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 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.
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, India. Electronic address: sanjay@iitr.res.in.
Sanjay
S
Yadav
CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, India. Electronic address: Nishant.Singh@iitr.res.in.
Nishant
N
Singh
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202. Electronic address: Parag.Shah@Louisville.edu.
Parag P
PP
Shah
Integrative Oncology, British Columbia Cancer Agency, Vancouver, B.C., Canada V5Z 1L3. Electronic address: Drowbotham@bccrc.ca.
David A
DA
Rowbotham
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202. Electronic address: Danial.Malik@Louisville.edu.
Danial
D
Malik
CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, India. Electronic address: AnkitaBiochem@gmail.com.
Ankita
A
Srivastav
CSIR-Indian Institute of Toxicology Research, Lucknow, UP 226001, India. Electronic address: Jai.Shankar@iitr.res.in.
Jai
J
Shankar
Integrative 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 2B5. Electronic address: WanLam@bccrc.ca.
Wan L
WL
Lam
Integrative 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 2B5. Electronic address: Wlockwood@bccrc.ca.
William W
WW
Lockwood
James 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. Electronic address: Levi.Beverly@Louisville.edu.
Levi J
LJ
Beverly
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D004781:Environmental Exposure / Q000009:adverse effects; D005786:Gene Expression Regulation; D064593:Heterografts; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D014410:Tumor Stem Cell Assay; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C107792:UBQLN1 protein, human; C405662:UBQLN2 protein, human; D014452:Ubiquitins; D001335:Vehicle Emissions