Plasma Fibrinogen-Like 1 as a Potential Biomarker for Radiation-Induced Liver Injury

Abstract

Liver damage upon exposure to ionizing radiation, whether accidental or because of therapy can contribute to liver dysfunction. Currently, radiation therapy is used for various cancers including hepatocellular carcinoma; however, the treatment dose is limited by poor liver tolerance to radiation. Furthermore, reliable biomarkers to predict liver damage and associated side-effects are unavailable. Here, we investigated fibrinogen-like 1 (FGL1)-expression in the liver and plasma after radiation exposure. We found that 30 Gy of liver irradiation (IR) induced cell death including apoptosis, necrosis, and autophagy, with fibrotic changes in the liver occurring during the acute and subacute phase in mice. Moreover, FGL1 expression pattern in the liver following IR was associated with liver damage represented by injury-related proteins and oxidative stress markers. We confirmed the association between FGL1 expression and hepatocellular injury by exposing human hepatocytes to radiation. To determine its suitability, as a potential biomarker for radiation-induced liver injury, we measured FGL1 in the liver tissue and the plasma of mice following total body irradiation (TBI) or liver IR. In TBI, FGL1 showed the highest elevation in the liver compared to other major internal organs including the heart, lung, kidney, and intestine. Notably, plasma FGL1 showed good correlation with radiation dose by liver IR. Our data revealed that FGL1 upregulation indicates hepatocellular injury in response to IR. These results suggest that plasma FGL1 may represent a potential biomarker for acute and subacute radiation exposure to the liver.

Fibrinogen-Like Protein 1 Modulates Sorafenib Resistance in Human Hepatocellular Carcinoma Cells

“…In addition, high plasma FGL1 expression is associated with poor response to immunotherapy, suggesting FGL1 as a potential biomarker for predicting the outcome of cancer immunotherapy [ 17 ]. Moreover, FGL1 expression had been reported to be upregulated both in vivo and in vitro following irradiation, indicating the possibility of FGL1 as a biomarker for liver injury [ 27 ]. In contrast, overall survival time was found to be remarkably shorter in patients with gastric cancer with high FGL1 expression than in gastric cancer patients showing low FGL1 expression [ 28 ].…”

“…Immunoblotting was performed as described previously [ 27 ]. Briefly, cells were lysed with RIPA buffer supplemented with protease inhibitor.…”

The role of Fibrinogen-like proteins in Cancer

“…While a study showed that FGL1 promotes HCC tumor formation by inhibiting the activation of antigen-specific T cells 15 , another study found that FGL1 could inhibit the growth and proliferation of HCC, which runs counter to previous conclusions 19 . Therefore, the actual effect of FGL1 on hepatocytes is controversial 17 .…”

“…FGL1 is inextricably linked to obesity 16 . Meanwhile recent researches have highlighted that FGL1 may be a dramatic and important benchmark for measuring radiation-induced liver damage 17 . FGL1 serves as a pivotal “bridge” between liver regeneration and adipose tissue function 18 .…”

Development of a nanobody-based immunoassay for the sensitive detection of fibrinogen-like protein 1

“…Trials in which therapies were tailored based on biomarker profiling indicated that matched therapy achieved a higher objective response rate and a lower toxicity [13,16,17]. From a clinical perspective, patients' circulating FGL1 may provide information on the activation status of the FGL1-LAG-3 pathway and serve as a diagnostic and prognostic biomarker in clinical studies to design and detect innovative immunotherapies [18][19][20]. In addition, the analysis of FGL1 in serum as a liquid biopsy is a simple and noninvasive alternative to surgical biopsies that allows doctors to gather a range of tumor-related information and provides clues to the most effective immunotherapy.…”