Dynamic Alteration in HLA-E Expression and Soluble HLA-E via Interaction with Natural Killer Cells in Gastric Cancer.

BACKGROUND: Some reports showed the immune tolerance of soluble human leukocyte antigen E (HLA-E), but the role that soluble HLA-E plays in gastric cancer (GC) is unknown. We aimed to clarify the molecular mechanism and clinical significance of soluble HLA-E in GC. METHODS: We examined the expression of HLA-E on GC cells and soluble HLA-E under co-culture with natural killer (NK) cells in a time-dependent manner. Changes in NK cell activity were investigated using anti-NK group 2 member A (NKG2A) antibodies in the presence of soluble HLA-E. Expression of soluble HLA-E in the serum of GC patients was determined. RESULTS: Whereas HLA-E expression on GC cells peaked with interferon (IFN)-γ secretion by NK cells in a time-dependent manner, soluble HLA-E was upregulated in conditioned medium. Pre-incubation with anti-NKG2A antibodies increased the activation of NKG2A+ NK cells in the presence of soluble HLA-E. Expression of soluble HLA-E in the serum of GC patients correlated with disease progression. CONCLUSIONS: HLA-E expression dynamically changes on GC cells and in conditioned medium. Furthermore, soluble HLA-E can contribute to immune escape in GC cell lines, which may have significance in clinical practice. Moreover, soluble HLA-E may be a potential prognostic biomarker.

Comprehensive Analysis of Multiple Primary Cancers in Patients With Esophageal Squamous Cell Carcinoma Undergoing Esophagectomy.

OBJECTIVE: The aim of this study was to elucidate the latest epidemiology and risk factors for multiple primary cancers (MPCs), and the association between neoadjuvant chemotherapy (NAC) and postoperative metachronous cancer (PMC) in patients with esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy. SUMMARY OF BACKGROUND DATA: Background data to derive appropriate screening strategies are insufficient. METHODS: This study consisted of 3 retrospective investigations. A total of 766 consecutive patients with ESCC who underwent esophagectomy between April 2005 and December 2019 were eligible for epidemiological analysis. Of these, 688 patients without missing data were analyzed for the risk of MPCs. In total, 364 patients who underwent NAC (115) and no preoperative treatments (249) were investigated for the association between NAC and PMC. RESULTS: Of 766 patients, 288 (38%) patients experienced 357 MPCs in their life. PMCs identified after the completion of 5-year postoperative follow-up were significantly more advanced (P = 0.019). Male sex [hazard ratio (HR) = 3.04, P = 0.038], older age (HR = 2.39, P < 0.001), and diabetes mellitus (HR = 1.76, P = 0.034) were risk factors for preoperative metachronous cancers. Heavy smoking (HR = 1.70, P = 0.014) and drinking (HR = 1.61, P = 0.029) were risk factors for synchronous cancers. NAC significantly reduced PMC incidence ( P = 0.043). NAC showed a trend to contribute to improved survival via reduced deaths from PMCs, although this did not reach significance ( P = 0.082). CONCLUSIONS: ESCC is associated with a high risk of MPCs. Continuing follow-up for PMCs after the completion of 5-year postoperative follow-up is important. NAC may reduce PMCs, representing a novel mechanism for improving survival in patients with locally advanced ESCC.

Evaluation of HLA-E Expression Combined with Natural Killer Cell Status as a Prognostic Factor for Advanced Gastric Cancer.

BACKGROUND: The NKG2A/HLA-E pathway functions as an immune checkpoint with potential for inhibition using therapeutic antibodies. Through this pathway, immune cells lose activity, which allows cancers to progress. We aimed to determine whether HLA-E expression combined with NK cell status serves as a prognostic biomarker for gastric cancer (GC). METHODS: We enrolled patients (n = 232) with advanced GC who underwent curative gastrectomy. Immunohistochemical analyses of global HLA-E expression, and the expression of CD56 and CD3 to identify NK cells were performed. Survival analysis was performed to evaluate the significance of HLA-E expression and NK status. RESULTS: Patients with HLA-E-positive was 104 (41.3%) and had significantly worse prognosis of relapse-free survival (RFS) compared with those with HLA-E-negative. Moreover, patients with NK Low status had worse prognoses for RFS compared with those with NK High status. Statistical analysis of RFS demonstrated that HLA-E expression was a significant independent factor for poor prognosis (HR 1.57, 95% CI 1.04-2.36, P = 0.031). Furthermore, HLA-E-positive patients with low NK low status experienced the shortest RFS, particularly those in the upper GC group. CONCLUSIONS: HLA-E served as a prognostic factor after curative resection of GC, and HLA-E expression combined with NK status served as a sensitive prognostic biomarker for advanced GC.

