MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis
Ubiquilin (UBQLN) proteins are adaptors thought to link ubiquitinated proteins to the proteasome. However, our lab has recently reported a previously unappreciated role for loss of UBQLN in lung cancer progression. In fact, UBQLN genes are lost in over 50% of lung cancer samples examined. However, a...
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doaj-696028db3a9b4d4089106d5307dacf3c2020-11-25T00:04:51ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862017-04-01194321332MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and TumorigenesisSanjay Yadav0Nishant Singh1Parag P. Shah2David A. Rowbotham3Danial Malik4Ankita Srivastav5Jai Shankar6Wan L. Lam7William W. Lockwood8Levi J. Beverly9James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, India; Address all correspondence to: L.J. Beverly, 505 S. Hancock Street, CTRB room 204, Louisville, KY 40202. Or S. Yadav, CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, India.CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, IndiaJames Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202Integrative Oncology, British Columbia Cancer Agency, Vancouver, B.C., Canada V5Z 1L3James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, IndiaCSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, IndiaIntegrative Oncology, British Columbia Cancer Agency, Vancouver, B.C., Canada V5Z 1L3; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, B.C., Canada V6T 2B5Integrative Oncology, British Columbia Cancer Agency, Vancouver, B.C., Canada V5Z 1L3; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, B.C., Canada V6T 2B5James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202; Address all correspondence to: L.J. Beverly, 505 S. Hancock Street, CTRB room 204, Louisville, KY 40202. Or S. Yadav, CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, India.Ubiquilin (UBQLN) proteins are adaptors thought to link ubiquitinated proteins to the proteasome. However, our lab has recently reported a previously unappreciated role for loss of UBQLN in lung cancer progression. In fact, UBQLN genes are lost in over 50% of lung cancer samples examined. However, a reason for the loss of UBQLN has not been proposed, nor has a selective pressure that could lead to deletion of UBQLN been reported. Diesel Exhaust Particles (DEP) are a major concern in the large cities of developing nations and DEP exposed populations are at an increased risk of developing a number of illnesses, including lung cancer. A connection between DEP and UBQLN has never been examined. In the present study, we determined the effect of DEP on lung cell lines and were interested to determine if UBQLN proteins could potentially play a protective role following treatment with DEP. Interestingly, we found that DEP treated cells have increased expression of UBQLN proteins. In fact, over-expression of UBQLN was capable of protecting cells from DEP toxicity. To investigate the mechanism by which DEP leads to increased UBQLN protein levels, we identified and interrogated microRNAs that were predicted to regulate UBQLN mRNA. We found that DEP decreases the oncogenic microRNA, MIR155. Further, we showed that MIR155 regulates the mRNA of UBQLN1 and UBQLN2 in cells, such that increased MIR155 expression increased cell invasion, migration, wound formation and clonogenicity in UBQLN-loss dependent manner. This is the first report of an environmental carcinogen regulating expression of UBQLN proteins. We show that exposure of cells to DEP causes an increase in UBQLN levels and that MIR155 regulates mRNA of UBQLN. Thus, we propose that DEP-induced repression of MIR155 leads to increased UBQLN levels, which in turn may be a selective pressure on lung cells to lose UBQLN1.http://www.sciencedirect.com/science/article/pii/S1476558617300027 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sanjay Yadav Nishant Singh Parag P. Shah David A. Rowbotham Danial Malik Ankita Srivastav Jai Shankar Wan L. Lam William W. Lockwood Levi J. Beverly |
spellingShingle |
Sanjay Yadav Nishant Singh Parag P. Shah David A. Rowbotham Danial Malik Ankita Srivastav Jai Shankar Wan L. Lam William W. Lockwood Levi J. Beverly MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis Neoplasia: An International Journal for Oncology Research |
author_facet |
Sanjay Yadav Nishant Singh Parag P. Shah David A. Rowbotham Danial Malik Ankita Srivastav Jai Shankar Wan L. Lam William W. Lockwood Levi J. Beverly |
author_sort |
Sanjay Yadav |
title |
MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis |
title_short |
MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis |
title_full |
MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis |
title_fullStr |
MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis |
title_full_unstemmed |
MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis |
title_sort |
mir155 regulation of ubiquilin1 and ubiquilin2: implications in cellular protection and tumorigenesis |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 |
publishDate |
2017-04-01 |
description |
Ubiquilin (UBQLN) proteins are adaptors thought to link ubiquitinated proteins to the proteasome. However, our lab has recently reported a previously unappreciated role for loss of UBQLN in lung cancer progression. In fact, UBQLN genes are lost in over 50% of lung cancer samples examined. However, a reason for the loss of UBQLN has not been proposed, nor has a selective pressure that could lead to deletion of UBQLN been reported. Diesel Exhaust Particles (DEP) are a major concern in the large cities of developing nations and DEP exposed populations are at an increased risk of developing a number of illnesses, including lung cancer. A connection between DEP and UBQLN has never been examined. In the present study, we determined the effect of DEP on lung cell lines and were interested to determine if UBQLN proteins could potentially play a protective role following treatment with DEP. Interestingly, we found that DEP treated cells have increased expression of UBQLN proteins. In fact, over-expression of UBQLN was capable of protecting cells from DEP toxicity. To investigate the mechanism by which DEP leads to increased UBQLN protein levels, we identified and interrogated microRNAs that were predicted to regulate UBQLN mRNA. We found that DEP decreases the oncogenic microRNA, MIR155. Further, we showed that MIR155 regulates the mRNA of UBQLN1 and UBQLN2 in cells, such that increased MIR155 expression increased cell invasion, migration, wound formation and clonogenicity in UBQLN-loss dependent manner. This is the first report of an environmental carcinogen regulating expression of UBQLN proteins. We show that exposure of cells to DEP causes an increase in UBQLN levels and that MIR155 regulates mRNA of UBQLN. Thus, we propose that DEP-induced repression of MIR155 leads to increased UBQLN levels, which in turn may be a selective pressure on lung cells to lose UBQLN1. |
url |
http://www.sciencedirect.com/science/article/pii/S1476558617300027 |
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