Investigation into the expression levels of MAGEA6 in esophageal squamous cell carcinoma and esophageal adenocarcinoma tissues

Cluster of differentiation (CD)-73 plays pivotal roles in the regulation of immune reactions via the production of extracellular adenosine, and the overexpression of CD73 is associated with worse outcomes in several types of cancers. Here, we identified 167 esophageal squamous cell carcinoma (ESCC) patients who underwent esophagectomy, including 64 and 103 patients with high and low expression levels of CD73, respectively. Univariate and multivariate analyses showed high expression of CD73 was an independent prognostic factor for worse disease-free survival and overall survival. In addition, we selected another cohort consisting of 38 ESCC patients receiving nivolumab or pembrolizumab and found that treatment response and survival benefit to immunotherapy were strongly correlated with the expression levels of CD73/programmed death ligand 1. Moreover, the transwell assay revealed knockdown of CD73 in two ESCC cell lines, TE1 and KYSE30, exhibited significantly reduced abilities of cell invasion and migration. CD73 silencing also showed that the protein expression levels of CD73, vimentin, and snail were downregulated, while those of E-cadherin were upregulated in Western blotting. The findings of our study indicate CD73 may be an independent prognostic factor for ESCC patients who underwent esophagectomy. Furthermore, it may be associated with the patient responses to immunotherapy.

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Serum microRNAs to predict the response to nivolumab in patients with esophageal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14511 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14511-e14511 ◽

Cited By ~ 1

Author(s):

Kazuki Sudo ◽

Ken Kato ◽

Juntaro Matsuzaki ◽

Junpei Kawauchi ◽

Satoko Takizawa ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Squamous Cell ◽

Phase Ii Study ◽

Progression Free Survival ◽

Free Survival ◽

Linear Discriminant ◽

Expression Levels

e14511 Background: A phase II study demonstrated that nivolumab (Nivo), a PD-1 inhibitor, had a meaningful activity for patients with esophageal squamous cell carcinoma. Although several biomarkers, including PD-L1 expression levels in tumor tissue, are explored to predict the efficacy of Nivo, further investigation is needed. Here we evaluated whether serum levels of microRNA (miRNA) could be a candidate of predictive markers. Methods: Among 65 patients who participated in the phase II study (JapicCTINo.142422) and received Nivo 3 mg/kg IV Q2W, 19 patients were treated at our institution. Patients were classified into responder and non-responder by investigators based on modified ir-RECIST. Serum samples were stored before and during treatment in the National Cancer Center Biobank. Comprehensive miRNA microarray analyses were performed using a 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc.), which was designed to detect 2565 miRNA expression levels. miRNA were compared between responders and non-responders using Fisher’s linear discriminant analysis, and then we calculated the area under curve (AUC) values of receiver operating characteristic curve. We explored the miRNA that showed AUC values of more than 0.8 and difference by 0.5 in the average log2 value of miRNA levels (log2miRNA) between responders and non-responders, and investigated their relation to progression-free survival using Kaplan-Meier curves and log-rank tests. Results: Among 19 patients, 5 responded (CR/PR, 1/4) to Nivo. We identified 3 miRNAs in the serum before treatment that were related to response to Nivo with AUC of 0.84 (log2miRNA of non-responder/responder: 13.16/12.47), 0.90 (8.65/10.20) and 0.81 (7.18/6.57), respectively. In the serum after the first treatment, 5 miRNAs were related to response to Nivo with AUC of 0.93 (11.93/11.09), 0.93 (11.87/11.13), 0.85 (7.92/8.53), 0.92 (6.61/5.82) and 0.93 (7.77/ 7.09), respectively. Among these 8 miRNAs, 4 miRNAs were significantly associated with progression-free survival. Conclusions: We identified miRNA candidates that could predict the response to Nivo. Further validation is warranted to confirm the results of our explorative research.

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PS02.200: A COMPREHENSIVE SCREENING OF THE FRA-1 REGULATORY GENES IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Diseases of the Esophagus ◽

10.1093/dote/doy089.ps02.200 ◽

2018 ◽

Vol 31 (Supplement_1) ◽

pp. 179-179

Author(s):

Takeshi Toyozumi ◽

Isamu Hoshino ◽

Haruhito Sakata ◽

Kentaro Murakami ◽

Masayuki Kano ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Candidate Genes ◽

