ABSTRACT
BACKGROUND: Cisplatin resistance (DDP-resistance) remains one of the major causes of poor prognosis in females with ovarian cancer. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of cellular processes, including chemoresistance. The aim of this study was to explore the role of HOX transcript antisense RNA (HOTAIR) in DDP-resistant ovarian cancer cells. METHODS: DDP-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. Real-time PCR, western blot, dual-luciferase reporter assay, and flow cytometry were then used to evaluate the effect of HOTAIR/miR-138-5p axis on chemoresistance of DDP-resistant ovarian cancer cells to DDP. RESULTS: We found that HOTAIR was upregulated in DDP-resistant cells, while miR-138-5p was downregulated. Knockdown of HOTAIR increased the expression of miR-138-5p in DDP-resistant cells and miR-138-5p is directly bound to HOTAIR. Upregulation of miR-138-5p induced by HOTAIR siRNA or by its mimics enhanced the chemosensitivity of DDP-resistant cells and decreased the expression of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1). Furthermore, the HOTAIR silencing-induced chemosensitivity of DDP-resistant cells was weakened by miR-138-5p inhibitor. CONCLUSIONS: These data demonstrate that HOTAIR acts as a sponge of miR-138-5p to prevent its binding to EZH2 and SIRT1, thereby promoting DDP-resistance of ovarian cancer cells. Our work will shed light on the development of therapeutic strategies for ovarian cancer treatment.
Subject(s)
Humans , Female , Ovarian Neoplasms/genetics , Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , RNA, Long Noncoding/genetics , Gene Expression Regulation, Neoplastic/drug effects , Up-Regulation , Apoptosis/drug effects , MicroRNAs/antagonists & inhibitors , Cell Line, Tumor , Gene Knockout Techniques/methods , Sirtuin 1/antagonists & inhibitors , Real-Time Polymerase Chain Reaction , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitorsABSTRACT
Objetivo: Avaliar o balanço hídrico acumulado durante o período do choque e determinar o que ocorre com ele nos 7 dias que se seguem à reversão do choque. Métodos: Estudo prospectivo e observacional, realizado em pacientes com choque séptico. Foram incluídos pacientes com pressão arterial média ≥ 65mmHg e lactato < 2,0mEq/L desmamados há menos de 12 horas do uso de vasopressores, sendo esse dia considerado o Dia 1. O balanço hídrico diário foi registrado por 7 dias após recuperação do choque. Os pacientes foram divididos em dois grupos, segundo a mediana da coorte para o balanço hídrico acumulado durante o período do choque: Grupo 1 ≤ 4,4L (n = 20) e Grupo 2 > 4,4L (n = 20). Resultados: Inscrevemos, neste estudo, um total de 40 pacientes. No Dia 1 do estudo, o balanço hídrico acumulado era de 1,1 [0,6 - 3,4] L no Grupo 1 e 9,0 [6,7 - 13,8] L no Grupo 2. No Dia 7 do estudo, o balanço hídrico acumulado era de 8,0 [4,5 - 12,4] L no Grupo 1 e 14,7 [12,7 - 20,6] L no Grupo 2 (p < 0,001 para ambos). A seguir, após a recuperação do choque, o balanço hídrico continuou a aumentar em ambos os grupos. Em comparação ao Grupo 1, o Grupo 2 teve um tempo mais longo de permanência na unidade de terapia intensiva e no hospital. Conclusão: São frequentemente observados balanços hídricos positivos em pacientes com choque séptico, o que pode estar relacionado a desfechos piores. Durante o período do choque, mesmo que o balanço hídrico fosse previamente positivo, este se torna ainda mais positivo. Após a recuperação do choque, o balanço hídrico continua a aumentar. Esse grupo com um balanço hídrico mais positivo permaneceu por mais tempo na unidade de terapia intensiva e no hospital. .
Objective: We aimed to evaluate the cumulative fluid balance during the period of shock and determine what happens to fluid balance in the 7 days following recovery from shock. Methods: A prospective and observational study in septic shock patients. Patients with a mean arterial pressure ≥ 65mmHg and lactate < 2.0mEq/L were included < 12 hours after weaning from vasopressor, and this day was considered day 1. The daily fluid balance was registered during and for seven days after recovery from shock. Patients were divided into two groups according to the full cohort’s median cumulative fluid balance during the period of shock: Group 1 ≤ 4.4L (n = 20) and Group 2 > 4.4L (n = 20). Results: We enrolled 40 patients in the study. On study day 1, the cumulative fluid balance was 1.1 [0.6 - 3.4] L in Group 1 and 9.0 [6.7 - 13.8] L in Group 2. On study day 7, the cumulative fluid balance was 8.0 [4.5 - 12.4] L in Group 1 and 14.7 [12.7 - 20.6] L in Group 2 (p < 0.001 for both). Afterwards, recovery of shock fluid balance continued to increase in both groups. Group 2 had a more prolonged length of stay in the intensive care unit and hospital compared to Group 1. Conclusion: In conclusion, positive fluid balances are frequently seen in patients with septic shock and may be related to worse outcomes. During the shock period, even though the fluid balance was previously positive, it becomes more positive. After recovery from shock, the fluid balance continues to increase. The group with a more positive fluid balance group spent more time in the intensive care unit and hospital. .