Abstract 4544: PTP4A3 expression associated with increased invasion in esophageal adenocarcinoma

Abstract

Abstract Esophageal adenocarcinoma (EAC) is the most rapidly growing solid malignancy with an overall 5-year survival rate of only 19%. The majority of EACs are diagnosed with advanced locoregional disease requiring neoadjuvant chemoradiation followed by esophagectomy. Understanding the molecular mechanisms associated with locoregional invasion are crucial for improving the treatment outcome. Protein tyrosine phosphatase (PTP) type IVA member 3 (PTP4A3/PRL-3) is part of the PTP subfamily, which are phosphatases with dual-specificity. PTP4A3 has been shown to be overexpressed in a number of cancer types and often correlates with cell proliferation, migration, invasion, tumor growth, and metastasis. Here, we examine PTP4A3’s potential role in the invasive properties of EAC. Methods: We analyzed PTP4A3 mRNA levels of 122 chemo-naïve EAC samples using Human Gene 2.1 ST Arrays and compared these to available histological features. We also used RNA-seq analysis to examine the expression of PTP4A3 in 68 samples that consisted of Barrett’s Esophagus, low-grade dysplasia, high-grade dysplasia, and EAC. PTP4A3 knockdown was achieved by using small interfering RNA and a rhodamine derivative (BR-1) inhibitor and was confirmed by both RT-PCR and Western blot. WST and clonogenic assays were performed to assess cell proliferation in cell lines derived from EAC tumors. Cell invasion and migration were measured by matrigel invasion and cell migration assays. Results: PTP4A3 was significantly overexpressed in EAC samples compared to a cohort of normal esophageal samples (p<0.001). In addition, the expression of PTP4A3 increased with progression from Barrett’s to EAC. PTP4A3 was overexpressed in 15 EACs relative to 26 Barrett’s samples on U133A Array, which was confirmed in the 68-sample RNAseq progression cohort (p<0.01). Analysis of 122 EAC samples indicated that overexpression of PTP4A3 was significantly associated with decreased survival (p<0.05) and correlated with poor differentiation, high immune cell infiltration, and a high desmoplastic response (p<0.05). Inhibition of PTP4A3 in EAC cell lines led to a decrease in cell invasion and migration (p<0.01). However, there was no significant change in cell proliferation following knockdown. Conclusion: PTP4A3 is frequently overexpressed in EAC and is associated with decreased survival. Inhibition of PTP4A3 decreased matrigel invasion and cancer cell migration, suggesting that PTP4A3 may play a role in the invasion and metastases of EAC cells and could serve as a biomarker of more aggressive disease. Note: This abstract was not presented at the meeting. Citation Format: Zhuwen Wang. PTP4A3 expression associated with increased invasion in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4544.