Prophylactic laparoscopic total gastrectomy for gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): the first report in Asia.

A 41-year-old woman was admitted to our hospital for epigastralgia. She had been admitted to another hospital for fundic gland polyposis (FGP) without any symptoms, and no malignancy had been noted in her previous endoscopy. However, a biopsy performed at our hospital revealed adenocarcinoma, and computed tomography (CT) revealed multiple liver and peritoneal metastases. We clinically suspected gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and indicated genetic testing. The point mutation in exon 1B of APC was revealed. She was diagnosed with GAPPS with multiple liver metastases and underwent systemic chemotherapy. She has two older brothers who also have FGP. The same genomic mutation was observed in both brothers and their mother, and they were also diagnosed with GAPPS. The brothers underwent prophylactic laparoscopic total gastrectomy with D1 lymph-node dissection.

Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer.

BACKGROUND: The predictive significance of programmed death ligand 1 (PD-L1) for programmed death 1 (PD-1) inhibitors remains unclear in gastric cancer (GC) due to the dynamic alteration by treatments. We aimed to elucidate the effects of trastuzumab (Tmab) on PD-L1 expression in GC. METHODS: PD-L1 expression was evaluated by multicolour flow cytometry analysis after co-culturing GG cell lines and immune cells with Tmab. IFN-γ in the co-culture experiments was quantified. Immunohistochemistry (IHC) for PD-L1 expression using clinical samples was also performed to confirm PD-L1 alteration by Tmab. RESULTS: PD-L1 expression was significantly upregulated by Tmab in HER2-amplified GC cell lines co-cultured with peripheral blood mononuclear cells (PBMCs). PD-L1 upregulation by Tmab was also observed in the GC cells co-cultured with NK cells in time-dependent manner, but not with monocytes. IFN-γ concentration in conditioned media from co-cultured PBMCs and NK cells with Tmab was significantly higher and anti-IFN-γ significantly suppress the Tmab-induced PD-L1 upregulation. IHC also suggested PD-L1 upregulation after Tmab treatment. CONCLUSIONS: Tmab can upregulate PD-L1 expression on GC cells through interaction with NK cells. These results suggest clinical implications in the assessment of the predictive significance of PD-L1 expression for PD-1 inhibitors.

Oligometastatic recurrence as a prognostic factor after curative resection of esophageal squamous cell carcinoma.

PURPOSE: In recent years, the concept of oligometastasis, which represents limited metastatic disease, has gained much interest. This study focuses on the oligometastatic recurrence (OLR) of esophageal squamous cell carcinoma (ESCC) after esophagectomy. METHODS: From among 514 patients who underwent curative resection for ESCC at our hospital between April 2005 and December 2019, 97 patients with recurrence were enrolled in this study. OLR was defined as fewer than five recurrences in a single organ. We analyzed the prognostic factors for patients with OLR after curative resection of ESCC, especially the relationship between the recurrence pattern and prognosis according to treatment, defined as metastasis-directed therapy (MDT) and chemotherapy with local therapy as combined local therapy (CLT). RESULTS: OLR was identified in 43 (44%) of the 97 patients with recurrence. The OLR group had a significantly better prognosis than the non-OLR group (P = 0.003). Multivariate analysis revealed that OLR was a prognostic factor after recurrence (P = 0.007) and that CLT after recurrence was the only prognostic factor in the OLR group (P = 0.024). CONCLUSIONS: The findings of this study suggest that OLR is a prognostic factor after resection of ESCC and that CLT is a promising treatment modality for patients with OLR after curative resection of ESCC.

Correction: Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

[This corrects the article DOI: 10.1371/journal.pgen.1005778.].

The role of FBXW7, a cell-cycle regulator, as a predictive marker of recurrence of gastrointestinal stromal tumors.

BACKGROUND: Few reliable prognostic markers have been established despite elucidation of the molecular mechanisms of gastrointestinal stromal tumor (GIST) development. We evaluated F-box and WD repeat domain-containing 7 (FBXW7), a cell-cycle-regulating and tumor suppressor, in GISTs. We aimed to determine the clinical relevance of FBXW7 in GISTs and characterize the molecular mechanism of FBXW7 in a GIST cell line. METHODS: We measured FBXW7 expression in 182 GIST cases, correlated the expression levels with clinicopathological features, and characterized the molecular mechanism underlying suppressed FBXW7 expression in GIST cells in vitro. RESULTS: Of the 182 GISTs, 98 (53.8%) and 84 (46.2%) were categorized in the high and low FBXW7 expression groups, respectively. Compared with the high FBXW7 expression group, the low expression group showed a significantly poorer prognosis in terms of recurrence-free (P = 0.01) and overall (P = 0.03) survival. FBXW7 expression was a significant independent factor affecting the 10-year recurrence-free survival rate (P = 0.04). In vitro, FBXW7-specific siRNAs enhanced c-myc and Notch 1 protein expression and upregulated cell proliferation, invasion, and migration. CONCLUSION: FBXW7 is a potential predictive marker of recurrence after curative resection of GISTs. FBXW7 expression may help identify patients benefitting from adjuvant therapy more precisely compared with a conventional risk stratification model.

Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer.

Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.

Assessment of Sarcopenia as a Predictor of Poor Outcomes After Esophagectomy in Elderly Patients With Esophageal Cancer.

OBJECTIVE: The objective of the study was to elucidate the impact of sarcopenia in elderly patients with esophageal cancer on postoperative complications and long-term survival after surgery for esophageal cancer. SUMMARY BACKGROUND DATA: Sarcopenia, defined as loss of skeletal muscle mass with age, has been identified as a poor prognostic factor for malignancies. This retrospective study investigated the effect of sarcopenia on surgical outcomes among young and elderly patients with esophageal cancer. METHODS: Data were collected for 341 consecutive patients who underwent esophagectomy for esophageal cancer. Patients were assigned to 2 groups according to age (younger than 65 years and 65 years or older) and the presence of sarcopenia. RESULTS: Sarcopenia was present in 170 of 341 patients (49.9%) with esophageal cancer and in 74 of 166 elderly patients (44.6%). The incidence of anastomotic leak and in-hospital death was significantly higher in the elderly sarcopenia group than in the elderly nonsarcopenia group (31.5% vs 15.2%, P = 0.015, 6.8 vs 0.0%, P = 0.037, respectively), and the overall survival rate in patients with sarcopenia correlated with a significantly poor prognosis in the elderly group (P < 0.001). Multivariate analysis revealed that sarcopenia was a risk factor for an anastomotic leak (P = 0.034) and was an unfavorable prognostic factor for survival (P < 0.001). Those correlations between sarcopenia and surgical outcomes were not observed in the young group. CONCLUSIONS: Sarcopenia and worse surgical outcomes were significantly associated patients with in esophageal cancer aged 65 years and older but not in those younger than 65 years.

Colorectal Cancer Stem Cells Acquire Chemoresistance Through the Upregulation of F-Box/WD Repeat-Containing Protein 7 and the Consequent Degradation of c-Myc.

The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. Chugai previously established an LGR5+ human colorectal cancer (CRC) stem-cell-enriched cell line (colorectal CSCs) that expresses well-accepted colorectal CSC markers and that can dynamically switch between proliferative and drug-resistant noncycling states. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, we found that c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7), as evidenced through FBXW7-small interfering RNA knockdown experiments that resulted in enhanced cell sensitivity to anticancer agents. Upregulation of FBXW7 following drug treatment was not evident in commercially available cancer cell lines. Colorectal CSCs were induced to differentiation by Matrigel and fetal bovine serum. Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents. Inhibition of FBXW7-upregulation in CSCs following chemotherapy may enhance the response to anticancer agents and represents an attractive strategy for the elimination of colorectal CSCs. Stem Cells 2017;35:2027-2036.

Controlling Nutritional Status (CONUT) score is a prognostic marker for gastric cancer patients after curative resection.

BACKGROUND: Controlling Nutritional Status (CONUT), as calculated from serum albumin, total cholesterol concentration, and total lymphocyte count, was previously shown to be useful for nutritional assessment. The current study investigated the potential use of CONUT as a prognostic marker in gastric cancer patients after curative resection. METHODS: Preoperative CONUT was retrospectively calculated in 416 gastric cancer patients who underwent curative resection at Kumamoto University Hospital from 2005 to 2014. The patients were divided into two groups: CONUT-high (≥4) and CONUT-low (≤3), according to time-dependent receiver operating characteristic (ROC) analysis. The associations of CONUT with clinicopathological factors and survival were evaluated. RESULTS: CONUT-high patients were significantly older (p < 0.001) and had a lower body mass index (p = 0.019), deeper invasion (p < 0.001), higher serum carcinoembryonic antigen (p = 0.037), and higher serum carbohydrate antigen 19-9 (p = 0.007) compared with CONUT-low patients. CONUT-high patients had significantly poorer overall survival (OS) compared with CONUT-low patients according to univariate and multivariate analyses (hazard ratio: 5.09, 95% confidence interval 3.12-8.30, p < 0.001). In time-dependent ROC analysis, CONUT had a higher area under the ROC curve (AUC) for the prediction of 5-year OS than the neutrophil lymphocyte ratio, the Modified Glasgow Prognostic Score, or pStage. When the time-dependent AUC curve was used to predict OS, CONUT tended to maintain its predictive accuracy for long-term survival at a significantly higher level for an extended period after surgery when compared with the other markers tested. CONCLUSIONS: CONUT is useful for not only estimating nutritional status but also for predicting long-term OS in gastric cancer patients after curative resection.

