Abstract
ObjectiveTuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body. Our previous study showed the abnormal up-regulation of miRNAs plays an important part in the pathogenesis of TSC-related renal angiomyolipoma (TSC-RAML). circRNAs were known as important regulators of miRNA, but little is known about the circRNAs in TSC-RAMLs.MethodsMicroarray chips and RNA sequencing were used to identify the circRNAs and mRNAs that were differently expressed between the TSC-RAML and normal kidney tissue. A competitive endogenous RNA (ceRNA) regulatory network was constructed to reveal the regulation of miRNAs and mRNAs by the circRNAs. The biological functions of circRNA and mRNA were analyzed by pathway analysis. Microenvironmental cell types were estimated with the MCP-counter package.ResultsWe identified 491 differentially expressed circRNAs (DECs) and 212 differentially expressed genes (DEGs), and 6 DECs were further confirmed by q-PCR. A ceRNA regulatory network which included 6 DECs, 5 miRNAs, and 63 mRNAs was established. Lipid biosynthetic process was significantly up-regulated in TSC-RAML, and the humoral immune response and the leukocyte chemotaxis pathway were found to be down-regulated. Fibroblasts are enriched in TSC-RAML, and the up-regulation of circRNA_000799 and circRNA_025332 may be significantly correlated to the infiltration of the fibroblasts.ConclusioncircRNAs may regulate the lipid metabolism of TSC-RAML by regulation of the miRNAs. Fibroblasts are enriched in TSC-RAMLs, and the population of fibroblast may be related to the alteration of circRNAs of TSC-RAML. Lipid metabolism in fibroblasts is a potential treatment target for TSC-RAML.
Highlights
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body
The mutation in TSC1 or TSC2 gene could cause the inactivation of the tuberin or hamartin protein, which further lead to the over-activation of mTOR signaling pathway. mTOR inhibitors were used as the major treatment for TSC-RAML [6, 7]
rank aggregation (RRA) package was used for differentially expressed genes (DEGs) list integration, and 98 up-regulated DEGs and 114 down-regulated DEGs were identified after the integration
Summary
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body. TSC-related renal angiomyolipoma (TSC-RAML) can occur in 70–90% TSC patients, and it is the leading cause of mortality in male adult TSC patients [3]. Most TSC-RAMLs are bilateral multiple kidney tumors [4]. The mutation in TSC1 or TSC2 gene could cause the inactivation of the tuberin or hamartin protein, which further lead to the over-activation of mTOR signaling pathway. MTOR inhibitors were used as the major treatment for TSC-RAML [6, 7]. EXISTII trial showed that 58% of the TSC-RAML patients reached 50% reduction in tumor size after receiving everolimus treatment for 1 year. 21% of these patients have poor response to everolimus treatment, and 14.3% of the TSC-RAMLs even showed tumor progression. Further knowledge of the pathogenesis of TSCRAML is needed in order to find new treatment targets of the TSC-RAML
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