COL8A1 Promotes NSCLC Progression Through IFIT1/IFIT3-Mediated EGFR Activation.

Xiangyi Zan,Shuyan Li,Xiaoxia Yan,Junnian Shi,Yan Zhao,Lanting Zhao,Shixiong Wei,Yuping Wang,Yongning Zhou,Yuanyi Zhang,Yixin Wan,Liping Gao,Rong Liu

doi:10.3389/fonc.2022.707525

Abstract

Activation of EGFR is a major risk factor for non-small cell lung cancer (NSCLC). Understanding the molecular events promoting EGFR activation can help us gain more insights into the progression of NSCLC. In this study, we demonstrate that collagen type VIII alpha 1 chain (COL8A1), an extracellular matrix component, was overexpressed in NSCLC. In NSCLC cells, knockdown of COL8A1 suppressed cell growth, cycle progression, and migration, and induced cell apoptosis. While COL8A1 overexpression promoted cell proliferation and inhibited cell apoptosis. In addition, we found that COL8A1 depletion reduced interferon response signaling and downregulated (IFIT1) and interferon-induced proteins with tetratricopeptide repeats 3 (IFIT3). Moreover, we indicated that COL8A1 could upregulate IFIT1 and IFIT3 mediated EGFR activation in vitro and in vivo. Lastly, there was a positive correlation among COL8A1, IFIT1, and IFIT3 expression, and EGFR activity in patients with NSCLC. Overall, our data demonstrate that COL8A1 contributes to NSCLC proliferation and invasion through EGFR activation, dependent on IFIT1 and IFIT3 expression.

Highlights

Non-small cell lung cancer (NSCLC) is one of the most frequent malignancies, with high incidence and mortality rates worldwide [1]
Previous studies revealed that COL8A1 may function as an important player in several solid tumors [24, 25]; whether COL8A1 is a pivotal player in non-small cell lung cancer (NSCLC) remains unclear
IHC assays were performed to evaluate COL8A1 expression levels in 94 NSCLC and 86 adjacent normal tissue samples and demonstrated that COL8A1 was aberrantly upregulated in NSCLC tissues, highlighting a potential role for COL8A1 as a novel prognostic biomarker of NSCLC, in which positive expression COL8A1 was associated with advanced pathological stage, consistent with a previous study [26]

Summary

Introduction

Non-small cell lung cancer (NSCLC) is one of the most frequent malignancies, with high incidence and mortality rates worldwide [1]. Numerous genetic elements are involved in the pathogenesis and progression of NSCLC, including EGFR and K-Ras [4–6], which function as oncogenes and play important roles in human cancer development. It is evident that COL8A1 has important roles in various biological processes, and its dysregulation has been linked to various cancers, including hepatic carcinoma and hemangioma [10]. Increasing evidence indicates that COL8A1 functions as a pivotal player in atherogenesis and vascular remodeling, partly via controlling cell proliferation and invasion [11]. COL8A1 serves as novel non-fibrillar collagen that is overexpressed in dilated cardiomyopathy, which is associated with left ventricular mass index and involved in the progression of cardiac dilation and remodeling [12]. The function of COL8A1 is not completely elucidated, its dysregulation in various cancers has led to a proposed role in NSCLC development and progression

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