TY - JOUR

T1 - LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development

AU - Lu, Liwen

AU - Teixeira, Vitor H

AU - Yuan, ZhengQiang

AU - Graham, Trevor A

AU - Endesfelder, David

AU - Kolluri, Krishna

AU - Al-Juffali, Noura

AU - Hamilton, Nicholas

AU - Nicholson, Andrew G

AU - Falzon, Mary

AU - Kschischo, Maik

AU - Swanton, Charles

AU - Wright, Nicholas A

AU - Carroll, Bernadette

AU - Watt, Fiona M

AU - George, Jeremy P

AU - Jensen, Kim B

AU - Giangreco, Adam

AU - Janes, Sam M

N1 - Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PY - 2013/3

Y1 - 2013/3

N2 - Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.

AB - Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.

KW - Animals

KW - Cadherins

KW - Carcinoma, Squamous Cell

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cell Transformation, Neoplastic

KW - Contact Inhibition

KW - Gene Expression Regulation, Neoplastic

KW - Homeostasis

KW - Humans

KW - Loss of Heterozygosity

KW - Lung Neoplasms

KW - Male

KW - Membrane Glycoproteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred NOD

KW - Mice, Knockout

KW - Mice, SCID

KW - Multiprotein Complexes

KW - Nerve Tissue Proteins

KW - Precancerous Conditions

KW - Receptor, Epidermal Growth Factor

KW - Sequence Deletion

KW - Signal Transduction

U2 - 10.1002/path.4148

DO - 10.1002/path.4148

M3 - Journal article

C2 - 23208928

VL - 229

SP - 608

EP - 620

JO - Journal of Pathology and Translational Medicine

JF - Journal of Pathology and Translational Medicine

SN - 2383-7837

IS - 4

ER -