Wnt/β-Catenin Signaling Exacerbates Keloid Cell Proliferation by Regulating Telomerase

Abstract

Objectives: Our goal was to investigate the relationship between keloid and telomerase as well as clarifying the influence of Wnt/β-catenin signaling on keloid cell proliferation. Methods: Tissues from 18 keloid patients were collected for further study. Keloid progenitor cells (KPC) and skin progenitor cells (SKP) were both included in this study. Lenti-virus transfection was used to divide cells into different groups in which cells were treated with different substances: negative control (NC) group, wnt10a siRNA group, β-catenin siRNA group and TERT siRNA group. KPC cells were injected into 20 male BALB/c nude mice in order to build tumor models. Several experiments including immunohistochemistry, western blot and RT-PCR were conducted in order to detect the corresponding protein expressions and relative mRNA levels. MTT assay and flow cytometry were also conducted for assessing cell proliferation and apoptosis status. Results: β-catenin and telomerase expression levels in keloid tissues were elevated compared to normal tissues (all P < 0.05). KPC cells in keloid exhibited more dynamic telomerase activity than SKP cells (P < 0.05). Luciferase activity assay confirmed that β-catenin could directly interact with telomerase. After wnt10a/β-catenin signaling pathway was inhibited, the proliferation of KPC cells was significantly suppressed and the apoptosis rate was remarkably increased (all P < 0.05). Results from tumor models also validated that wnt10a/β-catenin signaling pathway influenced the activity and length of telomerase. Conclusions: Wnt/β-catenin signaling pathway is able to exacerbate keloid cell proliferation and inhibit the apoptosis of keloid cells through its interaction with telomerase.

TRAF4 Promotes Fibroblast Proliferation in Keloids by Destabilizing p53 via Interacting with the Deubiquitinase USP10

“…It is believed that TGFb functions as an indirect mitogen by inducing the expression of other growth-promoting factors in fibroblasts, such as platelet-derived growth factor and basic fibroblast growth factor 2 (Zhang et al, 2017). In addition, Wnt/b-catenin and STAT3 pathways, as well as some micro-RNAs and long non-coding RNAs, have been reported to promote keloid fibroblast proliferation via different mechanisms (Chua et al, 2011;Feng et al, 2017;Lim et al, 2006;Park et al, 2008;Rang et al, 2016;Shi et al, 2018;Wu et al, 2014;Yu et al, 2016;Zhang et al, 2016). In the current study, we identified the TRAF4/p53 axis as a pathway that controls keloid fibroproliferation.…”

“…During the proliferative phase, TGFb stimulates fibroblast proliferation, collagen synthesis, and angiogenesis (Bettinger et al, 1996;Douglas, 2010;Lichtman et al, 2016). In addition to TGFb, Wnt/b-catenin signaling exacerbates keloid cell proliferation via regulating telomerase and increase fibronectin production (Chua et al, 2011;Yu et al, 2016), and STAT3 contributes to keloid pathogenesis by promoting collagen production, cell proliferation, and migration (Lim et al, 2006).…”

Integrated analysis of the critical region 5p15.3–p15.2 associated with cri-du-chat syndrome

“…Among the bioprocesses investigated in the protein interaction network, we identified the negative regulation of the Wnt receptor signaling pathway. Through Wnt signaling, δ-catenin prevents Rho GTPase signaling, modulating the Ras superfamily in cytoskeletal reorganization (Lu et al , 2016). Perturbations in this pathway, observed after depletion of δ-catenin, may contribute to functional neurological alterations (Arikkath et al , 2009).…”

Identification of a novel mutation in the mechanoreceptor-encoding gene CXCR1 in patients with keloid

“…Transforming growth factor-beta (TGF-beta)/Smad signaling plays a key role in excessive fibrosis and keloid formation [6] Wnt signaling also plays key roles in various cellular functions including proliferation, differentiation, survival, apoptosis and migration, [8] which can exacerbate keloid cell proliferation and inhibit keloid cell apoptosis through its interaction with telomerase [16]. …”