RESUMO
Increasing reports demonstrate that long noncoding RNAs participate in the regulation of numerous malignancies, cervical cancer included. Although lncRNA LOXL1 antisense RNA 1 has been commonly accepted to be an oncogene in many cancers. Here, the role of LOXL1-AS1 in CC still need to be explored. In this study, LOXL1-AS1 was found elevated in CC tissues and cells. LOXL1-AS1 depletion restrained CC cell proliferation, migration, invasion, and angiogenesis in vivo. Furthermore, we found that LOXL1-AS1 upregulated Lysophospholipase 1 expression via sequestering miR-526b-5p. Rescue assays revealed that overexpression of LYPLA1 reversed the LOXL1-AS1 silencing-induced inhibitory effects on the malignant phenotypes of CC cells. To conclude, this study showed that LOXL1-AS1 facilitates cellular process in CC via functioning as a miR-526b-5p sponge.
Assuntos
Aminoácido Oxirredutases , MicroRNAs , RNA Longo não Codificante , Neoplasias do Colo do Útero , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Oncogenes , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismoRESUMO
Late-onset hypogonadism (LOH) is defined as a clinical and biochemical syndrome with multiple symptoms caused by testosterone deficiency in aging males. An in-depth exploration of the molecular mechanism underlying LOH development is insufficient. We previously identified miR-125a-5p as a dysregulated microRNA in LOH patients and potential diagnostic biomarker for LOH. The present study demonstrated that plasma miR-125a-5p was upregulated after testosterone supplementation in both LOH patients and castrated mice, and positively associated with the testosterone concentrations, suggesting direct regulation of miR-125a-5p expression by testosterone. Androgen response element in the promoter of miR-125a-5p was subsequently identified. Target gene screening and confirmation verified that LYPLA1, encoding acyl-protein thioesterase 1 which catalyzed protein depalmitoylation process, was a target gene of miR-125a-5p. Furthermore, in cells cultured with testosterone deprivation and organs from castrated mice, testosterone deficiency led to decreased global protein palmitoylation level. In aging males, global protein palmitoylation in peripheral blood showed a notable decline in LOH patients contrast to the normal elderly males. And the palmitoylation level was positively correlative with serum testosterone concentrations. Our results suggested that testosterone could regulate global palmitoylation level through miR-125a-5p/LYPLA1 signaling pathway. Given that protein palmitoylation is pivotal for protein function and constitutes the pathogenesis of various diseases, testosterone/miR-125a-5p/LYPLA1 may contribute to the molecular mechanism underlying multiple symptoms caused by testosterone deficiency in LOH patients, and aberrant global palmitoylation could be a potential biomarker for LOH.
Assuntos
Hipogonadismo/enzimologia , Lipoilação , MicroRNAs/metabolismo , Processamento de Proteína Pós-Traducional , Testosterona/deficiência , Tioléster Hidrolases/metabolismo , Fatores Etários , Idoso , Animais , Estudos de Casos e Controles , Castração , Modelos Animais de Doenças , Células HEK293 , Terapia de Reposição Hormonal , Humanos , Hipogonadismo/sangue , Hipogonadismo/tratamento farmacológico , Hipogonadismo/genética , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , Células PC12 , Regiões Promotoras Genéticas , Ratos , Elementos de Resposta , Testosterona/sangue , Testosterona/uso terapêutico , Tioléster Hidrolases/genéticaRESUMO
Macroautophagy/autophagy is a highly conserved metabolic process that degrades intracellular components and recycles bioenergetic substrates. SQSTM1/p62 (sequestosome 1) is a classical autophagy receptor that participates in selective autophagy to eliminate abnormal intracellular components and recycle bioenergetic substrates. In autophagy, SQSTM1 recruits ubiquitinated substrates to form SQSTM1 droplets and delivers these cargoes to phagophores, the precursors to autophagosomes. Recently, we reported a previously unidentified SQSTM1 S-acylation, which is catalyzed by S-acyltransferase ZDHHC19 and reversed by LYPLA1/APT1. S-acylation of SQSTM1 enhances the affinity of SQSTM1 droplets with the phagophore membrane, thereby promoting efficient autophagic degradation of ubiquitinated substrates. Our study uncovers the role of the S-acylation-deacylation cycle in regulating SQSTM1-mediated selective autophagy.