Researchers identified a new mechanism through which C-MYC may induce the proliferation and differentiation of pulmonary fibroblasts in a rodent model with idiopathic pulmonary fibrosis (IPF), as published in Cellular Signalling. The mechanism involves the microRNA miR-9-5p and the TATA box-binding protein-like 1 (TBPL1).

“This identification of a functional role of C-MYC furthers the existing information of the mechanisms of IPF, with potential to guide future development of a treatment modality involving the C-MYC/miR-9-5p/TBPL1 axis in IPF,” the researchers said.

They observed overexpression of C-MYC in IPF mice’s lung tissue. Upregulation of C-MYC led to the activation of miR-9-5p which, in turn, negatively regulated the expression of TBPL1. These events promoted the proliferation and differentiation of pulmonary fibroblasts.


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Accordingly, treatment of IPF mice’s lung tissue cells with the C-MYC inhibitor 10058-F4 decreased the expression of miR-9-5p and repressed pulmonary fibrosis by up-regulating TBPL1.

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In addition, the researchers observed an increase in fibrotic markers (such as α-SMA, COL1, and FN) in response to C-MYC overexpression. The expression of these markers decreased in response to treatment with the C-MYC inhibitor.

The results presented in this study are further supported by other studies that reported increased levels of miR-9-5p in patients with IPF. Moreover, these studies suggested that miR-9-5p is involved in the transformation of fibroblasts into myofibroblasts.

“Myofibroblasts in IPF secrete collagen, leading to abnormal lung function, and are furthermore characterized by increased focal-adhesion formation and expression of α-SMA protein,” the researchers explained.

Previous studies also showed that TBPL1, which is a known target of other microRNAs, promotes myofibroblast activation by interfering with the formation of focal adhesions via integrin-β1. However, its role on pulmonary fibroblasts proliferation and differentiation remains to be elucidated.

Reference

Qin H, Tang Y, Mao Y, et al. C-MYC induces idiopathic pulmonary fibrosis via modulation of miR-9-5p-mediated TBPL1. Cell Signal. Published online February 3, 2022. doi:10.1016/j.cellsig.2022.110274