Sarcopenia is an independent predictor of complications after colorectal cancer surgery.

PURPOSE: The significance of sarcopenia after colorectal cancer (CRC) resection has only been discussed with relatively small samples or short follow-up periods. This study aimed to clarify the clinical significance of sarcopenia in a large-sample study. METHODS: We retrospectively analyzed the relationship between sarcopenia and clinical factors, surgical outcomes, and the survival in 494 patients who underwent CRC surgery between 2004 and 2013. Sarcopenia was defined based on the sex-specific skeletal muscle mass index measured by preoperative computed tomography. RESULTS: Sarcopenia was associated with sex (higher rate of male, P < 0.0001), and low body mass index (P < 0.0001), but not age or tumor stage. Sarcopenia was associated with higher incidence of all postoperative complications (P = 0.02), especially for patients with Clavien-Dindo classification grade ≥2 (CDC; P = 0.0007). Postoperative hospital stays were significantly longer for sarcopenic patients than for non-sarcopenic patients (P = 0.02). In a multivariate analysis, sarcopenia was an independent predictor for postoperative complications (P = 0.01, odds ratio 1.82, 95% confidence interval 1.13-3.00). Among postoperative complications (CDC grade ≥2), sarcopenia was correlated with non-surgical-site infections (P = 0.03). Sarcopenia was not correlated with the overall or recurrence-free survival. CONCLUSIONS: Sarcopenia was an independent predictive factor for postoperative complications after CRC surgery.

Prognostic Significance of Sarcopenia in Patients with Esophagogastric Junction Cancer or Upper Gastric Cancer.

BACKGROUND: The association between sarcopenia and postoperative outcomes for patients with gastrointestinal malignancies remains controversial. This study aimed to assess the impact of sarcopenia on short- and long-term outcomes after surgery for esophagogastric junction cancer (EGJC) or upper gastric cancer (UGC). METHODS: The study reviewed 148 patients with EGJC or UGC who underwent surgical resection. The patients were categorized into the sarcopenia group or the non-sarcopenia group according to their skeletal muscle index calculated using abdominal computed tomography images. The study compared clinicopathologic factors, postoperative complications, and prognosis between the two groups. RESULTS: Sarcopenia was present in 19 patients (32.2%) with EGJC and 23 patients (25.8%) with UGC. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were significantly poorer in the sarcopenia group than in the non-sarcopenia group (OS 85.5 vs 54.8%, P = 0.0010; RFS 78.7 vs 51.7%, P = 0.0054). The development of postoperative complications did not differ significantly between the two groups. Both the uni- and multivariate analyses showed that N stage (P < 0.0001) and sarcopenia (P = 0.0024 and 0.0293, respectively) were independent poor prognostic factors for OS. CONCLUSIONS: Sarcopenia was strongly associated with a poor long-term prognosis for patients with EGJC or UGC who underwent surgery. The results suggest that special attention might be needed during the development of treatment strategies for patients with sarcopenia who intend to undergo operations for EGJC and UGC.

The Presence of Serum p53 Antibody Predicts the Pathological Tumor Response to Neoadjuvant Chemotherapy with Docetaxel, Cisplatin and Fluorouracil (DCF) in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Docetaxel, cisplatin and fluorouracil (DCF) is a candidate neoadjuvant chemotherapy (NAC) regimen for esophageal squamous cell carcinoma (ESCC). Although the efficacy and safety of DCF have been reported, the markers that predict the patient's response are still unknown. The aim of this study was to identify the predictive markers for a response to NAC with DCF in patients with ESCC. METHODS: A total of 79 patients who received preoperative DCF followed by esophagectomy between August 2008 and December 2014 were enrolled in this study. All of the patients completed 2 preoperative courses of DCF. The clinical and pathological responses to DCF were investigated, and the associations between the pathological response, the clinicopathological factors and the prognosis were retrospectively analyzed. RESULTS: Among the 79 patients, the pathological response to DCF (evaluated according to the Japanese Classification of Esophageal Cancer) was grade 3 (complete pathological response) in 7 patients (8.9 %), grade 2 in 13 patients (16.5 %), grade 1b in 8 patients (10.1 %) and grade 1a in 51 patients (64.6 %). A good pathological response (grade 2-3) was significantly associated with both favorable disease-free survival (P = 0.0051) and favorable cancer-specific survival (P = 0.0366). A multivariate analysis revealed that a good clinical response (HR 13.743, 95 % CI 2.455-76.917) and the presence of serum p53 antibody before treatment (HR 3.987, 95 % CI 1.103-14.416) were independent predictors of good pathological response. CONCLUSIONS: The presence of serum p53 antibody can be used as a novel, noninvasive predictor of the pathological tumor response to NAC with DCF in ESCC patients.

