miR-141 regulates TGF-β1-induced epithelial-mesenchymal transition through repression of HIPK2 expression in renal tubular epithelial cells

Abstract

Epithelial-mesenchymal transition (EMT) plays a critical role in embryonic development, wound healing, tissue regeneration, cancer progression and organ fibrosis. The proximal tubular epithelial cells undergo EMT, resulting in matrix-producing fibroblasts and thereby contribute to the pathogenesis of renal fibrosis. The profibrotic cytokine, TGF-β, is now recognized as the main pathogenic driver that has been shown to induce EMT in tubular epithelial cells. Increasing evidence indicate that HIPK2 dysfunction may play a role in fibroblasts behavior, and therefore, HIPK2 may be considered as a novel potential target for anti-fibrosis therapy. Recently, members of the miR-200 family (miR-200a, b and c and miR-141) have been shown to inhibit EMT. However, the steps of the multifactorial renal fibrosis progression that these miRNAs regulate, particularly miR-141, are unclear. To study the functional importance of miR-141 in EMT, a well-established in vitro EMT assay was used to demonstrate renal tubulointerstitial fibrosis; transforming growth factor-β1-induced EMT in HK-2 cells. Overexpression of miR-141 in HK-2 cells, either with or without TGF-β1 treatment, hindered EMT by enhancing E-cadherin and decreasing vimentin and fibroblast-specific protein 1 expression. miR-141 expression was repressed during EMT in a dose- and time-dependent manner through upregulation of HIPK2 expression. Ectopic expression of HIPK2 promoted EMT by decreasing E-cadherin. Furthermore, co-transfection of miR-141 with the HIPK2 ORF clone partially inhibited EMT by restoring E-cadherin expression. miR-141 downregulated the expression of HIPK2 via direct interaction with the 3′-untranslated region of HIPK2. Taken together, these findings aid in the understanding of the role and mechanism of miR-141 in regulating renal fibrosis via the TGF-β1/miR-141/HIPK2/EMT axis, and miR-141 may represent novel biomarkers and therapeutic targets in the treatment of renal fibrosis.

Downregulation of miRNA‐141 in breast cancer cells is associated with cell migration and invasion: involvement of ANP32E targeting

“…Overexpression of hsa-miR-141 has been shown to inhibit invasion and migration of breast cancer, colorectal cancer, and pancreatic cancer [10,21,22]. miR-141 was also found to regulate cancer cell growth and metastasis in lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and prostate cancer [8][9][10][11][12][13]. In this study, we found that miR-141 was downregulated in breast cancer in tumor tissues compared with matched surrounding tissues.…”

“…In BC cells, miR-141 targets EGFR, and inhibits its translation [7]. miR-141 was also found to regulate cancer cell growth and metastasis in lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and prostate cancer [8][9][10][11][12][13].…”

The Roles of MicroRNA-141 in Human Cancers: From Diagnosis to Treatment

“…As is well-known, EMT is a facilitator of tissue remodeling in many physiological progressions such as embryonic development, wound healing, tissue regeneration and organ fibrosis [65]. EMT is also a fatal early step in tumor metastasis formation by controlling the detachment of invasive cancer cells from the primary tumor [66].…”

Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome

“…In HIV-infected renal tubular epithelial cells, HIPK2 induced expression of pro-fibrosis markers via activating p53, TGF-β, and Wnt/Notch pathways [84]. Downregulation of HIPK2 leads to upregulated C-cadherin and decreases epithelial to mesenchymal transition [90]. These results suggest that HIPK2 is one of crucial regulators of kidney fibrosis by activating the upstream fibrosis signaling pathway.…”