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Introduction: Esophageal cancer is the sixth leading cause of cancer-related death worldwide. However, molecular targeted therapy and novel therapeutic targets are needed for esophageal squamous cell cancer (ESCC). In a previous study, we reported that protocadherin (PCDH) B9 plays an important role in several cancers. Therefore, in this study, we examined the clinical significance of PCDHB9 expression in ESCC., Methods: PCDHB9 expression was examined using immunohistochemistry in 128 cases and using quantitative reverse transcription-polymerase chain reaction in 16 cases of ESCC. PCDHB9 function in ESCC cells was examined using RNA interference., Results: High PCDHB9 expression was identified in 5 of 16 (31.3%). In total, 51 (40%) ESCC cases showed strong PCDHB9 expression, whereas nonneoplastic mucosa rarely showed its expression. High PCDHB9 expression was significantly associated with T classification, N grade, and stage in ESCC. In ESCC cell lines, PCDHB9 knockdown affected cell growth, migration, and adhesion. Further, the expression of integrin (ITG) A3, ITGA4, ITGA5, ITGB1, ITGB6, vimentin, snail family transcriptional repressor 1, and cadherin 2 (NCAD) was significantly reduced and cadherin 1 was significantly increased in PCDHB9 knockdown ESCC cells., Conclusion: These results suggest that PCDHB9 plays a tumor-promoting role and is a potential biomarker and therapeutic target in ESCC., (© 2022 S. Karger AG, Basel.)

Objectives: Esophageal cancer is the sixth most common malignancy worldwide. Signal peptidase complex 18 (SPC18) protein, which is encoded by the SEC11A gene, is one of the subunits of the signal peptidase complex and plays an important role in the secretion of proteins including transforming growth factor α (TGF-α). In this study, we investigated the significance of SPC18 expression in human esophageal squamous cell carcinoma (ESCC)., Methods: SPC18 expression was examined by immunohistochemistry. RNA interference was used to inhibit SPC18 expression in ESCC cell lines. To examine cell viability, we performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The effects of SPC18 inhibition on epidermal growth factor receptor (EGFR) signaling were analyzed by Western blot., Results: In total, 46 (50%) of 92 ESCC cases were positive for SPC18. SPC18 staining was observed more frequently in stage II/III/IV cases than in stage I cases (p = 0.028). We found that SPC18 expression was significantly associated with increased cancer-specific mortality (p = 0.006, log-rank test). SPC18 expression was frequently found in EGFR-positive cases compared with EGFR-negative cases. Cell proliferation and EGFR signaling were inhibited by SPC18 knockdown., Conclusion: Specific inhibitors of SPC18 may be promising anticancer drugs for patients with ESCC., (© 2020 S. Karger AG, Basel.)

Objective: Esophageal cancer is one of the deadliest cancers in the world, and the main subtype is esophageal squamous cell carcinoma (ESCC), which comprises 90% of cases. Expression of tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan catabolism, has been linked with tumor survival and poor prognosis of brain and breast cancer. However, no studies have investigated the potential role of TDO2 in esophageal cancer. Here we explored the expression and biological significance of TDO2 in ESCC., Methods: TDO2 protein expression was evaluated in 90 ESCC tissue samples by immunohistochemistry. TDO2 function in ESCC cell lines and spheroid colony formation were evaluated by RNA interference (RNAi)., Results: TDO2 overexpression was associated with tumor stage, recurrence status, and the CD44 cancer stem cell marker in ESCC. TDO2 overexpression was correlated with poor outcome of ESCC patients. Inhibition of TDO2 expression by RNAi in TE-10 and TE-11 cell lines reduced both the number and the size of spheroid colonies as well as cell proliferation. Knockdown of TDO2 expression also induced inactivation of the epidermal growth factor receptor signaling pathway., Conclusion: Our results imply that TDO2 could play an important role in the progression of ESCC. Furthermore, TDO2 may be a potential therapeutic target in ESCC., (© 2018 S. Karger AG, Basel.)

