TGFBI, Protein Linked to Lung Cancer, May Be IPF Treatment Target

Pulmonary fibrosis research suggests new way to block lung scarring response

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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The levels of transforming growth factor-beta-induced protein (TGFBI), a molecule involved in lung development and cancer, are significantly increased in cellular and rodent models of idiopathic pulmonary fibrosis (IPF), a study showed.

TGFBI was also found to mediate the pro-scarring effects of transforming growth factor-beta (TGF-beta) — a protein that plays a key role in IPF — through the regulation of GPSM2 and Snail, two proteins with opposing effects in cancer.

Notably, TGFBI suppression prevented a TGF-beta-induced scarring response and normalized the GPSM2/Snail axis.

These findings point to TGFBI as a new mediator of lung scarring, or fibrosis, and thereby a potential therapeutic target in IPF, the researchers noted.

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The study, “Transforming growth factor-β induced protein regulates pulmonary fibrosis via the G-protein signaling modulator 2 /Snail axis,” was published in the journal Peptides.

IPF is marked by lung scarring due to fibroblast maturation into myofibroblasts — the main cellular drivers of lung fibrosis that produce excessive amounts of extracellular matrix (ECM) molecules.

ECM molecules surround and support cells, but can cause tissue fibrosis when produced excessively.

Research to discover how TGFBI regulates pulmonary fibrosis

TGF-beta, a major pro-fibrotic molecule, can promote the production of TGFBI, an ECM protein implicated in lung development and in several cancers, including lung cancer. TGFBI is essential for epithelial-to-mesenchymal transition, a process whose dysregulation is key for cancer cell growth and for the development and progression of fibrosis.

Notably, Snail, a molecule with pro-cancer and pro-fibrotic properties, is known to be activated by TGFBI and suppressed by GPSM2, an inhibitory factor in lung cancer.

While this suggests that TGFBI and GPSM2 signaling pathways may interact, “whether TGFBI regulates pulmonary fibrosis via the GPSM2/Snail axis remains unclear,” the researchers wrote.

To address this, a research team in China evaluated the levels of TGFBI and its effects on GPSM2 and Snail in cellular and rat models of IPF.

The cellular model consisted of lab-grown human fibroblasts exposed to TGF-beta. IPF-like disease was induced in rats through the administration of bleomycin, a highly toxic chemotherapy agent, directly into their airways.

Researchers here found that TGFBI and Snail levels were significantly increased whereas those of GPSM2 were significantly lower in both IPF models. These changes were reversed upon exposure to a TGF-beta blocker.

The team then used the cellular model to better understand the dynamics between these molecules.

Notably, TGFBI suppression was found to reverse TGF-beta-induced fibrosis, while reducing Snail and increasing GPSM2 levels. Overproduction of GPSM2 significantly eased TGF-beta-induced pro-fibrotic effects and lowered Snail levels, while blocking Snail production also reduced fibrosis.

These findings suggested that TGF-beta promotes the production of TGFBI, which increases Snail by suppressing its repressor GPSM2.

Further analysis also suggested that TGFBI’s pro-fibrotic effects are mediated by its binding to a receptor protein called integrin alpha v beta 3.

Findings highlight that “the extracellular matrix protein TGFBI mediates pulmonary fibrosis through regulation of the GPSM2/Snail axis,” the researchers wrote.

As such, TGFBI “may be a potential therapeutic target for the treatment of pulmonary fibrosis,” they added.

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