Formin mDia1 contributes to migration and epithelial‐mesenchymal transition of tubular epithelial cells exposed to TGF‐β1

Abstract

Renal tubular epithelial cells may undergo epithelial‐mesenchymal transition (EMT) in response to stimuli, such as transforming growth factor (TGF)‐β1, leading to myofibroblast activation and renal fibrosis. The formin mDia1 is required for nucleation and polymerization of actin and the microtubule cytoskeleton. The present study sought to explore the role of mDia1 in EMT of tubular epithelial cells. A rat model of unilateral ureteral obstruction (UUO) was established. The expression of TGF‐β1, collagen I, collagen III, and mDia1 in the kidneys was examined at day 7 after surgery. The effect of mDia1 on EMT was explored in NRK‐52E cells by exposing them to TGF‐β1. Increased expression of TGF‐β1, collagen I, collagen III, and mDia1 was found in obstructive kidneys of UUO model rats. Exposing rat tubular epithelial cells to TGF‐β1 promoted collagen I and collagen III expression but had no effect on mDia1 expression. Silencing mDia1 expression impeded epithelial cell migration as well as reduced TGF‐β1, collagen, and Profilin1 expression, whereas mDia1 overexpression exerted an opposite effect. Furthermore, mDia1 regulated the expression of vimentin, α‐smooth muscle actin, and E‐cadherin and focal adhesion‐kinase (FAK)/Src activation through Profilin1. Inhibition of the mDia1 activator RhoA by fasudil reversed EMT, and FAK/Src activation induced by mDia1. In conclusion, mDia1 regulated tubular epithelial cell migration, collagen expression, and EMT in NRK‐52E cells exposed to TGF‐β1. Thus, suppression of mDia1 activation might be a strategy to counteract renal fibrosis.

DpdtC-Induced EMT Inhibition in MGC-803 Cells Was Partly through Ferritinophagy-Mediated ROS/p53 Pathway

“…The immunofluorescence and Western blotting analysis confirmed our speculation because of the alteration in epithelial-mesenchymal markers after DpdtC treatment (Figure 4), in accordance with others observation [45]. To corroborate the ability of DpdtC in induction, the EMT model that induced by TGF-β1 needed to be established for this method has been widely accepted in molecular biology [46]. It was interesting that DpdtC abolished the action of TGF-β1 on EMT induction in the present study ( Figure 5), demonstrating that DpdtC was able to inhibit EMT, which was in accordance with the action of the iron chelator reported previously [47].…”

Fibrogenic signals persist in DAA-treated HCV patients after sustained virological response

“…So far, we focused on the protein diaphanous homolog 1 (DIAPH1) belonging to the family of formin proteins and recently described to promote myofibroblastic activation of HSCs. [36][37][38] Indeed, this protein was found as the most upregulated in T0, and worthy of note, also in T6 samples despite viral clearance. With the intent to validate this evidence by means of a different approach and in order to extend it to a broader patient group, western blot analysis was performed on 14 HD and 20 longitudinally enrolled HCV patient (T0 and T6) EV samples.…”

“…DIAPH1 has a key role in myofibroblast differentiation and is involved in actin nucleation/ elongation and ACTA2 induction. 37,38 Notably, it has recently been shown that DIAPH1 stimulates myofibroblastic activation of HSCs, promoting the endocytosis of TGFbRII 36 ; it may also contribute to HSC activation by favoring the formation of ACTA2positive stress fibers. Moreover, DIAPH1 inactivation suppresses HSCs' tumor-promoting effects in a tumor implantation mouse model.…”

Epithelial Mesenchymal Transition (EMT) and Associated Invasive Adhesions in Solid and Haematological Tumours

“…Formins are responsible for the linear polymerisation of F-actin in filopodia while fascin cross-links the formed filaments in parallel bundles [ 68 , 69 ]. Formation of filopodia [ 70 , 71 ] downstream of activation of TWIST1 and SNAIL1 [ 72 ] and the expression of formins [ 73 , 74 ] regulate the migration of cancer cells undergoing EMT. Additionally, the upregulation of formins contributes to metastasis formation [ 75 ], and high levels of fascin correlate with poor prognosis in a number of cancers including breast, lung, gastrointestinal and oral squamous cell carcinoma [ 64 , 76 , 77 ], suggesting that their role in EMT contributes to cell invasion and the formation of secondary tumour foci.…”