Major Facilitator Superfamily Domain Containing 12 Is Overexpressed in Lung Cancer and Exhibits an Oncogenic Role in Lung Adenocarcinoma Cells.

Major facilitator superfamily domain containing 12 (MFSD12) regulates lysosomal cysteine import and promotes the proliferation and survival of melanoma cells. However, the expression and function of MFSD12 in other cancers, particularly in lung cancer, remain unclear. The expression of MFSD12 across various types of cancers and corresponding control tissues was examined using TIMER. MFSD12 expression in lung adenocarcinoma (LUAD) and its correlation with distinct clinicopathological features of LUAD patients were analyzed with UALCAN. The correlation between MFSD12 expression and survival of LUAD patients was assessed using the R package, survival, and the relationship between MFSD12 expression and immune infiltration status in LUAD was investigated using CIBERSORT. In addition, MFSD12 expression was knocked down in PC9 LUAD cells and their proliferation, capacity for expansion, cell cycle, apoptosis, and migration/invasion were evaluated through CCK-8 assays, colony formation assays, 7-AAD staining, Annexin V/PI staining, and Transwell assays, respectively. The stemness of these PC9 cells was determined through Western blotting, flow cytometry, and tumor sphere formation assays. MFSD12 mRNA levels were significantly elevated in multiple types of cancers, including LUAD. MFSD12 expression was also positively correlated with cancer stage, nodal metastasis, and infiltration of various immune cells in LUAD, and high MFSD12 levels predicted poor survival among LUAD patients. Knockdown of MFSD12 in PC9 cells resulted in decreased proliferation, attenuated colony formation capacity, cell cycle arrest, elevated apoptosis, impaired migration/invasion, and reduced stemness in PC9 cells. MFSD12 is an oncogene in LUAD.

A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance.

Anaplastic lymphoma kinase (ALK) is a highly responsive therapeutic target for ALK-rearranged non-small cell lung cancer (NSCLC). However, patients with this cancer invariably relapse because of the development of ALK inhibitor resistance resulting from mutations within the ALK tyrosine kinase domain. Herein, we report the discovery of dEALK1, a small-molecule degrader of EML4-ALK fusion proteins, with capability of overcoming resistance to ALK inhibitor ceritinib. dEALK1 induces rapid and selective degradation of wild-type (WT) EML4-ALK and mutated EML4-ALKs acquiring resistance to ceritinib, leading to inhibition of cell proliferation and increase of apoptosis in NSCLC cells expressing WT EML4-ALK or ceritinib-resistant EML4-ALK mutants in vitro. Furthermore, dEALK1 also exerts a potent antitumor activity against EML4-ALK-positive xenograft tumors without or with harboring ceritinib-resistant EML4-ALK mutations in vivo. Our study suggests that dEALK1-induced degradation of EML4-ALK fusion proteins is a promising therapeutic strategy for treatment of ALK-rearranged lung cancer with ceritinib resistance.

ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.

Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections.

Neoadjuvant immunotherapy combined with chemotherapy in the treatment of stage III lung squamous cell carcinoma: a retrospective cohort study.

Background: Neoadjuvant immunochemotherapy has been proven to be a successful therapeutic strategy for patients with locally advanced non-small cell lung cancer (NSCLC). Nevertheless, there is a paucity of information regarding surgical feasibility and safety as well as tumor response. The present study aimed to investigate the therapeutic and surgical outcomes for patients with stage III lung squamous cell carcinoma (LSCC). Methods: Patients with stage III potentially resectable LSCC treated with neoadjuvant immunochemotherapy at The First Affiliated Hospital of Ningbo University between March 2020 and June 2022 were retrospectively included. Oncologic outcomes and intraoperative and postoperative variables were assessed. Results: A total of 17 locally advanced LSCC patients were included in the study. Patients in stages IIIA and IIIB were represented by 10 (58.8%) and 7 (41.2%) cases, respectively. A minimally invasive procedure was successfully completed in 12 out of 17 cases (70.6%). A total of 10 patients (58.8%) had standard lobectomies performed, 1 (5.9%) had a bilobectomy, 3 (17.6%) had pneumonectomies, and 1 (5.9%) had a wedge resection. A total of 7 patients (41.2%) experienced postoperative complications, and there were no 30- or 90-day mortalities. The 2-year disease-free survival (DFS) and overall survival (OS) rates were 76.6% and 82.5%, respectively. The rate of major pathological response (MPR) was 70.6%. Conclusions: Lung resection after immunochemotherapy for potentially resectable stage III LSCC is feasible and safe. This treatment strategy results in a significant pathologic response and promising rates of OS at 2 years.

