Knockdown of lncRNA-ATB suppresses autocrine secretion of TGF-β2 by targeting ZNF217 via miR-200c in keloid fibroblasts

Abstract

Abnormally high activation of transforming growth factor-β (TGF-β) signaling has been demonstrated to be involved in the initiation and progression of keloids. However, the functional role of long non-coding RNA (lncRNA)-activated by TGF-β (lncRNA-ATB) in keloids has not been documented. Here we investigated the role of lncRNA-ATB in the autocrine secretion of TGF-β in keloid fibroblasts (KFs) and explored the underlying molecular mechanism. Using immunohistochemistry and quantitative RT-PCR analysis, we showed that lncRNA-ATB and ZNF217, a transcriptional activator of TGF-β, were overexpressed and miR-200c, which targets ZNF217, was under-expressed in keloid tissue and keloid fibroblasts. Through gain- and loss-of-function studies, we demonstrated that knockdown of lncRNA-ATB decreased autocrine secretion of TGF-β2 and ZNF217 expression but upregulated expression of miR-200c in KFs. Stable downregulation of ZNF217 expression decreased the autocrine secretion of TGF-β2. miR-200c was endogenously associated with lncRNA-ATB, and inhibition of miR-200c overcame the decrease in ZNF217 expression in KFs. Taken together, these findings indicate that lncRNA-ATB governs the autocrine secretion of TGF-β2 in KFs, at least in part, by downregulating the expression level of ZNF217 via miR-200c, suggesting a signaling axis consisting of lncRNA-ATB/miR-200c/ZNF217/TGF-β2. These findings may provide potential biomarkers and targets for novel diagnostic and therapeutic approaches for keloids.

Elevated expression of ZNF217 promotes prostate cancer growth by restraining ferroportin-conducted iron egress

“…Deregulated methylation status at the ZNF217 gene promoter has been observed in glioblastoma and breast cancer. LncRNA-ATB also regulates ZNF217 expression via miR-200c in keloid fibroblasts and breast cancer [44, 45]. In the current study, we found two functional binding sites of MAZ within the promoter of ZNF217 by ChIP assay and luciferase assay.…”

Retracted: lncRNA‐ATB promotes viability, migration, and angiogenesis in human microvascular endothelial cells by sponging microRNA‐195

“…miRs are small endogenous noncoding RNAs (21‐24 nucleotides) that act as critical roles in numerous biological processes . Accumulating evidence has identified that several lncRNAs function through regulating expression of miRs, including lncRNA‐ATB . miR‐195, located at chromosome 17, has been reported to repress angiogenesis in breast cancer .…”

The Long Non-Coding RNA LncRNA8975-1 is Upregulated in Hypertrophic Scar Fibroblasts and Controls Collagen Expression

“…The proliferation of hypertrophic scar fibroblasts was reported to be affected by the non-coding RNAs miR-200b, miR-21 and miR-143-3p [27][28][29]. The functional interactions of lncRNAs, miRNAs and mRNAs could lead to a new explanation for the pathogenesis of keloids [8]. We used DIANA-LncBase v2 (www.microrna.gr/LncBase) [30], LNCipedia v4.0 (www.lncipedia.org) [31] and NPInter v3.0 (www.bioinfo.org/NPInter/) [32] to determine whether any miRNAs could associate with lncRNA8975-1.…”

“…Several studies have shown that lncRNAs play important roles in keloid formation [8], scleroderma [9], lung fibrosis [10], and other fibrotic disorders [11] by acting through diverse mechanisms. Recently, our group discovered that lncRNA8975-1 (TCONS_00013888 in UCSC hg38; also named NONHSAT122029 in NONCODEv4), an lncRNA located upstream of the COL1A2 gene on chromosome 7 (UCSC hg38, chr7:94278999-94392179, ChIPBase named it lncRNA8975-1), was overexpressed in regressive scars compared to mature scar tissues [12].…”