Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity

Chang, Lei; Shi, Runlin; Yang, Tao; Fan, Li; Li, Guohao; Guo, Yonglian; Liu, Bin; Ye, Weimin; Zhuang, Qianyuan; Xu, Hua

doi:10.1186/1756-9966-32-101

Cited by 18 publications

(14 citation statements)

References 29 publications

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“…Given the broad impact of LRIG1 on cell signaling pathways relevant to migration and invasion, LRIG1 should be effective in a variety of cellular contexts. In support of this, LRIG1 was previously found to inhibit the invasion of EGFRvIII-positive glioblastoma cells ( 59 ) and EGFR-expressing bladder cancer cells ( 60 ). Furthermore, LRIG1 knock-down in head and neck cancer cells led to increased migration and invasion through the EGFR/MAPK/SPHK1 pathway ( 14 ).…”

Section: Resultsmentioning

confidence: 67%

LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells

et al. 2015

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LRIG1, a member of the LRIG family of transmembrane leucine rich repeat-containing proteins, is a negative regulator of receptor tyrosine kinase signaling and a tumor suppressor. LRIG1 expression is broadly decreased in human cancer and in breast cancer, low expression of LRIG1 has been linked to decreased relapse-free survival. Recently, low expression of LRIG1 was revealed to be an independent risk factor for breast cancer metastasis and death. These findings suggest that LRIG1 may oppose breast cancer cell motility and invasion, cellular processes which are fundamental to metastasis. However, very little is known of LRIG1 function in this regard. In this study, we demonstrate that LRIG1 is down-regulated during epithelial to mesenchymal transition (EMT) of human mammary epithelial cells, suggesting that LRIG1 expression may represent a barrier to EMT. Indeed, depletion of endogenous LRIG1 in human mammary epithelial cells expands the stem cell population, augments mammosphere formation and accelerates EMT. Conversely, expression of LRIG1 in highly invasive Basal B breast cancer cells provokes a mesenchymal to epithelial transition accompanied by a dramatic suppression of tumorsphere formation and a striking loss of invasive growth in three-dimensional culture. LRIG1 expression perturbs multiple signaling pathways and represses markers and effectors of the mesenchymal state. Furthermore, LRIG1 expression in MDA-MB-231 breast cancer cells significantly slows their growth as tumors, providing the first in vivo evidence that LRIG1 functions as a growth suppressor in breast cancer.

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Section: Resultsmentioning

confidence: 67%

LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells

et al. 2015

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“…Ectopic expression of full length LRIG1 has been shown to inhibit the growth, motility and/or invasion of a variety of tumor cells, in vitro and in vivo (Laederich et al ., 2004, Shattuck et al ., 2007, Stutz et al ., 2008, Miller et al ., 2008, Ye et al ., 2009, Thomasson et al ., 2011, Li et al ., 2011, Krig et al ., 2011, Wang et al ., 2012, Lu et al ., 2013, Chang et al ., 2013, Qi et al ., 2013), making its potential restoration to LRIG1-deficient tumors of great interest. However, the translational applications of expressing full length LRIG1 are limited at this time due to its large size and membrane-bound nature.…”

Section: Soluble Lrig1 As a Therapeuticmentioning

confidence: 99%

The LRIG family: enigmatic regulators of growth factor receptor signaling

Simion¹,

Cedano-Prieto²,

Sweeney³

2014

Endocrine-Related Cancer

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The LRIG (leucine-rich repeats and immunoglobulin-like domains) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2, LRIG3) and one member each in flies (Lambik) and worms (Sma-10). LRIGs have stepped into the spotlight as essential regulators of growth factor receptors, including receptor tyrosine and serine/threonine kinases. LRIGs have been found to both negatively (LRIG1, LRIG3) and positively (Sma-10, LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood. The most is known about LRIG1, which was recently demonstrated to be a tumor suppressor. Indeed, in vivo experiments reinforce the essential link between LRIG1 and repression of its targets for tissue homeostasis. LRIG1 has also been identified as a stem cell marker and regulator of stem cell quiescence in a variety of tissues, discussed within. Comparably less is known about LRIG2 and LRIG3 although studies to date suggest that their functions are largely distinct from LRIG1 and that they likely do not serve as growth/tumor suppressors. Finally, the translational applications of expressing soluble forms of LRIG1 in LRIG1-deficient tumors are being explored and hold tremendous promise.

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“…Down-regulation of LRIG1 aggravates the aggressive properties of glioma cells by activating the EGFR pathway [16]. While restoring LRIG1 expression reportedly inhibits bladder cancer cell growth by suppressing EGFR activity [17]. Moreover, LRIG1 loss increases the risk of early and late relapse of breast cancer [13], but its overexpression inhibits EMT and cell invasion [12].…”

Section: Introductionmentioning

confidence: 99%

LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial–mesenchymal transition

Zhou

2019

Bioscience Reports

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Intratumoral hypoxia is a well-known feature of solid cancers and constitutes a major contributor to cancer metastasis and poor outcomes including melanoma. Leucine-rich repeats and Ig-like domains 1 (LRIG1) participate in the aggressive progression of several tumors, where its expression is frequently decreased. In the present study, hypoxia exposure aggravated melanoma cell invasion, migration, vasculogenic mimicry (VM), and epithelial–mesenchymal transition (EMT). During this process, LRIG1 expression was also decreased. Importantly, overexpression of LRIG1 notably counteracted hypoxia-induced invasion, migration, and VM, which was further augmented after LRIG1 inhibition. Mechanism analysis corroborated that LRIG1 elevation muted hypoxia-induced EMT by suppressing E-cadherin expression and increasing N-cadherin expression. Conversely, cessation of LRIG1 further potentiated hypoxia-triggered EMT. Additionally, hypoxia stimulation activated the epidermal growth factor receptor (EGFR)/ERK pathway, which was dampened by LRIG1 up-regulation but further activated by LRIG1 inhibition. More important, blocking this pathway with its antagonist erlotinib abrogated LRIG1 suppression-induced EMT, and subsequently cell invasion, migration, and VM of melanoma cells under hypoxia. Together, these findings suggest that LRIG1 overexpression can antagonize hypoxia-evoked aggressive metastatic phenotype by suppressing cell invasion, migration, and VM via regulating EGFR/ERK-mediated EMT process. Therefore, these findings may provide a promising target for melanoma therapy.

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Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity

Cited by 18 publications

References 29 publications

LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells

LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells

The LRIG family: enigmatic regulators of growth factor receptor signaling

LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial–mesenchymal transition

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