EGFR-Induced and c-Src-Mediated CD47 Phosphorylation Inhibits TRIM21-Dependent Polyubiquitylation and Degradation of CD47 to Promote Tumor Immune Evasion.

Tumor cells often overexpress immune checkpoint proteins, including CD47, for immune evasion. However, whether or how oncogenic activation of receptor tyrosine kinases, which are crucial drivers in tumor development, regulates CD47 expression is unknown. Here, it is demonstrated that epidermal growth factor receptor (EGFR) activation induces CD47 expression by increasing the binding of c-Src to CD47, leading to c-Src-mediated CD47 Y288 phosphorylation. This phosphorylation inhibits the interaction between the ubiquitin E3 ligase TRIM21 and CD47, thereby abrogating TRIM21-mediated CD47 K99/102 polyubiquitylation and CD47 degradation. Knock-in expression of CD47 Y288F reduces CD47 expression, increases macrophage phagocytosis of tumor cells, and inhibits brain tumor growth in mice. In contrast, knock-in expression of CD47 K99/102R elicits the opposite effects compared to CD47 Y288F expression. Importantly, CD47-SIRPα blockade with an anti-CD47 antibody treatment significantly enhances EGFR-targeted cancer therapy. In addition, CD47 expression levels in human glioblastoma (GBM) specimens correlate with EGFR and c-Src activation and aggravation of human GBM. These findings elucidate a novel mechanism underlying CD47 upregulation in EGFR-activated tumor cells and underscore the role of the EGFR-c-Src-TRIM21-CD47 signaling axis in tumor evasion and the potential to improve the current cancer therapy with a combination of CD47 blockade with EGFR-targeted remedy.

Deletion of osteopontin in non-small cell lung cancer cells affects bone metabolism by regulating miR-34c/Notch1 axis: a clue to bone metastasis.

Lung cancer is prone to bone metastasis, and osteopontin (OPN) has an important significance in maintaining bone homeostasis. The goal of this study was to explore the impact of OPN level on bone metabolism and the molecular mechanism of inhibiting bone metastasis in non-small cell lung cancer (NSCLC). The expression of OPN in NSCLC was ascertained by Western blot and immunohistochemistry, and the correlation between the expression level of OPN and survival of patients was analyzed. Then the shRNA technology was applied to reduce the expression of OPN in NSCLC cells, and CCK-8 assay was carried out to investigate the effect of low expression of OPN on the proliferation of NSCLC cells. In addition, the effects of low expression of OPN on osteoclast differentiation, osteoblast generation and mineralization were studied using osteoclast precursor RAW264.7 and human osteoblast SaOS-2 cells, and whether OPN could regulate miR-34c/ Notch pathway to affect bone metabolism was further explored. The findings showed that the high level of OPN in NSCLC was closely related to the poor prognosis of patients and the abnormal proliferation of NSCLC cell lines. The suppression of OPN was beneficial to inhibit the differentiation of osteoclasts and promote the mineralization of osteoblasts. Besides, this study confirmed that the deletion of OPN can regulate bone metabolism through the regulation of miR-34c/Notch1 pathway, which will contribute to inhibiting the occurrence of osteolytic bone metastasis in NSCLC.

The Regulatory Mechanism of Rab21 in Human Diseases.

Rab proteins are important components of small GTPases and play crucial roles in regulating intracellular transportation and cargo delivery. Maintaining the proper functions of Rab proteins is essential for normal cellular activities such as cell signaling, division, and survival. Due to their vital and irreplaceable role in regulating intracellular vesicle transportation, accumulated researches have shown that the abnormalities of Rab proteins and their effectors are closely related to human diseases. Here, this review focused on Rab21, a member of the Rab family, and introduced the structures and functions of Rab21, as well as the regulatory mechanisms of Rab21 in human diseases, including neurodegenerative diseases, cancer, and inflammation. In summary, we described in detail the role of Rab21 in human diseases and provide insights into the potential of Rab21 as a therapeutic target for diseases.

