TIAM1, a Gene Associated with Lung Cancer, Inhibits Fibroblast Differentiation in a Mouse Model of PF
A gene previously shown to be associated with cancer — called T-cell lymphoma invasion and metastasis 1 (TIAM1) — may be an effective therapeutic target in pulmonary fibrosis (PF), a new study from China suggests.
The study reporting the findings, “TIAM1 inhibits lung fibroblast differentiation in pulmonary fibrosis,” was published in the journal Experimental and Therapeutic Medicine.
The study’s senior author was Lixia Ma, from the Department of Thoracic Oncology, Jilin Province Cancer Hospital, Changchun, in Jilin, China.
The differentiation (specialization) of fibroblasts is critical for the development of idiopathic PF (IPF). Fibroblasts are a common cell type in the lung, responsible for the production of extracellular matrix, which provides structural and biochemical support to cells.
In disease, such as in IPF, activated fibroblasts resist death and exhibit high proliferation and differentiation rates.
Human TIAM1, an oncogene (genes that may cause cancer), regulates cell adhesion, invasion and migration, which are implicated in cancer development. Previous studies in humans and cells found a positive correlation between TIAM1 levels and lung cancer. Associations with amyotrophic lateral sclerosis (ALS) and colorectal cancer also have been described. However, the oncogene’s role in lung fibroblasts in PF remains unclear.
Cytokines (molecules released by immune cells) are among the key factors involved in fibroblast differentiation and lung fibrosis. In particular, the cytokine transforming growth factor-β (TGF-β) induces fibroblast growth and PF in mice. Among the molecules involved in TGF-β effects on gene expression, nuclear factor (NF)-κB has been shown to be active in lung fibroblasts in PF.
For this study, scientists used an experimentally-induced mouse model of PF to determine the production and roles of TIAM1 in lung fibroblasts during the disease.
Results showed that TIAM1 levels were significantly augmented in fibrotic lung tissue and lung fibroblasts from PF mice compared to controls.
Furthermore, TGF-β augmented TIAM1 production and differentiation in human lung fibroblasts. This effect was significantly diminished after blocking NF-κB biological mechanisms.
Importantly, the researchers further observed that exaggerated production of TIAM1, in contrast, significantly inhibited fibroblast differentiation induced by TGF-β.
Overall, the results indicate that “TIAM1 is critical for fibroblast differentiation and PF,” the team wrote. The results also “indicate that the expression of TIAM1 is associated with differentiation of lung fibroblasts, and that TGF-β, which is a key factor of [PF], directly stimulates fibroblast differentiation and TIAM1 expression via an NF-κB-dependent pathway.”
The reported inhibition of the differentiation of lung fibroblasts by TIAM1 is a promising therapeutic target in PF, the researchers concluded.