Esophageal squamous cell carcinoma (ESCC) is one of the most common human cancers. We previously reported that KIFC1 is involved in gastric cancer pathogenesis and that KIFC1 plays an important role in gastric cancer spheroid colony formation. However, the significance of KIFC1 in ESCC has not been examined. In the present study, we analyzed the expression and distribution of KIFC1 in 132 ESCC cases by immunohistochemistry. In contrast to weak or no staining of KIFC1 in non-neoplastic mucosa, ESCC tissue showed stronger, more extensive KIFC1 staining. In total, 95 (72%) of 132 ESCC cases were positive for KIFC1. Immunostaining of ALDH1 was also performed, and KIFC1-positive ESCC cases were significantly frequently found in ALDH1-positive ESCC cases compared with ALDH1-negative ESCC cases. Spheroid colony formation is an effective method to characterize CSCs, thus we analyzed sphere number and size at 15days in ESCC cells downregulated for KIFC1 by siRNA transfection. Both the number and size of sphere from TE-1 cells were significantly reduced in KIFC1 siRNA-transfected TE-1 cells than in negative control siRNA-transfected cells. These results suggest that KIFC1 plays an important role in ESCC pathogenesis., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: Gastrointestinal (GI) cancer, including gastric cancer (GC), colorectal cancer (CRC), and esophageal squamous cell carcinoma (ESCC), is the most common malignancy worldwide. To identify genes that encode transmembrane proteins present in GI cancer, Escherichia coli ampicillin secretion trap libraries were generated from MKN-74 GC cells, and BST2 was identified as overexpressed in GC. This study analyzed the expression and function of the BST2 gene in human GI cancers and examined the relationship between bone marrow stromal antigen-2 (BST-2) expression and GI patient clinicopathologic characteristics., Methods: Expression and distribution of BST-2 protein was analyzed by immunohistochemistry in 180 GC cases, 140 CRC cases, and 132 ESCC cases. Cell growth was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay., Results: Immunohistochemical analysis of BST-2 in GC tissues showed that 65 (36 %) of 180 GC cases were positive for BST-2. Uni- and multivariate analyses demonstrated that BST-2 expression is an independent prognostic classifier of GC patients. Immunohistochemical analysis showed that 46 % of 140 CRC cases and 27 % of 132 ESCC cases were positive for BST-2. In ESCC, BST-2 expression was an independent prognostic predictor for survival. The growth of BST2 small interfering RNA (siRNA)-transfected GC cells was significantly slower than the growth of negative control siRNA-transfected GC cells. The levels of phosphorylated epidermal growth factor receptor, extracellular signal-regulated kinase, and Akt were lower in BST2 siRNA-transfected GC cells than in control cells., Conclusions: The results suggest that BST-2 is involved in tumor progression and serves as an independent prognostic classifier for patients with GC. Because BST-2 is expressed on the cell membrane, BST-2 could be a therapeutic target for GC, CRC, and ESCC.