A 20-gene mutation signature predicts the efficacy of immune checkpoint inhibitor therapy in advanced non-small cell lung cancer patients.

BACKGROUND: There is an unmet need to identify novel predictive biomarkers that enable more accurate identification of individuals who can benefit from immune checkpoint inhibitor (ICI) therapy. The US FDA recently approved tumor mutational burden (TMB) score of ≥ 10 mut/Mb as a threshold for pembrolizumab treatment of solid tumors. Our study aimed to test the hypothesis that specific gene mutation signature may predict the efficacy of ICI therapy more precisely than high TMB (≥ 10). METHODS: We selected 20 candidate genes that may predict for the efficacy of ICI therapy by the analysis of data from a published cohort of 350 advanced non-small cell lung cancer (NSCLC) patients. Then, we compared the influences of various gene mutation signatures on the efficacy of ICI treatment. They were also compared with PD-L1 and TMB. The Kaplan-Meier method was utilized to evaluate the prognosis univariates, while selected univariates were adopted to develop a systematic nomogram. RESULTS: A high mutation signature, where three or more of the 20 selected genes were mutated, was associated with the significant benefits of ICI therapy. Specifically, patients with high mutation signature were confirmed to have better prognosis for ICI treatment, compared with those with wild type (the median PFS: 7.17 vs. 2.90 months, p = 0.0004, HR = 0.47 (95% [CI]:0.32-0.68); the median OS: unreached vs. 9 months, p = 1.8E-8, HR = 0.17 (95% [CI]:0.11-0.25)). Moreover, those patients with the high mutation signature achieved significant ICI treatment benefits, while there was no difference of OS and PFS between patients without the signature but TMB-H (≥ 10) and those without the signature and low TMB(< 10). Finally, we constructed a novel nomogram to evaluate the efficacy of ICI therapy. CONCLUSION: A high mutational signature with 3 or more of the 20-gene panel could provide more accurate predictions for the outcomes of ICI therapy than TMB ≥ 10 in NSCLC patients.

Interpreting the Therapeutic Efficiency of Multifunctional Hybrid Nanostructure against Glioblastoma.

Glioblastoma is considered the most fatal malignant brain tumor that starts from the central nervous system (CNS), where the blood-brain barrier (BBB) remains the biggest challenge for active targeting of drugs in malignant brain tumor. Thereby, we have designed a paclitaxel PTX@ANG/FA-NPs hybrid novel nanodrug delivery system that can overcome the clinical BBB. The structural and morphological characterization of PTX@ANG/FA-NPs confirmed successful synthesis of nanomicelles with the size range of about 160 to 170 nm. The overall repressive effect of PTX@ANG/FA-NPs on human glioblastoma U251 cells was 1.2-times that of PTX alone. In vitro cellular uptake assay also demonstrated that the dual-targeted nanoparticles (NPs) were more easily taken up by glioblastoma U251 cells. Although the antiglioblastoma activity was confirmed by cell migration assay, apoptosis assay, and cellular uptake assay, the absorption was studied by in vivo fluorescence imaging and brain distribution. The synthesized PTX@ANG/FA-NPs probe significantly inhibited the migration of U251 within the cells and promoted the apoptosis process. Moreover, the RhB@ANG/FA-NPs and PTX@ANG/FA-NPs showed higher accumulating potential at sites of tumor BBB disruption. The novel nanodrug delivery system mediated enhanced distribution of drugs at the targeted site for therapeutics efficacies against glioblastomas across the BBB.

Experimental Study on Gas Loss Derived from Positive Pressure.

