic regression model, nomogram, and artificial neural network (ANN), were reviewed. The areas under the receiver operating characteristic curve of these models reached 0.789-0.938, and the ANN performed best. As all these models relied on postoperative pathology, further models focusing on serum markers, imaging and immunohistochemical indicators are still needed. Various factors were predictive of lymph node metastasis in early esophageal cancer, and present comprehensive models predicting lymph node metastasis in early ESCC mainly relied on postoperative pathology. Further studies focusing on serum markers, imaging and immunohistochemical indicators are still in need.

A protein complex of LCN2, LOXL2 and MMP9 facilitates tumor metastasis in esophageal cancer.

During malignant tumor development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodeling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of esophageal squamous cell carcinoma (ESCC) cells, as well as tumor growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumor growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumor cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican-1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3β signaling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumor progression through multiple mechanisms, and could be a potential therapeutic target.

KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer.

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer, but its function and regulatory network in metastasis remain unclear. A comprehensive investigation of key regulators in cancer metastasis is urgently needed. Transcriptome sequencing (RNA-seq) of primary esophageal squamous cell carcinoma (ESCC) and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4 (KCTD4) as a driver of cancer metastasis. KCTD4 expression was found upregulated in metastatic ESCC. High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis invitro and invivo. Mechanistically, KCTD4 binds to CLIC1 and disrupts its dimerization, thus increasing intracellular Ca2+ level to enhance NFATc1-dependent fibronectin transcription. KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner, which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback. Furthermore, a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4‒CLIC1 interaction, providing a potential therapeutic strategy. Taken together, our study not only uncovers KCTD4 as a regulator of calcium homeostasis, but also reveals KCTD4/CLIC1-Ca2+-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis. These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.