Epigenetic inactivation of follistatin-like 1 mediates tumor immune evasion in nasopharyngeal carcinoma.

Xiaoying Zhou,Bo Li,Ning Ma,Tingting Huang,Zhe Zhang,Xue Xiao,Guangwu Huang,Shumin Wang,Xianjie Zeng,Wensheng Wen,Chunping Du,Yingxi Mo,Mariko Murata

doi:10.18632/oncotarget.7654

Abstract

Follistatin like-1 (FSTL1) is a secreted glycoprotein involved in a series of physiological and pathological processes. However, its contribution to the development of cancer, especially the pathogenesis of nasopharyngeal carcinoma (NPC), remains to be elucidated. We aimed to investigate the dysregulation of FSTL1 and its possible function in NPC. FSTL1 was frequently downregulated in NPC cell lines and primary tumor biopsies by promoter hypermethylation. Ectopic expression of FSTL1 significantly suppressed the colony formation, proliferation, migration and invasion ability of NPC cells and induced cell apoptosis. Overexpression of FSTL1 decreased the tumorigenicity of NPC cells in vivo. In addition, the proliferation of NPC cells in vitro was inhibited by treatment with soluble recombinant FSTL1 protein. The protein level of FSTL1 was decreased in primary NPC tumors and was associated with downregulated interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). Furthermore, recombinant human FSTL1 protein induced secretion of IL-1β and TNF-α in macrophage cultures, therefore FSTL1 might activate macrophages and attenuate the immune evasion of NPC cells. In conclusion, the epigenetic downregulation of FSTL1 may suppress the proliferation and migration of NPC cells, leading to dysfunctional innate responses in surrounding macrophages.

Highlights

Nasopharyngeal carcinoma (NPC) is a unique head and neck malignancy with a specific geographical distribution, whose etiology involves a complex crossinteraction between genetic susceptibility, environmental carcinogens and Epstein-Barr virus (EBV) infection [1]
We evaluated the transcriptional level of Follistatin like-1 (FSTL1) in NPC cell lines and primary tumors
FSTL1 expression was significantly inactivated in CNE2 and C666-1 cells and its level was decreased in the NPC cell lines CNE1, HONE1, HNE1 and TW03 (Figure 1A)

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a unique head and neck malignancy with a specific geographical distribution, whose etiology involves a complex crossinteraction between genetic susceptibility, environmental carcinogens and Epstein-Barr virus (EBV) infection [1]. Epigenetic alterations, including aberrant DNA methylation and histone modifications, have been considered important factors in the carcinogenesis of NPC, leading to the silencing of tumor suppressor genes and disruption of important signaling pathways such as Ras and Rho GTPase signaling, cell adhesion and apoptosis signaling [2]. A limited set of potentially immunogenic latency-associated viral antigens is expressed in NPC cells, which do not evoke antitumor immune responses in the large infiltrate of stromal immune cells in tumors and surrounding tissues. These stromal immune cells might be rendered anergic by factors released in the tumor microenvironment [3, 4]

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Conclusion