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.
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2025, Vol. 31 
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