Increased Expression of lncRNA UCA1 and HULC Is Required for Pro-inflammatory Response During LPS Induced Sepsis in Endothelial Cells

Abstract

Systemic uncontrolled inflammatory response, also termed as sepsis, is responsible for many mortalities. Bacterial endotoxin, lipopolysaccharide (LPS), is a major cause of sepsis in endothelial cells. Even though a lot of research has been done to define underlying mechanisms of LPS induced sepsis, the role of long non-coding RNAs (lncRNAs), a group of >200 kb RNAs in sepsis is not well-defined. Expression of pro-inflammatory mediators IL6, ICAM1, and VCAM1 (which encodes interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, respectively) were determined following LPS treatment of human dermal microvascular endothelial cells (HMECs) for 24 h to confirm sepsis induction. RNA immunoprecipitation (RIP) analysis was performed using the chromatin modifying proteins (CMPs), heterogeneous nuclear ribonucleoprotein (hnRNP) K and corepressors of the RE-1 silencing transcription factor (coREST) as individual baits. Quantitative real time polymerase chain reaction (qRT-PCR) was performed on RNA isolated from immunoprecipitated pellets for six different lncRNAs. The effect of the differentially expressed lncRNAs were determined by ectopic overexpression of the lncRNAs before induction of sepsis. Expression of IL6, ICAM1, and VCAM1 were significantly upregulated following treatment of the HMECs with LPS for 24 h confirming induction of sepsis. RIP and qRT-PCR analysis revealed that the lncRNAs HULC, UCA1, and MALAT-1 were significantly enriched with the CMPs after sepsis. RNA interference using siRNAs targeting HULC and UCA1, but not MALAT-1, decreased the expression of IL6, ICAM1, and VCAM1 to endogenous levels. Our results were further validated in an in vivo model of sub-lethal LPS-induced sepsis, whereby siRNA mediated knockdown of UCA1 and HULC lncRNAs prevented induction of VCAM1, ICAM1, and IL6, as assayed by immunohistochemistry. Cumulatively, these results suggest that LPS induced in vitro sepsis in endothelial cells and induction of pre-inflammatory mediators are at least in part due to increased expression of the UCA1 and HULC lncRNAs.

Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA

“…The Long non-coding RNA UCA1 was located in chromosome 9p13.12, and has been found to be overexpressed in tumor tissues, such as esophageal squamous cell carcinoma,colorectal cancer, ovarian cancer, bile duct carcinoma and melanoma etc. [16][17][18][19][20][21][22][23].UCA1 are participated in the tumorigenesis and progression, functioning as an oncogene [24][25][26][27][28][29][30]. However, the relation between UCA1 and renal cancer is still unknown and mysterious particularly.…”

“…Accumulating evidences suggested that long non-coding RNAs (lncRNAs) perform important or vital functions in the malignant tumors [9][10][11][12][13][14][15]. LncRNA urothelial cancer associated 1 (UCA1) is abnormally expressed in esophageal squamous cell carcinoma, colorectal cancer, gastric cancer melanoma cells, pancreatic cancer, thyroid cancer, lung cancer and so on [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. In vitro and in vivo assays were conducted to further explore its underlying roles in tumor progression.…”

Potential role of lncRNA HULC/miR‑128‑3p/RAC1 axis in the inflammatory response during LPS‑induced sepsis in HMEC‑1 cells

“…Wang et al (8) reported that lncrna nuclear paraspeckle assembly transcript 1 (neaT1) knockdown could ameliorate sepsis-induced myocardial damage in mice, including the decrease of edema in myocardial tissues in mice, as well as the inhibition of apoptosis and inflammation. Previous literature has suggested that lncrna highly upregulated in liver cancer (Hulc) was involved in the decrease of pre-inflammatory mediators in lipopolysaccharide (lPS)-induced sepsis in vitro (9). nevertheless, the mechanism of action of Hulc in lPS-induced sepsis remains to be elucidated.…”

Whole blood transcriptomic investigation identifies long non-coding RNAs as regulators in sepsis

“…CRNDE, an oncogene that is usually overexpressed in tumor cells, contributes a lot to cellular proliferation, migration, invasion, and apoptosis [40]. More importantly, CRNDE can modulate the TLR3-NF-κB cytokine signaling pathway to trigger inflammation [41,42], suggesting that CRNDE may serve as a regulator in sepsis. In sepsis, genes or gene modules inducted by MALAT1 may modulate their expression pattern in endothelial cells, which is critical as MALAT1 has been reported to mediate inflammation in traumatic brain injury [42].…”

“…More importantly, CRNDE can modulate the TLR3-NF-κB cytokine signaling pathway to trigger inflammation [41,42], suggesting that CRNDE may serve as a regulator in sepsis. In sepsis, genes or gene modules inducted by MALAT1 may modulate their expression pattern in endothelial cells, which is critical as MALAT1 has been reported to mediate inflammation in traumatic brain injury [42]. Also, it was reported that TUG1 is able to affect the development of sepsis-associated acute kidney injury via modulating NF-κB pathway [43].…”