USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation

Chih-Hao Lu,S.-L Catherine Jin,Yi-Ling Liu,Chao-Yang Lai,Alan Yueh-Luen Lee,Tsung-Hsien Chuang,Li-Rung Huang,Da-Wei Yeh

doi:10.1038/s41388-018-0411-0

Abstract

Macrophage accumulation and inflammation in the lung owing to stresses and diseases is a cause of lung cancer development. However, molecular mechanisms underlying the interaction between macrophages and cancer cells, which drive inflammation and stemness in cancers, are poorly understood. In this study, we investigated the expression of ubiquitin-specific peptidase 17 (USP17) in lung cancers, and role of elevated USP17 in the interaction between macrophages and lung cancer cells. USP17 expression in lung cancers was associated with poor prognosis, macrophage, and inflammatory marker expressions. Macrophages promoted USP17 expression in cancer cells. TNFR-associated factor (TRAF) 2-binding and TRAF3-binding motifs were identified in USP17, through which it interacted with and disrupted the TRAF2/TRAF3 complex. This stabilized its client proteins, enhanced inflammation and stemness in cancer cells, and promoted macrophage recruitment. In different animal studies, co-injection of macrophages with cancer cells promoted USP17 expression in tumors and tumor growth. Conversely, depletion of macrophages in host animals by clodronate liposomes reduced USP17 expression and tumor growth. In addition, overexpression of USP17 in cancer cells promoted tumor growth and inflammation-associated and stemness-associated gene expressions in tumors. These results suggested that USP17 drives a positive-feedback interaction between macrophages and cancer cells to enhance inflammation and stemness in cancer cells, and promotes lung cancer growth.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide
To elucidate the mechanism of ubiquitin-specific peptidase 17 (USP17) induction in lung cancers, we examined the expression of USP17 and macrophage and inflammatory markers in a set of cDNA array using 48 cDNA samples from patients with lung cancer with clinical data as shown in Supplementary Table 1
Correlations were observed between the increase in USP17 expression and the expression of inflammatory and macrophage markers in these lung cancer samples (Supplementary Figure 1a, b), suggesting a relationship among macrophage accumulation, inflammation, USP17 expression, and poor prognosis in lung cancers

Summary

Introduction

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. The two main histological subtypes are non-small-cell lung cancer and small-cell lung cancer, accounting for 85% and 15% of cases, respectively [1, 2]. Inflammatory stress is a major risk factor for lung cancer. The tumor microenvironment contains various cells, including cancer cells, cancer stem cells (CSCs), and stromal cells such as fibroblasts, endothelial cells, and leukocytes. These tumor-associated macrophages (TAMs) promote tumor-associated inflammation, CSC niches, and all aspects of tumor initiation, growth, and development [3,4,5]. In lung and other cancers, extensive macrophage infiltration is often associated with poor prognosis [6,7,8]

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Conclusion