The putative tumour suppressor protein Latexin is secreted by prostate luminal cells and is downregulated in malignancy

Robert I Seed,Daniel J Wilcock,Norman J Maitland,Aled Clayton,Leanne K Archer,Giovanna Nappo,John L Petrie,Holger H H Erb,Saburo Ito,Mark Gurney,Alberto J Taurozzi,Martin G Rumsby,Martin L Read,Anne T Collins

doi:10.1038/s41598-019-41379-8

Abstract

Loss of latexin (LXN) expression negatively correlates with the prognosis of several human cancers. Despite association with numerous processes including haematopoietic stem cell (HSC) fate, inflammation and tumour suppression, a clearly defined biological role for LXN is still lacking. Therefore, we sought to understand LXN expression and function in the normal and malignant prostate to assess its potential as a therapeutic target. Our data demonstrate that LXN is highly expressed in normal prostate luminal cells but downregulated in high Gleason grade cancers. LXN protein is both cytosolic and secreted by prostate cells and expression is directly and potently upregulated by all-trans retinoic acid (atRA). Whilst overexpression of LXN in prostate epithelial basal cells did not affect cell fate, LXN overexpression in the luminal cancer line LNCaP reduced plating efficiency. Transcriptome analysis revealed that LXN overexpression had no direct effects on gene expression but had significant indirect effects on important genes involved in both retinoid metabolism and IFN-associated inflammatory responses. These data highlight a potential role for LXN in retinoid signaling and inflammatory pathways. Investigating the effects of LXN on immune cell function in the tumour microenvironment (TME) may reveal how observed intratumoural loss of LXN affects the prognosis of many adenocarcinomas.

Highlights

Loss of latexin (LXN) expression negatively correlates with the prognosis of several human cancers
LXN expression is downregulated in lymphoma, gastric carcinoma and thyroid carcinoma[11,21,33] and loss of LXN expression correlates with diverse biological effects in different cancer cell lines[15,17]
Despite multiple attempts to determine a role for loss of LXN expression in adenocarcinoma, thorough characterisation of LXN in normal epithelia or malignancy is www.nature.com/scientificreports

Summary

Introduction

Loss of latexin (LXN) expression negatively correlates with the prognosis of several human cancers. Our data demonstrate that LXN is highly expressed in normal prostate luminal cells but downregulated in high Gleason grade cancers. Transcriptome analysis revealed that LXN overexpression had no direct effects on gene expression but had significant indirect effects on important genes involved in both retinoid metabolism and IFNassociated inflammatory responses. These data highlight a potential role for LXN in retinoid signaling and inflammatory pathways. Despite the success of surgical intervention, radiotherapy and androgen ablation therapies, there remains a significant recurrence rate of up to 30%2,3 Such recurrences almost inevitably lead to more aggressive and treatment-resistant cancer such as castrate resistant and neuroendocrine tumours[4]. In different cancer models the biological effects of LXN appear to be diverse and its biological function is increasingly multi-faceted

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