The newly identified role of ARID1A gene mutations could explain key aspects of the etiopathogenesis of cholangiocarcinoma (CCA), a study suggests.
“The identification of ARID1A as critical to the function of the [transforming growth factor β (TGF-β)-Smad pathway] in biliary cells and that ARID1A suppresses [CCA] offers insight into the epidemiologic finding that mutations in this pathway are enriched in [CCAs] arising in the settings of primary biliary injury when TGF-β-Smad is likely to function to restrain biliary carcinogenesis,” wrote Aram F. Hezel, of the University of Rochester Medical Center in Rochester, New York, and colleagues.
The findings were published online in the journal Cell Reports.
This experimental study used culture cells and murine models to observe the behavior of molecular signals and gene expression in the presence of ARID1A mutations and compare them to those of cells with the normal ARID1A genotype.
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The researchers demonstrated that mutations in both Kras and ARID1A likely promote the expression of tumor precursors in the biliary compartment and may be responsible for the development of CCA. These changes occurred more quickly in the presence of hepatic inflammation.
Cells with an ARID1A mutation exhibited important differences in their division patterns when compared to the wild-type. Specifically, the cellular events that corresponded to the loss of this gene included increased cellular proliferation while avoiding control mechanisms in the cell cycle, senescence, and ample variations in the chromatic configuration, such as closure at enhancer regions.
Moreover, to understand the exact mechanism through which such genetic variations could lead to an increased risk of developing CCA, the study explained the intracellular pathways involved. Notably, defects in the Kras and ARID1A genes led to decreased tumor-suppressing activity of the TGF-β-Smad4 pathway.
Although mutations in ARID1A have already been associated with CCA, their exact role in the pathophysiology of this disease has not yet been described. For a neoplasm with such a high mortality rate and scarce therapeutic options that result in a disease-free outcome, understanding intracellular actors could potentially lead to the identification of novel biomarkers and treatment targets.
“It will be important to understand whether manipulation of the TGF-β axis could offer a therapeutic strategy in advanced human [CCAs] that harbor ARID1A mutations,” the authors concluded.
Guo B, Friedland SC, Alexander W, et al. Arid1a mutation suppresses TGF-β signaling and induces cholangiocarcinoma. Cell Rep. 2022;40(9):111253. doi:10.1016/j.celrep.2022.111253