Background: Oesophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) are common types of human cancer. Spheroid colony formation is used to characterize cancer stem cell (CSCs). In the present study, we analyzed the significance of kinesin family 11 (KIF11 in human ESCC and CRC., Materials and Methods: Expression of KIF11 in 105 ESCC and 100 CRC cases was determined using immunohistochemistry. RNA interference was used to inhibit KIF11 expression in ESCC and CRC cell lines., Results: In total, 61 out of 105 (58%) ESCC and 62 out of 100 (62%) CRC cases were positive for KIF11. Expression of KIF11 was not associated with any clinicopathological characteristics. Both the number and size of spheres produced by from TE-5 ESCC cells and DLD-1 CRC cells were significantly reduced upon KIF11 siRNA transfection compared to negative control siRNA transfection., Conclusion: These results indicate that KIF11 plays an important role in CSCs of ESCC and CRC., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. In the present study, to identify novel prognostic markers or therapeutic targets for ESCC, we reviewed a list of genes with upregulated expression in ESCC compared with normal esophagus, as identified by our serial analysis of gene expression (SAGE) analysis. We focused on the NRD1 gene, which encodes the nardilysin protein. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in 34 ESCC tissue samples revealed that mRNA expression of NRD1 was upregulated in 56% of ESCC tissue samples. Immunohistochemical analysis of nardilysin in 109 ESCC tissue samples demonstrated that 43 (39%) ESCC cases were positive for nardilysin. Nardilysin-positive ESCC cases were more advanced in terms of T classification (P = 0.0007), N classification (P = 0.0164), and tumor stage (P < 0.0001) than nardilysin-negative ESCC cases. Furthermore, nardilysin expression was significantly associated with poorer prognosis (P = 0.0258). Univariate and multivariate analyses revealed that nardilysin expression is an independent prognostic classifier of patients with ESCC. The invasiveness of NRD1-knockdown TE1 and TE5 esophageal cancer cell lines was less than that of the negative control siRNA-transfected cell lines. Expression of MMP2 and MMP3 mRNA was significantly lower in NRD1-knockdown TE5 cells than in negative control siRNA-transfected cells. These results suggest that nardilysin is involved in tumor progression, and is an independent prognostic classifier in patients with ESCC., (© 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: Patients diagnosed with stage II and III esophageal squamous cell carcinoma (ESCC) have variable prognosis. This group would benefit greatly from the discovery of prognostic markers that are capable of identifying individuals for whom adjuvant treatment would be advantageous. The aim of this study was to investigate the impact of immunohistochemically detected cytokeratin 7 (CK7) expression on disease-free survival, overall survival (OS), or therapeutic outcome in patients with ESCC., Methods: Immunohistochemical analysis of CK7 was performed on 225 surgically resected specimens of stage 0-III ESCC., Results: In total, 20 (9%) of 225 ESCC cases were positive for CK7. In stage 0-III ESCC patients, CK7 expression was statistically significantly associated with OS, independent of clinical covariates, including tumor, node, metastasis system stage. In stage II and III ESCC patients (n = 124), CK7 expression was significantly associated with poorer OS (P = 0.0377). Furthermore, in stage II and III ESCC patients who did not receive adjuvant chemotherapy (n = 73), CK7 expression was significantly associated with poorer OS (P = 0.0003). CK7 expression was not associated with therapeutic outcome in patients with stage II and III ESCC who received adjuvant chemotherapy. In patients with CK7-positive ESCC (n = 16), receipt of adjuvant chemotherapy tended to be beneficial for patients with stage II and III ESCC (P = 0.0654)., Conclusions: Immunohistochemical analysis of CK7 will help to identify high-risk patients.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. To identify potential diagnostic markers for ESCC and therapeutic targets for ESCC, we used Serial Analysis of Gene Expression (SAGE) on one ESCC sample. We obtained a total of 14,430 tags, including 5765 that were unique. By comparing SAGE tags from the ESCC sample with those from normal human squamous esophagus, we found several genes that were differentially expressed between ESCC and normal squamous esophagus. Among these, we focused on the ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) gene because quantitative RT-PCR analysis showed a high level of ADAMTS16 expression in eight out of 20 ESCC samples (40%), but not in 15 kinds of normal tissues. Western blot analysis also showed upregulation of ADAMTS16 protein in ESCC tissues. Furthermore, ADAMTS16 protein was detected in culture media from the TE5 esophageal cancer cell line. Knockdown of ADAMTS16 in TE5 cells inhibited both cell growth and invasion ability. Our present SAGE data provide a list of genes potentially associated with ESCC. ADAMTS16 could be a novel diagnostic and therapeutic target for ESCC.

Background: The human homologue of Drosophila prune (PRUNE, which encodes h-prune) protein interacts with glycogen synthase kinase 3 and promotes cell motility. The aim of our study was to investigate the impact of immunohistochemically detected h-prune expression on the survival of patients with esophageal squamous cell carcinoma (ESCC)., Methods: Immunohistochemical staining of h-prune was performed for 205 surgically resected specimens of ESCC., Results: In total, 43 (21%) of 205 ESCC cases were positive for h-prune. h-prune-positive ESCC cases showed a more-advanced T stage (P < 0.0001), N stage (P < 0.0001), and tumor stage (P < 0.0001) than h-prune-negative ESCC cases. In the group of 116 stage II and III ESCC cases, recurrence of ESCC was frequently found in h-prune-positive cases. In patients with lung recurrence, the tumors were more likely to be h-prune positive than h-prune negative. Univariate analysis revealed that T stage (P < 0.0001), N stage (P < 0.0001), tumor stage (P < 0.0001), and h-prune staining (P < 0.0001) were significant prognostic factors for survival. Multivariate analysis indicated that N stage (P = 0.0182) and h-prune staining (P < 0.0001) were independent predictors for survival., Conclusions: These results indicate that immunostaining of h-prune is useful to identify patients at high risk for recurrence or poor prognosis associated with ESCC.

Acute arterial occlusion as a result of embolization from a malignant tumor is rare and infrequently reported. Recently a 70-year-old man initially presented with acute arterial occlusion of the left lower limb. He underwent embolectomy, and embolus was diagnosed as a squamous cell carcinoma histologically. Subsequent upper gastrointestinal endoscopy showed superficial esophageal cancer in the thoracic esophagus. Although scheduled to undergo chemotherapy, he died of acute pneumonia on the 81st day from onset. Autopsy showed superficial esophageal cancer, measuring 1.5 cm in diameter, and widespread tumor extension into arterial vessels such as the left femoral artery, the superior mesenteric artery, bilateral intrapulmonary arteries and veins such as bilateral brachiocephalic vein to the supra vena cava, despite small tumor size and shallow tumor invasion depth of the submucosal layer. This case is particularly interesting because the cancer manifested as arterial cancer embolism.