Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion

Abstract

BackgroundUnexplained recurrent spontaneous abortion (URSA) is a common pregnancy complication and the etiology is unknown. URSA-associated lncRNAs are expected to be potential biomarkers for diagnosis, and might be related to the disease pathogenesis.ObjectiveTo investigate differential lncRNAs in peripheral blood of non-pregnant URSA patients and matched healthy control women and to explore the possible mechanism of differential lncRNAs leading to URSA.MethodsWe profiled lncRNAs expression in peripheral blood from 5 non-pregnant URSA patients and 5 matched healthy control women by lncRNA microarray analysis. Functions of URSA-associated lncRNAs were further investigated in vitro.ResultsRP11-115N4.1 was identified as the most differentially expressed lncRNA which was highly upregulated in peripheral blood of non-pregnant URSA patients (P = 3.63E-07, Fold change = 2.96), and this dysregulation was further validated in approximately 26.67% additional patients (4/15). RP11-115N4.1 expression was detected in both lymphocytes and monocytes of human peripheral blood, and in vitro overexpression of RP11-115N4.1 decreased cell proliferation in K562 cells significantly. Furthermore, heat-shock HSP70 genes (HSPA1A and HSPA1B) were found to be significantly upregulated upon RP11-115N4.1 overexpression by transcriptome analysis (HSPA1A (P = 4.39E-08, Fold change = 4.17), HSPA1B (P = 2.26E-06, Fold change = 2.99)). RNA pull down and RNA immunoprecipitation assay (RIP) analysis demonstrated that RP11-115N4.1 bound to HNRNPH3 protein directly, which in turn activate heat-shock proteins (HSP70) analyzed by protein-protein interaction and HNRNPH3 knockdown assays. Most importantly, the high expression of HSP70 was also verified in the serum of URSA patients and the supernatant of K562 cells with RP11-115N4.1 activation, and HSP70 in supernatant can exacerbate inflammatory responses in monocytes by inducing IL-6, IL-1β, and TNF-α and inhibit the migration of trophoblast cells, which might associate with URSA.ConclusionOur results demonstrated that the activation of RP11-115N4.1 can significantly increase the protein level of HSP70 via binding to HNRNPH3, which may modulate the immune responses and related to URSA. Moreover, RP11-115N4.1 may be a novel etiological biomarker and a new therapeutic target for URSA.

Transaminase elevation during the first trimester and early pregnancy loss in patients with recurrent spontaneous abortion: a cross-sectional study

“…Pregnancy causes changes in physiology and laboratory of liver 18 . According to previous studies, inflammatory microenvironment was associated with RSA 19,20 . It may implicate that local and systemic inflammation may be independent etiological factors of EPL.…”

Decoding contextual crosstalk: revealing distinct interactions between non-coding RNAs and unfolded protein response in breast cancer

“…Further research is needed to comprehend the precise mechanisms underlying the destabilization by these miRNAs and the functional significance of this regulatory network in various biological processes and disease conditions [ 46 ]. According to reports, overexpressing lncRNA RP11-115N4.1 dramatically reduces K562 cell proliferation and modifies the immunological response by triggering HSP70 production by binding to HNRNPH3 [ 47 ]. The results strongly suggest that the lncRNA Hotair functions as a positive regulator in laryngeal squamous cell carcinoma by influencing the stability of GRP78 through posttranscriptional modifications, coordinated by the regulation of hsa-miR-30a-5p.…”

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

“…Hence, Cxcl14 up-regulation likely represents a strong compensatory response because of a decline in Cxcl14 proteostasis. The biological role(s) of hnRNPH3 remains scant, but emerging evidence suggests that hnRNPH3 mediates pro-inflammatory and stress signals [194] and in which Cxcr4, Mmp28, and STAT3 partake important roles [191,[195][196][197][198][199]. Notably, the concurrent and selective loss of Ranbp2 in Thy1-motoneurons and retinal ganglion neurons elicits the rapid activation of retinal microglia in the absence of loss of retinal ganglion neurons [121].…”