HMGB1调节铁死亡水平促进分化型甲状腺癌放射性碘耐药的分子机制研究

doi:10.3969/j.issn.1006-6233.2025.04.04

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Abstract Objective: To explore the possible molecular mechanisms of chronic inflammation in reducing the sensitivity of differentiated thyroid cancer to radioactive iodine therapy. Methods: Surgical resection tissues of patients with differentiated thyroid cancer (DTC tissues,21 cases) or radioiodine (RAI) refractory differentiated thyroid cancer (RR-DTC tissues,13 cases) and corresponding adjacent tissues (Adjacent tissues,34 cases) were included.The mRNA levels of HMGB1,TNF-α,IL-1β and IL-6 were determined by qPCR.The levels of Fe²⁺ and malondialdehyde (MDA) were determined by chemiluminescent assay.The relative expression levels of TLR4,NIS,p-p38 MAPK,p-PI3K and p-AKT were determined by Western blot.Twenty-four 5-6 weeks old female NOD SCID mice were randomly divided into 4 groups with 6 mice in each group:①K1 group,②K1+ Lienti-NIS KI group,③K1+ Lienti-NIS KI+ Lienti-TLR4 OE group,④K1+ Lienti-NIS KI+ Lienti-vector group.Human papilloma thyroid cancer cell line K1 cells were transfected with lentiviral particles of Lenti-NIS KI to mediate knock-in NIS,or were combined transfected with Lentiviral particles of Lenti-NIS KI + Lenti-TLR4 OE to mediate knockin NIS+ over-expression TLR4.The knock-in control group was Lenti-NIS KI + Lenti-vector group.The K1 cells were injected subcutaneously into the right shoulder back of mice to construct xenografts.Two weeks later,the mice were treated with 3.7 MBq Na¹³¹I intravenously.The xenografts' growth was monitored every 2 days.On the 36th day,mice were sacrificed and the tumors were collected.The relative expression levels of TLR4,NIS,HMGB1,p-p38 MAPK,p-PI3K,and p-AKT were determined by Western blot.The levels of Fe²⁺ and MDA in tumors were determined by chemiluminescent assay. Results: Compared with Adjacent tissues,in DTC tissues,HMGB1,TNF-α,IL-1β,and IL-6 mRNA levels were increased (P<0.05).Fe²⁺ and MDA levels were increased (P<0.05).The relative expression levels of TLR4,p-p38 MAPK,p-PI3K,and p-AKT were increased (P<0.05).The above indexes were further increased in RR-DTC tissues (P<0.05).The relative expression levels of NIS were decreased in RR-DTC tissues (P<0.05).Compared with K1 group,in K1+ Lenti-NIS KI group,the relative expression levels of NIS and HMGB1,as well as Fe²⁺ and MDA levels were increased (P<0.05),and the tumor growth rates were significantly inhibited (P<0.05).Compared with K1 + Lenti-NIS KI group,in K1 + Lenti-NIS KI+ Lenti-TLR4 OE group,the relative expression levels of TLR4,p-p38 MAPK,p-PI3K,and p-AKT in tumors were up-regulated,while the relative expression levels of NIS and HMGB1 were decreased.The levels of Fe²⁺ and MDA were decreased,and the tumor growth rates were significantly increased (P<0.05). Conclusion: DTC up-regulated HMGB1 to inhibit ferroptosis through up-regulation of TLR4 expression,and reduce the sensitivity of DTC to RAI treatment.

Key words： Differentiated thyroid cancer Radioactive iodine therapy resistance HMGB1 TLR4 Ferroptosis

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	WUFUER Yimaer
	DAERHAN Sailikebieke
	DENG Chao
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WUFUER Yimaer,DAERHAN Sailikebieke,DENG Chao, et al. Molecular Mechanisms of HMGB1 in Regulating Ferroptosis to Promote Radioactive Iodine Resistance in Differentiated Thyroid Cancer[J]. HeBei Med, 2025, 31(4): 549-556.

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http://www.hbyxzzs.cn/EN/10.3969/j.issn.1006-6233.2025.04.04 OR http://www.hbyxzzs.cn/EN/Y2025/V31/I4/549

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