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MiR-320b/RAD21 axis affects hepatocellular carcinoma radiosensitivity to ionizing radiation treatment through DNA damage repair signaling.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and is associated with high mortality. Ionizing radiation (IR)-based therapy causes DNA damage, exerting a curative effect; however, DNA damage repair signaling pathways lead to HCC resistance to IR-based therapy. RAD21 is a component of the cohesion complex, crucial for chromosome segregation and DNA damage repair, while it is still unclear whether RAD21 is implicated in DNA damage and influences IR sensitivity in HCC. The current research explores the effect and upstream regulatory mechanism of RAD21 on IR sensitivity in HCC. In the present study, RAD21 mRNA and protein expression were increased within HCC tissue samples, particularly within IR-insensitive HCC tissues. The overexpression of RAD21 partially attenuated the roles of IR in HCC by promoting the viability and suppressing the apoptosis of HCC cells. RAD21 overexpression reduced the culture medium 8-hydroxy-2-deoxyguanosine concentration and decreased the protein levels of ?H2AX and ATM, suggesting that RAD21 overexpression attenuated IR treatment-induced DNA damage to HCC cells. miR-320b targeted RAD21 3'-UTR to inhibit RAD21 expression. In HCC tissues, particularly in IR-insensitive HCC tissues, miR-320b expression was significantly downregulated. miR-320b inhibition also attenuated IR treatment-induced DNA damage to HCC cells; more importantly, RAD21 silencing significantly attenuated the effects of miR-320b inhibition on IR treatment-induced DNA damage, suggesting that miR-320b plays a role through targeting RAD21. In conclusion, an miR-320b/RAD21 axis modulating HCC sensitivity to IR treatment through acting on IR-induced DNA damage was demonstrated. The miR-320b/RAD21 axis could be a novel therapeutic target for further study of HCC sensitivity to IR treatment.

SUBMITTER: Wang J

PROVIDER: S-EPMC7894001 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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MiR-320b/RAD21 axis affects hepatocellular carcinoma radiosensitivity to ionizing radiation treatment through DNA damage repair signaling.

Wang Jianyang J Zhao Hong H Yu Jing J Xu Xin X Jing Hao H Li Ning N Tang Yuan Y Wang Shulian S Li Yexiong Y Cai Jianqiang J Jin Jing J

Cancer science 20201231 2

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and is associated with high mortality. Ionizing radiation (IR)-based therapy causes DNA damage, exerting a curative effect; however, DNA damage repair signaling pathways lead to HCC resistance to IR-based therapy. RAD21 is a component of the cohesion complex, crucial for chromosome segregation and DNA damage repair, while it is still unclear whether RAD21 is implicated in DNA damage and influences IR sensitivity i ...[more]

PMID: 33251678

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Project description:BackgroundMajor genomic surveillance mechanisms regulated in response to DNA damage exist at the G1/S and G2/M checkpoints. It is presumed that these delays provide time for the repair of damaged DNA. Cells have developed multiple DNA repair pathways to protect themselves from different types of DNA damage. Oxidative DNA damage is processed by the base excision repair (BER) pathway. Little is known about the BER of ionizing radiation-induced DNA damage and putative heterogeneity of BER in the cell cycle context. We measured the activities of three BER enzymes throughout the cell cycle to investigate the cell cycle-specific repair of ionizing radiation-induced DNA damage. We further examined BER activities in G2 arrested human cells after exposure to ionizing radiation.ResultsUsing an in vitro incision assay involving radiolabeled oligonucleotides with specific DNA lesions, we examined the activities of several BER enzymes in the whole cell extracts prepared from synchronized human HeLa cells irradiated in G1 and G2 phase of the cell cycle. The activities of human endonuclease III (hNTH1), a glycosylase/lyase that removes several damaged bases from DNA including dihydrouracil (DHU), 8-oxoguanine-DNA glycosylase (hOGG1) that recognizes 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG) lesion and apurinic/apyrimidinic endonuclease (hAPE1) that acts on abasic sites including synthetic analog furan were examined.ConclusionOverall the repair activities of hNTH1 and hAPE1 were higher in the G1 compared to G2 phase of the cell cycle. The percent cleavages of oligonucleotide substrate with furan were greater than substrate with DHU in both G1 and G2 phases. The irradiation of cells enhanced the cleavage of substrates with furan and DHU only in G1 phase. The activity of hOGG1 was much lower and did not vary within the cell cycle. These results demonstrate the cell cycle phase dependence on the BER of ionizing radiation-induced DNA damage. Interestingly no evidence of enhanced BER activities was found in irradiated cells arrested in G2 phase.

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MiR-320b/RAD21 axis affects hepatocellular carcinoma radiosensitivity to ionizing radiation treatment through DNA damage repair signaling.

Publications

MiR-320b/RAD21 axis affects hepatocellular carcinoma radiosensitivity to ionizing radiation treatment through DNA damage repair signaling.

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