Tumor Endothelial Marker 8 Promotes Proliferation and Metastasis via the Wnt/β-Catenin Signaling Pathway in Lung Adenocarcinoma.

Ye Meng,Alice Charwudzi,Heqin Zhan,Yang Wan,Linhui Hu,Chen Ding,Youliang Wang,Xianwen Hu,Jingrong Li,Shudao Xiong,Lihua Gao,Jun Liu,HuiPing Wang,Jiali Zhang,Huimin Zheng

doi:10.3389/fonc.2021.712371

Abstract

Tumor endothelial marker 8 (TEM8), also known as ANTXR1, was highly expressed in cancers, and was identified as a biomarker for early diagnosis and prognosis in some cancers. However, the clinical role and molecular mechanisms of TEM8 in lung adenocarcinoma (LUAD) are still unclear. The present study aimed to explore its clinical value and the molecular mechanisms of TEM8 underlying the progression of LUAD. Our study found the elevation of TEM8 in LUAD cell lines and tissues. What’s more, we observed that the TEM8 expression level was associated with tumor size, primary tumor, and AJCC stage, and LUAD patients with high TEM8 expression usually have a poor prognosis. Then, we conducted a series of experiments by the strategy of loss-of-function and gain-of-function, and our results suggested that the knockdown of TEM8 suppressed proliferation, migration, and invasion and induced apoptosis in LUAD whereas overexpression of TEM8 had the opposite effect. Molecular mechanistic investigation showed that TEM8 exerted its promoting effects mainly through activating the Wnt/β-catenin signaling pathway. In short, our findings suggested that TEM8 played a crucial role in the progression of LUAD by activating the Wnt/β-catenin signaling pathway and could serve as a potential therapeutic target for LUAD.

Highlights

Lung cancer is the major cause of tumor-related death worldwide [1]
These findings suggested that Tumor endothelial marker 8 (TEM8) was significantly elevated in lung adenocarcinoma (LUAD) tissues and cell lines
Our results demonstrated the elevation of TEM8 in LUAD cell lines and cancer tissues

Summary

Introduction

Lung cancer is the major cause of tumor-related death worldwide [1]. Non‐small cell lung cancer (NSCLC), which includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, represents approximately 85% of all lung cancer cases [2, 3]. A deeper understanding of the molecular mechanisms underlying the development of LUAD might establish effective therapeutic targets that are urgently needed. Tumor endothelial marker 8 (TEM8), an integrin-like cell surface protein, was demonstrated as a tumor-associated marker in colorectal cancer by St. Croix in 2000 [9]. A previous study reported TEM8 as a specific protein molecule upregulated in tumor endothelial cells, required for tumor angiogenesis [11]. In early 2020, researchers had reported that TEM8 might be used as an early diagnostic indicator of lung cancer, providing a reference for the early diagnosis of lung cancer in future clinical practice [16]. The mechanism and clinical value in LUAD are not clear and need to be elucidated

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