Abstract
Radiotherapy often causes unwanted side effects such as radiation-induced fibrosis and second malignancies. Fucoidan, a sulfated polysaccharide extracted from brown seaweed, has many biological effects including anti-inflammation and anti-tumor. In the present study, we investigated the radioprotective effect of Oligo-Fucoidan (OF) using a zebrafish animal model. Adult zebrafish of wild-type and transgenic fish with hepatocellular carcinoma were orally fed with Oligo-Fucoidan before irradiation. Quantitative PCR, Sirius red stain, hematoxylin, and eosin stain were used for molecular and pathological analysis. Whole genomic microarrays were used to discover the global program of gene expression after Oligo-Fucoidan treatment and identified distinct classes of up- and downregulated genes/pathways during this process. Using Oligo-Fucoidan oral gavage in adult wild-type zebrafish, we found Oligo-Fucoidan pretreatment decreased irradiation-induced fibrosis in hepatocyte. Using hepatitis B virus X antigen (HBx), Src and HBx, Src, p53−/+ transgenic zebrafish liver cancer model, we found that Oligo-Fucoidan pretreatment before irradiation could lower the expression of lipogenic factors and enzymes, fibrosis, and cell cycle/proliferation markers, which eventually reduced formation of liver cancer compared to irradiation alone. Gene ontology analysis revealed that Oligo-Fucoidan pretreatment increased the expression of genes involved in oxidoreductase activity in zebrafish irradiation. Oligo-Fucoidan also decreased the expression of genes involved in transferase activity in wild-type fish without irradiation (WT), nuclear outer membrane-endoplasmic reticulum membrane network, and non-homologous end-joining (NHEJ) in hepatocellular carcinoma (HCC) transgenic fish. Rescue of those genes can prevent liver cancer formation. Conclusions: Our results provide evidence for the ability of Oligo-Fucoidan to prevent radiation-induced fibrosis and second malignancies in zebrafish.
Highlights
Radiotherapy (RT) consists of high-energy X-ray irradiation that is meant to target rapidly dividing cells such as tumor cells
We identified 149 candidate genes that were upregulated by irradiation (R/control) and downregulated by Oligo-Fucoidan pretreatment before radiation (OF + R/R) at least two-fold with a p-value less than 0.05 (Figure 6D,E); these genes were enriched in transferase activity (Figure 6F)
We identified 234 genes that were upregulated by 40 Gy irradiation in hepatitis B virus X antigen (HBx),src transgenic fish with diet-induced obesity (DIO) (DIO + R/DIO) and upregulated by Oligo-Fucoidan pretreatment before radiation in both batches (DIO + OF + R/R) at least two-fold with a p-value less than 0.05, and those genes involved Oligo-Fucoidan decreased the expression of genes involved in nuclear outer membrane-endoplasmic reticulum membrane network and non-homologous end-joining (NHEJ) in hepatocellular carcinoma (HCC) transgenic fish (Figure 7D–F)
Summary
Radiotherapy (RT) consists of high-energy X-ray irradiation that is meant to target rapidly dividing cells such as tumor cells. RT damages the DNA within cells, often resulting in impaired cell division and subsequent cell death [1,2]. RT entails a balance between destroying cancerous cells and minimizing damage to normal cells [3] since RT can kill dividing cancerous cells as well as dividing non-cancerous cells, resulting in many undesired side effects [3]. RT-induced secondary malignancies (SM) may develop after X-ray irradiation [4]. RT leads to DNA mutations and cell death directly and generates free radical damage to essential cellular enzymes [4]. The secondary malignancy (SM) or so-called late effect may not be observed right after the end of treatment [6,7,8]
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