PTIP Inhibits Cell Invasion in Esophageal Squamous Cell Carcinoma via Modulation of EphA2 Expression.

Xiao Han,Kairong Han,Yu Zhou,Yaning Zhu,Chao Jiang,Li Shen,Liqun Pang,Lianshu Ding,Jun Xie,Chengwan Zhang,Hao Gu,Wubi Zhou,Yijun Yang

doi:10.3389/fonc.2021.629916

Abstract

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy and treatment failure is largely due to metastasis and invasion. Aberrant tumor cell adhesion is often associated with tumor progression and metastasis. However, the exact details of cell adhesion in ESCC progression have yet to be determined. In our study, the clinical relevance of Pax2 transactivation domain-interacting protein (PTIP/PAXIP1) was analyzed by immunohistochemistry of ESCC tissues. We found that low expression of PTIP was associated with lymph node metastasis in ESCC, and loss-of-function approaches showed that depletion of PTIP promoted ESCC cell migration and invasion both in vitro and in vivo. Analysis integrating RNA-seq and ChIP-seq data revealed that PTIP directly regulated ephrin type-A receptor 2 (EphA2) expression in ESCC cells. Moreover, PTIP inhibited EphA2 expression by competing with Fosl2, which attenuated the invasion ability of ESCC cells. These results collectively suggest that PTIP regulates ESCC invasion through modulation of EphA2 expression and hence presents a potential therapeutic target for its treatment.

Highlights

Esophageal cancer, a highly aggressive malignancy, globally ranks seventh in the incidence of cancer cases and sixth as the leading cause of cancer-related deaths
Our results showed that PTIP was downregulated in Esophageal squamous cell carcinoma (ESCC) samples positive for lymph node metastasis
A significantly negative correlation was detected between PTIP expression and the lymph node metastasis status of ESCC patients

Summary

Introduction

Esophageal cancer, a highly aggressive malignancy, globally ranks seventh in the incidence of cancer cases and sixth as the leading cause of cancer-related deaths. In 2018, the number of new esophageal cancer cases and deaths worldwide was about 572000 and 509000, respectively [1]. ESCC is PTIP Inhibits ESCC Tumor Invasion the predominant subtype of esophageal cancer in China, accounting for 90% of esophageal carcinomas [3]. 50% of patients when diagnosed with ESCC already have distant metastases and more than one-third develop distant metastases following surgery or radiotherapy [4, 5]. Most distant metastases of ESCC involve the distant lymph nodes [5]. Dissecting the mechanisms underlying esophageal cancer invasion and metastasis is fundamental for the development of effective therapeutic strategies to improve patients’ outcomes

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Conclusion