Positive pressure sampling enables the fixed-point and rapid acquisition of coal samples, but the derivation of loss volume during sampling is usually based on the law of gas desorption from granular coal at atmospheric pressure, which seriously affects the reasonableness of loss amounts under positive pressure and thus leads to errors in gas content determination. The gas loss under positive pressure is the key to the accurate determination of the gas content of coal seams. To obtain reliable loss data, under different positive pressures, we tested the gas desorption process of anthracite coal samples with different adsorption equilibrium pressures, analyzed the effect of positive pressure on gas desorption, studied the changes in the gas desorption rate caused by positive pressure, recorded the fluctuation of the amount of gas loss, and compared the values of loss under different conditions. The results show that the positive pressure is the main factor affecting gas desorption compared to the adsorption equilibrium pressure. The positive pressure has an inhibitory influence on gas desorption. Under the same positive pressure, the gas desorption rate shows a decreasing trend over time, and at the same time, the gas desorption rate gradually decreases accompanied by the increasing positive pressure. The gas loss error rate increases with increasing adsorption pressure under the same positive pressure. However, under the same adsorption pressure, the error rate of loss quantity presents a significant increase with positive pressure. The relative error of gas loss under different positive pressures can reach 63-180%, and the positive pressure has an obvious influence on gas loss. This study has experimentally confirmed that positive pressure has a greater effect on gas desorption than adsorption pressure, which will theoretically improve the method of deriving the amount of gas loss and will provide a basis for the accurate determination of gas content under positive pressure in engineering terms.

Effect of vascular endothelial growth factor rs35569394 in esophageal cancer and response to chemotherapy.

The objective of this study was to investigate the possible association between the single nucleotide polymorphism (SNP), rs35569394, of the vascular endothelial growth factor gene (VEGF) and the risk of esophageal cancer (EC) in the Han Chinese population. A total of 290 EC subjects and 322 ethnically matched unrelated healthy controls free from the esophageal disease were studied. Genomic DNA was isolated from peripheral blood by salting out. Genotyping of VEGF rs35569394 polymorphism was carried out via polymerase chain reaction followed by agarose gel electrophoresis. The results showed that the distribution of genotypes was significantly different across the gender groups (p=0.032) and clinical stages (p=0.034). VEGF rs35569394 was associated with EC risk (p= 0.012, OR=1.34). A gender analysis break-down showed that rs35569394-D allele frequency was significantly higher in females than in the controls (p=0.0004, OR=1.81). Moreover, significant associations were also found in females under the dominant model (II versus ID+DD: χ2=8.18, p=0.003, OR=2.12) and the recessive model (II+ID versus DD: χ2=8.25, p=0.004, OR=2.39). Additionally, we found that the genotype, rs35569394-DD, was associated with a complete response + partial response to chemotherapy when compared with rs35569394-II (χ2=4.67, p=0.030, OR=0.47). In conclusion, our case-control study showed that the VEGF rs35569394 was significantly associated with the clinical stages and the increased risk of EC in Han Chinese females. In addition, the genotype rs35569394-DD showed a better response to chemotherapy.

A prognosis model for predicting immunotherapy response of esophageal cancer based on oxidative stress-related signatures.

Oxidative stress (OS) is intimately associated with tumorigenesis and has been considered a potential therapeutic strategy. However, the OS-associated therapeutic target for esophageal squamous cell carcinoma (ESCC) remains unconfirmed. In our study, gene expression data of ESCC and clinical information from public databases were downloaded. Through LASSO-Cox regression analysis, a risk score (RS) signature map of prognosis was constructed and performed external verification with the GSE53625 cohort. The ESTIMATE, xCell, CIBERSORT, TIMER, and ImmuCellAI algorithms were employed to analyze infiltrating immune cells and generate an immune microenvironment (IM). Afterward, functional enrichment analysis clarified the underlying mechanism of the model. Nomogram was utilized for forecasting the survival rate of individual ESCC cases. As a result, we successfully constructed an OS-related genes (OSRGs) model and found that the survival rate of high-risk groups was lower than that of low-risk groups. The AUC of the ROC verified the strong prediction performance of the signal in these two cohorts further. According to independent prognostic analysis, the RS was identified as an independent risk factor for ESCC. The nomogram and follow-up data revealed that the RS possesses favorable predictive value for the prognosis of ESCC patients. qRT-PCR detection demonstrated increased expression of MPC1, COX6C, CYB5R3, CASP7, and CYCS in esophageal cancer patients. In conclusion, we have constructed an OSRGs model for ESCC to predict patients' prognosis, offering a novel insight into the potential application of the OSRGs model in ESCC.

