Abstract
Angiomyolipomas (AMLs) are associated with cell fibrosis in kidney of Tuberous Sclerosis Complex patients. The mechanism by which the fibrotic proteins accumulated in AMLs has not been explored. In the present study, we investigated the role of Akt/tuberin/mTOR pathway in the regulation cell fibrosis proteins. AML cells that expressed low levels of tuberin showed less expression of N-cadherin and higher of vimentin proteins compared to HEK293 cells. AML cells infected with Ad-tuberin showed a significant decrease in vimentin and an increase in N-cadherin protein expression. In addition, cells treated with rapamycin showed a significant increase in p-Akt and a decrease in p-p70S6K that was associated with a decrease expression of vimentin and a slight increase expression in N-cadherin. On the other hand, cells treated with Akt inhibitor revealed a significant decrease in p-Akt and p-p70S6K that was associated with a significant decrease in vimentin and an increase in N-cadherin expression. In addition, cells transfected with DN-Akt or DN-S6K show significant increase expression in N-cadherin and a decrease in vimentin. Moreover, cells transfected with siRNA against rictor or siRNA against raptor resulted in a decrease in vimentin and an increase N-cadherin expression. Kidney tumors from TSC patients showed significant decrease in N-cadherin and significant increased in vimentin protein expression compared to control kidney tissues. These data comprise the first report to provide the role of Akt/tuberin/mTORC1/2 in the regulation of N-cadherin and vimentin that are involved in the progression of fibrosis in kidney tumor of TSC patients.
Highlights
Tuberous Sclerosis complex (TSC) is a genetic disorder, which cause tumors to develop in many organs including kidney
We investigated the role of tuberin/ mammalian target of rapamycin (mTOR) in regulating N-cadherin and vimentin as major fibrosis proteins involved in the progression and development of angiomyolipomas in TSC patients
This study provides the first evidence that tuberin oppositely regulates the expressions of N-cadherin and vimentin in AML renal cells as well as in kidney angiomyolipomas of TSC patients
Summary
Tuberous Sclerosis complex (TSC) is a genetic disorder, which cause tumors to develop in many organs including kidney. AMLs are present in more than 80% of patients with TSC, which is an autosomal dominant tumor suppressor syndrome [1]. Kidney cancer is rarely developed in TSC with the occurrence of only 2–3% of all patients in which smooth muscle is often the only component [2,3,4]. The smooth muscle cells of angiomyolipomas are deriving from a precursor termed as the perivascular epithelioid cell (PEC) [5]. AMLs most commonly occur in the kidneys and are often asymptomatic, enlargement and bleeding could occur leading to hemorrhage and renal impairment [7,8,9]. Hereditary forms of renal angiomyolipoma tend to be www.impactjournals.com/oncotarget larger, bilateral, multiple and manifest at a younger age compared with sporadic forms [10]
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