Role of Homeodomain-Interacting Protein Kinase 2 in the Pathogenesis of Tissue Fibrosis in Keloid-Derived Keratinocytes

Abstract

Epithelial-mesenchymal transition (EMT) plays a critical role in fibrotic keloid formation, which is characterized by excessive collagen and extracellular matrix synthesis and deposition. Growing evidence suggests that the serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) acts upstream of several major fibrosis signaling pathways; however, the role of HIPK2 in the keloid fibrogenesis remains unknown. In the current study, we investigated the roles of HIPK2 in the pathogenesis of keloids. Primary normal skin and keloid keratinocytes were cultured and pretreated with transforming growth factor (TGF)-β1. Next, keratinocytes were transfected with scrambled small interfering RNA (siRNA) and anti-HIPK2 siRNA. The TGF-β1-associated HIPK2 alterations were investigated by quantitative real-time polymerase chain reaction. Protein levels were analyzed by western blotting. The HIPK2 was markedly increased in the keloid-derived keratinocytes compared with normal skin keratinocytes. In addition, HIPK2 induced the expression of EMT markers in normal skin keratinocytes by TGF-β1-SMAD family member 3 (SMAD3). The effect of TGF-β1-related EMT markers and SMAD3 phosphorylation in response to added TGF-β1 was significantly abrogated when the cells were transfected with HIPK2 siRNA. We conclude that HIPK2 is a crucial factor in the pathogenesis of keloids, suggesting that HIPK2 might be a novel potential drug target for antikeloid therapy.

CircRNA-016901 silencing attenuates irradiation-induced injury in bone mesenchymal stem cells via regulating the miR-1249-5p/HIPK2 axis

“…Research has reported that HIPK2 induces apoptosis in a dependent or non-dependent manner via the p53 gene (69). Phosphorylation at position 46 of p53 activates the expression of the negative regulator p53, thereby directing cells for DNA repair or apoptosis inhibition (53), while silencing HIPK2 reduces apoptosis (70). The current study revealed that miR-1249-5p overexpression significantly downregulated the expression of HIPK2.…”

Exosomal miR-19a from adipose-derived stem cells suppresses differentiation of corneal keratocytes into myofibroblasts

“…HIPK2 is a pro-fibrotic gene that modulates p53 and TGF-β/Smad3 signaling pathways [24,25]. HIPK2 kinase activity is significantly increased in keratocytes cultured with 10% FBS for 7 days compared to controls ( Figure 4A).…”

“…HIPK2 is a pro-fibrotic gene that plays an important role in kidney fibrosis [24]. Previous studies show that HIPK2 regulates fibrosis by acting upstream of p53, Transforming Growth Factor β (TGF-β), SMAD family member 3 (Smad3), and INT-1 (Wnt)/β-catenin pathways [24,25]. Hu et al showed that exosomal miR-1229 promotes angiogenesis of colorectal cancer cells by targeting HIPK2 [26].…”

The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region

“…Upon activation, HIPK2 triggers several pro-fibrotic, pro-inflammatory, and pro-apoptotic pathways, including TGF-␤/Smad3, Wnt/Notch, NF-B, and p53, which are all known to increase expression of pro-fibrosis markers (34 -37). Consequently, HIPK2 activation promotes cellular epithelialto-mesenchymal transition (EMT) (32,38). Expression of kinase-dead HIPK2 or its knockdown in human renal tubular epithelial cells significantly attenuates HIV-induced apoptosis and down-regulates EMT markers in Tg26 mice (31).…”