Lysophosphatidic acid-RAGE axis promotes lung and mammary oncogenesis via protein kinase B and regulating tumor microenvironment

Rashmi Ray,Nitish Jangde,Satyendra Kumar Singh,Sunita Sinha,Vivek Rai

doi:10.1186/s12964-020-00666-y

Abstract

BackgroundReceptor for advanced glycation end products (RAGE) is a multi-ligand transmembrane receptor of the immunoglobulin superfamily. Lysophosphatidic acid (LPA) is a ligand for RAGE and is involved in physiological and pathophysiological conditions including cancer. However, RAGE-LPA axis is unexplored in lung and mammary cancer.MethodsRAGE was silenced in A549, MDA MB-231 and MCF7 using RAGE shRNA. For in vitro tumorigenesis, we performed wound healing, colony formation, cell proliferation and invasion assays. Evaluation of expression of oncogenes, EMT markers and downstream signaling molecules was done by using western blot and immunohistochemistry. For subcellular expression of RAGE, immunofluorescence was done. In vivo tumorigenesis was assessed by intraperitoneal injection of cancer cells in nude mice.ResultsHere we show RAGE mediated profound increase in proliferation, migration and invasion of lung and mammary cancer cells via LPA in Protein kinase B (PKB) dependent manner. LPA mediated EMT transition is regulated by RAGE. In vivo xenograft results show significance of RAGE in LPA mediated lung and mammary tumor progression, angiogenesis and immune cell infiltration to tumor microenvironment.ConclusionOur results establish the significance and involvement of RAGE in LPA mediated lung and mammary tumor progression and EMT transition via RAGE. RAGE-LPA axis may be a therapeutic target in lung and mammary cancer treatment strategies.EdVB1f1yrz4Do4i3nWt_5KVideo

Highlights

Receptor for advanced glycation end products (RAGE) is a multi-ligand transmembrane receptor of the immunoglobulin superfamily
Our results confirmed the activation of ERK and Protein kinase B (PKB) pathways in nonsmall cell lung carcinoma (NSCLC) A549 cells via RAGE
We checked the epithelial to mesenchymal transition marker and found twist1 to be upregulated by Lysophosphatidic acid (LPA) treatment in A549 cells and RAGE silencing led to decrease in the level of twist1 after LPA treatment suggesting its role in metastasis of A549 cells (Fig. 1c)

Summary

Introduction

Receptor for advanced glycation end products (RAGE) is a multi-ligand transmembrane receptor of the immunoglobulin superfamily. Lysophosphatidic acid (LPA) is a ligand for RAGE and is involved in physiological and pathophysiological conditions including cancer. RAGE-LPA axis is unexplored in lung and mammary cancer. Receptor for advanced glycation end products (RAGE) is a multi-ligand transmembrane receptor belonging to immunoglobulin superfamily. RAGE extracellular domain binds to various ligands including advanced glycation end products (AGEs), amyloid beta (aβ), S100B proteins/calgranulins, high mobility group box proteins (HMGB1), phosphatidylserine and lysophosphatidic acid (LPA) [13,14,15,16]. RAGE is found to be associated with tumor progression in glioma, bladder, melanoma, liver, pancreatic, prostate, colorectal, ovarian, gastric and lung cancer [15, 17,18,19]. Blocking RAGE signaling inhibits cancer cell growth in vitro and reduce tumorigenicity in murine models [21, 22]

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