A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages.

Itaconate is a newly discovered endogenous metabolite promoting an anti-inflammatory program during innate immune response, but the precise mechanisms underlying its effect remains poorly understood owing primarily to the limitations of available itaconate-monitoring techniques. Here, we develop and validate a genetically encoded fluorescent itaconate biosensor, BioITA, for directly monitoring itaconate dynamics in subcellular compartments of living macrophages. Utilizing BioITA, we monitor the itaconate dynamics in response to lipopolysaccharide (LPS) stimulation in the context of modulating itaconate transportation and metabolism. Moreover, we show that STING activation induces itaconate production, and injection of AAVs expressing cytosolic BioITA into mice allows directly reporting elevation of itaconate level in activated macrophages derived from LPS-injected mice. Thus, BioITA enables subcellular resolution imaging of itaconate in living macrophages.

ATF4-dependent fructolysis fuels growth of glioblastoma multiforme.

Excessive consumption of fructose in the Western diet contributes to cancer development. However, it is still unclear how cancer cells coordinate glucose and fructose metabolism during tumor malignant progression. We demonstrate here that glioblastoma multiforme (GBM) cells switch their energy supply from glycolysis to fructolysis in response to glucose deprivation. Mechanistically, glucose deprivation induces expression of two essential fructolytic proteins GLUT5 and ALDOB through selectively activating translation of activating transcription factor 4 (ATF4). Functionally, genetic or pharmacological disruption of ATF4-dependent fructolysis significantly inhibits growth and colony formation of GBM cells in vitro and GBM growth in vivo. In addition, ATF4, GLUT5, and ALDOB levels positively correlate with each other in GBM specimens and are poor prognostic indicators in GBM patients. This work highlights ATF4-dependent fructolysis as a metabolic feature and a potential therapeutic target for GBM.

Argininosuccinate lyase drives activation of mutant TERT promoter in glioblastomas.

Cancer-specific TERT promoter mutations have been linked to the reactivation of epigenetically silenced TERT gene by creating de novo binding motifs for E-Twenty-Six transcription factors, especially GABPA. How these mutations switch on TERT from epigenetically repressed states to expressed states have not been defined. Here, we revealed that EGFR activation induces ERK1/2-dependent phosphorylation of argininosuccinate lyase (ASL) at Ser417 (S417), leading to interactions between ASL and GABPA at the mutant regions of TERT promoters. The ASL-generated fumarate inhibits KDM5C, leading to enhanced trimethylation of histone H3 Lys4 (H3K4me3), which in turn promotes the recruitment of c-Myc to TERT promoters for TERT expression. Expression of ASL S417A, which abrogates its binding with GABPA, results in reduced TERT expression, inhibited telomerase activity, shortened telomere length, and impaired brain tumor growth in mice. This study reveals an unrecognized mechanistic insight into epigenetically activation of mutant TERT promoters where GABPA-interacted ASL plays an instrumental role.

Treatment paradigms and survival outcomes in esophageal adenocarcinoma with liver metastasis: a retrospective cohort study using the SEER database.

Background: Esophageal adenocarcinoma with liver metastasis (EACLM) at the time of diagnosis has a poor prognosis and few therapeutic options. The best treatment options and prognostic factors for EACLM patients are unclear. The present study sought to explore the optimal treatment modalities for and the prognosis of these patients. Methods: Patients diagnosed with EACLM at the time of diagnosis were identified from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2015. The last follow-up date was December 31, 2018. Treatment patterns were divided into four groups: local therapy (surgery/radiation), systemic therapy [chemotherapy (CT)], combination therapy (surgery/radiation + CT), and no treatment. The Kaplan-Meier (K-M) method and log-rank test were used for overall survival (OS) and disease-specific survival (DSS). Univariable and multivariable Cox regression were performed to identify the prognostic factors. Propensity score-matching (PSM) analyses were performed for sensitive analyses. Results: A total of 925 patients diagnosed with EACLM were included in the study. The median OS was 12, 10, 3, and 2 months for combination therapy, systemic therapy, local therapy, and no treatment, respectively (P<0.001). After PSM, the patients who received systemic treatment had a better OS (median 9 vs. 2 months; P<0.001) and DSS (median 9 vs. 3 months; P<0.001) than those who received no treatment. Compared to systemic therapy, combination therapy did not increase patients' OS (median 13 vs. 12 months, P=0.069) but did improve their DSS (median 19 vs. 13 months, P=0.048). Conclusions: EACLM patients might benefit the most from systemic therapy and combination therapy. For patients who are well-tolerated, combination therapy should be considered as a preferable option.

