Abnormal serum microRNA profiles in tuberous sclerosis are normalized during treatment with everolimus: possible clinical implications.
BACKGROUND
Tuberous sclerosis (TSC) is a monogenic disease resulting from defects of the TSC1 or TSC2 genes, which encode the proteins forming hamartin-tuberin tumor suppressor complex, the mammalian target of rapamycin complex (mTOR). The mTOR pathway is constitutively activated in response to tuberin or hamartin defects. The mTOR pathway is also regulated by a multitude of epigenetic mechanisms, one of which is regulation by microRNA (miRNA) inhibition. This leads us to hypothesize that organ-level abnormalities of miRNA expression patterns are widespread in TSC. The aim of the study was to evaluate the serum profiles of miRNAs in patients with TSC and subependymal giant cell astrocytoma (SEGA) treated with mTOR inhibitor (everolimus).


METHODS
Serum microRNA profiling was performed in 10 TSC-patients before and three months after everolimus treatment, as well as in 10 sex- and age-matched healthy controls. MicroRNAs were profiled using qPCR panels (Exiqon).


RESULTS
Of 752 tested miRNAs, 11 showed statistically significant dysregulation in patients with TSC in comparison to controls. The following miRNAs were downregulated in TSC: miR-142-3p, miR-199a-5p, miR-142-5p and miR-136-5p; while miR-130a-3p, miR-378a-3p, miR-130b-3p, miR-192-5p, miR-25-3p, miR-215-5p and miR-222-3p were upregulated in TSC in comparison to the control group. After three months of everolimus treatment, mean dose 5.1 (2.6-9.7) mg/m2, seven miRNAs reached expression levels similar to healthy controls, with miR-142-3p and miR-136 showed significant increase over baseline levels in TSC patients. Moreover, miR-222-3p normalization due to treatment differed between patients with mutation in TSC1 and TSC2 gene.


CONCLUSIONS
Activation of the mTOR pathway in TSC patients alters serum miRNA levels, which may be partially reversed by an mTOR inhibitor. This indicates the involvement of miRNA dysregulation in the pathogenesis of TSC, linking miRNA profiles with treatment efficiency.
Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna Str., Lodz, 91-738, Poland. joanna.trelinska@umed.lodz.pl.
Joanna
J
Trelinska
Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna Str., Lodz, 91-738, Poland.|Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
Wojciech
W
Fendler
Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna Str., Lodz, 91-738, Poland.
Iwona
I
Dachowska
Department of Neurology & Epileptology and Pediatric Rehabilitation, The Children's Memorial Health Institute, Warsaw, Poland.
Katarzyna
K
Kotulska
Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.
Sergiusz
S
Jozwiak
Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland.
Karolina
K
Antosik
Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland.
Piotr
P
Gnys
Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland.
Maciej
M
Borowiec
Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna Str., Lodz, 91-738, Poland.
Wojciech
W
Mlynarski
Tuberous sclerosis; everolimus; mTOR inhibitor; microRNA
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