GLI pathogenesis-related 1 functions as a tumor-suppressor in lung cancer

Xiumei Sheng,Nathan Bowen,Zhengxin Wang

doi:10.1186/s12943-016-0508-4

Abstract

BackgroundGLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was also found to be down-regulated in prostate cancer. Functional studies revealed both growth suppression and proapoptotic activities for GLIPR1 in multiple cancer cell lines. GLIPR1’s role in lung cancer has not been investigated. Protein arginine methyltransferase 5 (PRMT5) is a protein arginine methyltransferase and forms a stoichiometric complex with the WD repeat domain 77 (WDR77) protein. Both PRMT5 and WDR77 are essential for growth of lung epithelial and cancer cells. But additional gene products that interact genetically or biochemichally with PRMT5 and WDR77 in the control of lung cancer cell growth are not characterized.MethodsDNA microarray and immunostaining were used to detect GLIPR1 expression during lung development and lung tumorigenesis. GLIPR1 expression was also analyzed in the TCGA lung cancer cohort. The consequence of GLIPR1 on growth of lung cancer cells in the tissue culture and lung tumor xenografts in the nude mice was observed.ResultsWe found that GLIPR1 expression is negatively associated with PRMT5/WDR77. GLIPR1 is absent in growing epithelial cells at the early stages of mouse lung development and highly expressed in the adult lung. Expression of GLIPR1 was down-regulated during lung tumorigenesis and its expression suppressed growth of lung cancer cells in the tissue culture and lung tumor xenografts in mice. GLIPR1 regulates lung cancer growth through the V-Erb-B avian erythroblastic leukemia viral oncogene homolog 3 (ErbB3).ConclusionsThis study reveals a novel pathway that PRMT5/WDR77 regulates GLIPR1 expression to control lung cancer cell growth and GLIPR1 as a potential therapeutic agent for lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0508-4) contains supplementary material, which is available to authorized users.

Highlights

GLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was found to be down-regulated in prostate cancer
GLIPR1 expression was suppressed by WD repeat domain 77 (WDR77) in lung cancer cells Silencing expression of WDR77 or Protein arginine methyltransferase 5 (PRMT5) dramatically inhibited proliferation of lung (A549 and PC14) and prostate (PC3 and lung (PC14) and prostate (LNCaP)) cancer cells [32, 36]
The anti-GLIPR1 antibody detected two protein bands, the upper one represents the N-glycosylated form of GLIPR1 [46]. These results suggest that WDR77 suppresses GLIPR1 expression in lung cancer A549 cells

Summary

Introduction

GLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was found to be down-regulated in prostate cancer Functional studies revealed both growth suppression and proapoptotic activities for GLIPR1 in multiple cancer cell lines. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumors [17, 18] These cell surface receptors are comprised of a composite extracellular domain which contains a well defined ligand-binding site, a single pass transmembrane domain, and an intracellular domain with tyrosine kinase activity [17, 19]. It was reported that ERBB3 played a major role in division, survival, motility, migration, and invasiveness of lung cancer cells [22, 23] and high ERBB3 expression was associated with poor prognosis in lung cancer patients [24,25,26]

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