Itaconate is a lysosomal inducer that promotes antibacterial innate immunity.

Lysosomes are the main organelles in macrophages for killing invading bacteria. However, the precise mechanism underlying lysosomal biogenesis upon bacterial infection remains enigmatic. We demonstrate here that LPS stimulation increases IRG1-dependent itaconate production, which promotes lysosomal biogenesis by activating the transcription factor, TFEB. Mechanistically, itaconate directly alkylates human TFEB at cysteine 212 (Cys270 in mice) to induce its nuclear localization by antagonizing mTOR-mediated phosphorylation and cytosolic retention. Functionally, abrogation of itaconate synthesis by IRG1/Irg1 knockout or expression of an alkylation-deficient TFEB mutant impairs the antibacterial ability of macrophages in vitro. Furthermore, knockin mice harboring an alkylation-deficient TFEB mutant display elevated susceptibility to Salmonella typhimurium infection, whereas in vivo treatment of OI, a cell-permeable itaconate derivative, limits inflammation. Our study identifies itaconate as an endogenous metabolite that functions as a lysosomal inducer in macrophages in response to bacterial infection, implying the potential therapeutic utility of itaconate in treating human bacterial infection.

The Role of Cancer Stem Cell-Derived Exosomes in Cancer Progression.

Cancer stem cells (CSCs) represent a small portion of tumor cells with self-renewal ability in tumor tissues and are a key factor in tumor resistance, recurrence, and metastasis. CSCs produce a large number of exosomes through various mechanisms, such as paracrine and autocrine signaling. Studies have shown that CSC-derived exosomes (CSC-Exos) carry a variety of gene mutations and specific epigenetic modifications indicative of unique cell phenotypes and metabolic pathways, enabling exchange of information in the tumor microenvironment (TME) to promote tumor invasion and metastasis. In addition, CSC-Exos carry a variety of metabolites, especially proteins and miRNAs, which can activate signaling pathways to further promote tumor development. CSC-Exos have dual effects on cancer development. Due to advances in liquid biopsy technology for early cancer detection, CSCs-Exos may become an important tool for early cancer diagnosis and therapeutic drug delivery. In this article, we will review how CSC-Exos exert the above effects based on the above two aspects and explore their mechanism of action.

C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 7(CXCR7) regulates epithelial-mesenchymal transition process and promotes the metastasis of esophageal cancer by activating signal transducer and activator of transcription 3 (STAT3) pathway.

Esophageal cancer is a malignant tumor of the digestive system that is prone to metastasis. Chemokines and their receptors act an essential role in the occurrence and development of tumors. Here, we investigated the regulatory mechanism of CXCL12/CXCR7 in the growth and metastasis of esophageal cancer. CXCR7 was found highly expressed in clinical tissues and cells of esophageal cancer. Knockdown of CXCR7 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process of esophageal cancer cells. The knockdown of chemokine CXCL12 also inhibited the expression of EMT-related proteins and the mesenchymal morphology changes of esophageal cancer cells, but the knockdown of C-X-C motif chemokine receptor 4 (CXCR4) had no such effect. Furthermore, the knockdown of CXCR7 attenuated the enhanced EMT process induced by CXCL12 overexpression, while the knockdown of CXCR4 cannot inhibit this process. In addition, overexpressed CXCL12/CXCR7 activated the downstream STAT3 pathway, but had little effect on the extracellular regulated protein kinase (ERK) or serine-threonine kinase (AKT) pathways. Inhibition of the STAT3 pathway using AZD9150 weakened the accelerated effects of CXCL12/CXCR7 on the growth and metastasis of esophageal cancer in vitro and in vivo. In conclusion, our research revealed that CXCL12/CXCR7 regulates EMT and other malignant processes by activating the STAT3 pathway to accelerate the growth and metastasis of esophageal cancer.