Cell Lines ◽

Squamous Cell ◽

Poor Prognosis ◽

Primary Tumors ◽

Expression Levels ◽

Hmga1 Expression

Abstract Background The expression of Fos-related antigen 1 (Fra-1) affects tumor progression, migration and invasion. We previously reported that a high Fra-1 expression level is associated with lymph node metastasis and a poor prognosis in patients with esophageal squamous cell carcinoma (ESCC). In this study, we identified the genes regulated by Fra-1 in ESCC. Methods We constructed Fra-1 knockdown models via the transfection of small interfering RNA (siRNA) into ESCC cell lines (TE10, TE11). The expression levels of the genes in the knockdown models were analyzed using a microarray experiment and Biobase Upstream Analysis (Cytoline Solutions, Tokyo, Japan), and candidate genes regulated by Fra-1 in the ESCC cell lines were detected. The actual connection of Fra-1 to the promoter region was identified in a ChIP-PCR experiment. The expression levels of the candidate genes regulated by Fra-1 in the primary tumors of surgical specimens obtained from ESCC patients (n = 135) were compared to those observed in normal tissues using real-time PCR and immunohistochemical staining, and the clinicopathological features were analyzed. Results The results of the Biobase Upstream Analysis and ChIP-PCR showed high mobility group protein 1 (HMGA1) and hyaluronan mediated motility receptor (HMMR) to be significant genes regulated by Fra-1. The expression levels of both HMGA1 and HMMR were found to closely correlate with the Fra-1 expression in the clinical specimens. The patients with a positive HMGA1 expression had a poorer prognosis than those with a negative expression (P = 0.017) and the patients with positive HMMR expression also had a poorer prognosis (P = 0.018). Moreover, a multivariate analysis demonstrated a positive HMGA1 expression to be a significant independent prognostic factor in the ESCC patients. Conclusion HMGA1 and HMMR are regulated by Fra-1 in the setting of ESCC and the HMGA1 expression is significantly associated with a poor prognosis in ESCC patients. Downregulating the HMGA1 and HMMR expression may become a practical treatment strategy against ESCC in the future. Disclosure All authors have declared no conflicts of interest.

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Preliminary evaluation for Bit1 as a potential biomarker for squamous cell carcinoma and adenocarcinoma of esophagus

Tumor Biology ◽

10.1177/1010428317708267 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831770826

Author(s):

Jing Chen ◽

Hongtao Liu ◽

Pan Gao ◽

Yiran Hui ◽

Zhenzhen Yang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Matrix Metalloproteinase ◽

Cell Carcinoma ◽

Esophageal Adenocarcinoma ◽

Squamous Cell ◽

Expression Patterns ◽

Matrix Metalloproteinase 2 ◽

Potential Biomarker ◽

Well Differentiated

Mounting evidence has demonstrated that Bit1 has been investigated as an etiological factor for certain cancers, including esophageal squamous cell carcinoma reported in our previous study, but data regarding possible roles of Bit1 in esophageal squamous cell carcinoma and esophageal adenocarcinoma remain to be elucidated. The purpose of this study was to examine whether Bit1 can be a novel diagnostic marker for the patients with esophageal squamous cell carcinoma and esophageal adenocarcinoma. The results revealed that Bit1 level in esophageal squamous cell carcinoma was significantly higher than that in esophageal adenocarcinoma tissues ( p < 0.05); notably, Bit1 level in esophageal adenocarcinoma tissues was lower than that in paired normal tissues but no difference was found ( p > 0.05). Bit1 expression patterns were completely in accordance with matrix metalloproteinase 2 and Bcl-2 in esophageal squamous cell carcinoma and esophageal adenocarcinoma. In addition, Bit1, Bcl-2, and matrix metalloproteinase 2 expression patterns in different differentiated esophageal squamous cell carcinoma were higher than those in corresponding normal esophageal tissues. Bit1 expression in poorly differentiated esophageal squamous cell carcinoma was significantly higher than that in normal esophageal tissues ( p < 0.05) but not in moderately and well-differentiated esophageal squamous cell carcinoma. Matrix metalloproteinase 2 expression patterns in poorly and moderately differentiated esophageal squamous cell carcinoma were significantly higher than those in corresponding normal esophageal tissues ( p < 0.01) but not in well-differentiated esophageal squamous cell carcinoma tissue ( p > 0.05). Bcl-2 expression patterns in various differentiated esophageal squamous cell carcinoma were higher than those in corresponding normal esophageal tissues with no statistical differences ( p > 0.05). Importantly, Bit1 expression was positively correlated with both matrix metalloproteinase 2 and Bcl-2 expression in esophageal squamous cell carcinoma and esophageal adenocarcinoma tissues ( p < 0.05). Collectively, these preliminary data support further investigation of Bit1 as an important diagnostic factor for esophageal squamous cell carcinoma and esophageal adenocarcinoma.

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