1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VD...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2013-11-01
|
Series: | Cancers |
Subjects: | |
Online Access: | http://www.mdpi.com/2072-6694/5/4/1504 |
_version_ | 1797708532036927488 |
---|---|
author | Pamela A. Hershberger Song Liu Moray Campbell Maochun Qin Suzanne Shoemaker Alissa Verone Santosh Kumar Upadhyay |
author_facet | Pamela A. Hershberger Song Liu Moray Campbell Maochun Qin Suzanne Shoemaker Alissa Verone Santosh Kumar Upadhyay |
author_sort | Pamela A. Hershberger |
collection | DOAJ |
description | 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDRhigh) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDRlow and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH)2D3 sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH)2D3 induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH)2D3-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH)2D3 opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH)2D3 may prevent lung cancer progression in a molecularly defined subset of NSCLC patients. |
first_indexed | 2024-03-12T06:24:01Z |
format | Article |
id | doaj.art-7e96aef4c4a44542b61121839738b64e |
institution | Directory Open Access Journal |
issn | 2072-6694 |
language | English |
last_indexed | 2024-03-12T06:24:01Z |
publishDate | 2013-11-01 |
publisher | MDPI AG |
record_format | Article |
series | Cancers |
spelling | doaj.art-7e96aef4c4a44542b61121839738b64e2023-09-03T02:03:59ZengMDPI AGCancers2072-66942013-11-01541504152110.3390/cancers50415041,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC TreatmentPamela A. HershbergerSong LiuMoray CampbellMaochun QinSuzanne ShoemakerAlissa VeroneSantosh Kumar Upadhyay1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDRhigh) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDRlow and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH)2D3 sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH)2D3 induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH)2D3-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH)2D3 opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH)2D3 may prevent lung cancer progression in a molecularly defined subset of NSCLC patients.http://www.mdpi.com/2072-6694/5/4/1504epithelial mesenchymal transitionvitamin D1,25-dihydroxyvitamin D3lung cancer, TGFβ |
spellingShingle | Pamela A. Hershberger Song Liu Moray Campbell Maochun Qin Suzanne Shoemaker Alissa Verone Santosh Kumar Upadhyay 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment Cancers epithelial mesenchymal transition vitamin D 1,25-dihydroxyvitamin D3 lung cancer, TGFβ |
title | 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment |
title_full | 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment |
title_fullStr | 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment |
title_full_unstemmed | 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment |
title_short | 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment |
title_sort | 1 25 dihydroxyvitamin d3 1 25 oh 2d3 signaling capacity and the epithelial mesenchymal transition in non small cell lung cancer nsclc implications for use of 1 25 oh 2d3 in nsclc treatment |
topic | epithelial mesenchymal transition vitamin D 1,25-dihydroxyvitamin D3 lung cancer, TGFβ |
url | http://www.mdpi.com/2072-6694/5/4/1504 |
work_keys_str_mv | AT pamelaahershberger 125dihydroxyvitamind3125oh2d3signalingcapacityandtheepithelialmesenchymaltransitioninnonsmallcelllungcancernsclcimplicationsforuseof125oh2d3innsclctreatment AT songliu 125dihydroxyvitamind3125oh2d3signalingcapacityandtheepithelialmesenchymaltransitioninnonsmallcelllungcancernsclcimplicationsforuseof125oh2d3innsclctreatment AT moraycampbell 125dihydroxyvitamind3125oh2d3signalingcapacityandtheepithelialmesenchymaltransitioninnonsmallcelllungcancernsclcimplicationsforuseof125oh2d3innsclctreatment AT maochunqin 125dihydroxyvitamind3125oh2d3signalingcapacityandtheepithelialmesenchymaltransitioninnonsmallcelllungcancernsclcimplicationsforuseof125oh2d3innsclctreatment AT suzanneshoemaker 125dihydroxyvitamind3125oh2d3signalingcapacityandtheepithelialmesenchymaltransitioninnonsmallcelllungcancernsclcimplicationsforuseof125oh2d3innsclctreatment AT alissaverone 125dihydroxyvitamind3125oh2d3signalingcapacityandtheepithelialmesenchymaltransitioninnonsmallcelllungcancernsclcimplicationsforuseof125oh2d3innsclctreatment AT santoshkumarupadhyay 125dihydroxyvitamind3125oh2d3signalingcapacityandtheepithelialmesenchymaltransitioninnonsmallcelllungcancernsclcimplicationsforuseof125oh2d3innsclctreatment |