Estimation of Physiologic Ability and Surgical Stress (E-PASS) versus modified E-PASS for prediction of postoperative complications in elderly patients who undergo gastrectomy for gastric cancer.

BACKGROUND: Improvements in operative technique and perioperative management have resulted in increasing numbers of elderly patients undergoing gastrectomy for gastric cancer (GC). We evaluated the accuracy of Estimation of Physiologic Ability and Surgical Stress (E-PASS) and modified (m)E-PASS scores in predicting postoperative complications in elderly patients with GC. METHODS: We retrospectively analyzed short-term outcomes in 413 patients who underwent gastrectomy for GC between 2005 and 2014. They were divided into two groups: Group N comprised 341 non-elderly patients <80 years of age and Group E comprised 72 elderly patients ≥80 years of age. We calculated the E-PASS and mE-PASS scores and evaluated the correlation between the comprehensive risk score (CRS) and occurrence of postoperative complications. RESULTS: Morbidity rates were 25.5 % in Group N and 31.9 % in Group E. In Group N, the CRS values of both the E-PASS (P < 0.0001) and mE-PASS (P < 0.0001) scores were significantly higher in patients with complications than in those without complications. In Group E, although the E-PASS CRS was significantly higher in patients with complications than in patients without complications (P = 0.01), the mE-PASS CRS fixed (CRSf) score was not significantly correlated with the occurrence of postoperative complications (P = 0.08). CONCLUSION: Both E-PASS and mE-PASS can be used to predict the occurrence of postoperative complications in GC patients undergoing gastrectomy. However, the E-PASS CRS is more accurate for elderly patients because variations in intraoperative parameters such as operation time, blood loss, and extent of skin incision have a strong influence on the occurrence of postoperative complications.

Current perspectives toward the identification of key players in gastric cancer microRNA dysregulation.

Acquired genetic and epigenetic alterations in normal cells give rise to transformed cells, which lead to tumor development. Elucidation of the precise mechanisms underlying primary and metastatic tumor formation is required. MicroRNAs (miRNAs) are small noncoding RNAs that play a major role in post-transcriptional gene regulation during various biological processes. Accumulating evidence suggests that dysregulation of miRNAs is intimately involved in the carcinogenesis, progression and metastasis of many cancers, including gastric cancers (GCs), while the alteration of certain miRNAs provides biomarkers to detect early GCs. This review summarizes the most recent findings into the mechanisms of miRNA-mediated regulation of GCs, which will support the development of diagnostic biomarkers and novel therapeutic strategies.

Lysine-specific demethylase-1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer.

Lysine-specific demethylase-1 (LSD1) removes the methyl groups from mono- and di-methylated lysine 4 of histone H3. Previous studies have linked LSD1 to malignancy in several human tumors, and LSD1 is considered to epigenetically regulate the energy metabolism genes in adipocytes and hepatocellular carcinoma. This study investigates the function of LSD1 in the invasive activity and the metabolism of esophageal cancer cells. We investigated whether LSD1 immunohistochemical expression levels are related to clinical and pathological features, including the maximum standard uptake value in fluorodeoxyglucose positron emission tomography assay. The influence of LSD1 on cell proliferation, invasion and glucose uptake was evaluated in vitro by using specific small interfering RNA for LSD1, and an LSD1 inhibitor. We also evaluated two major energy pathways (glycolytic pathway and mitochondrial respiration) by measuring the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) with an extracellular flux analyzer. High LSD1 immunohistochemical expression was significantly associated with high tumor stage, lymphovascular invasion, poor prognosis, and high maximum standard uptake value in esophageal cancer patients. In the in vitro analysis, LSD1 knockdown significantly suppressed the invasive activity and glucose uptake of cancerous cells, reduced their ECAR and increased their OCR and OCR/ECAR. LSD1 may contribute to malignant behavior by regulating the invasive activity and metabolism, activating the glycolytic pathway and inhibiting the mitochondrial respiration of esophageal cancer cells. The results support LSD1 as a potential therapeutic target.