Abstract：Objective To investigate the mechanism of hsa_circ_0006988 (circ_0006988) induced iron death in glioma cells. Methods The expression level of circ_0006988 in normal glioma cells HEB, A172, SHG44, and CHG-5 in gliomacells were detected. Glioma cells CHG-5 were then divided into Control group (blank control), si-NC group (transfected with siRNA control), si-circ group (transfected with circ_0006988 siRNA), si-Nrf2 group (transfected with Nrf2 siRNA), si-circ+Vector group (co-transfected circ_0006988 siRNA and negative control vector), si-circ+Nrf2 group (co-transfected circ_0006988 siRNA and Nrf2 overexpression vector). The expression of circ_0006988 in each group was detected by qRT-PCR. The content of Fe2+ was detected by colorimetry, the protein expressions of Nrf2, GPX4, Ferritin, TF, and TFR were detected by Western blot, ROS was detected by DCFHDA, and MDA was detected by thiobarbituric acid. Results The expression level of circ_0006988 in glioma cells A172, SHG44, and CHG-5 were higher than those in normal glioma cells (P＜0.05). The expression level of circ_0006988 in glioma cells A172 and SHG44 were lower than those of CHG-5 (P＜0.05). The contents of Fe2+, ROS, and MDA in glioma cells of si-circ group were higher than those of Control and si-NC group, and the protein expressions of Ferritin, TF, and TFR were higher than those of Control group and si-NC group (P＜0.05), while the protein expressions of Nrf2 and GPX4 were lower than those of Control group and si-NC group (P＜0.05). The protein expressions of Nrf2 and GPX4 in glioma cells in si-circ group were lower than those in si-NC group, the content of Fe2+, the protein expressions of Ferritin, TF and TFR, and the contents of ROS and MDA in glioma cells in si-NC group were higher than those in si-NC group (P＜0.05). The expression of Nrf2 and GPX4 proteins in glioma cells in si-circ+Nrf2 group were higher than that in si-circ+Vector group, the content of Fe2+, Ferritin, TF， and TFR proteins, the ROS and MDA contents in si-circ+Vector group were lower than those in si-circ+Vector group (P＜0.05). Conclusion Down-regulation of circ_0006988 can induce ferroptosis of glioma cells by inhibiting Nrf2/GPX4 signal.
赵水强 孟大伟 陈国强 李亮亮 王志文 胡甜甜 牛建星. hsa_circ_0006988诱导胶质瘤细胞铁死亡的机制研究[J]. 中国医药导报, 2023, 20(16): 11-15.
ZHAO Shuiqiang MENG Dawei CHEN Guoqiang LI Liangliang WANG Zhiwen HU Tiantian NIU Jianxing. Mechanism of iron death induced by hsa_circ_0006988 in glioma cells. 中国医药导报, 2023, 20(16): 11-15.
[1] Chao B，Jiang F，Bai H，et al. Predicting the prognosis of glioma by pyroptosis-related signature [J]. J Cell Mol Med，2022， 26（1）：133-143.
[2] Yang K，Wu Z，Zhang H，et al. Glioma targeted therapy：insi- ght into future of molecular approaches [J]. Molecular Cancer，2022，21（1）：1-32.
[3] Li J，Liu J，Xu Y，et al. Tumor heterogeneity in autophagy- dependent ferroptosis [J]. Autophagy，2021，17（11）：3361- 3374.
[4] Lei G，Zhuang L，Gan B. Targeting ferroptosis as a vulnerability in cancer [J]. Nat Rev Cancer，2022，22（7）：381-396.
[5] Zhang L，Tao H，Li J，et al. Comprehensive analysis of the competing endogenous circRNA-lncRNA-miRNA-mRNA network and identification of a novel potential biomarker for hepatocellular carcinoma [J]. Aging （Albany NY），2021，13（12）：15990-16008.
[6] Singh D，Kesharwani P，Alhakamy NA，et al. Accentuating CircRNA-miRNA-transcription factors axis：a conundrum in cancer research [J]. Front Pharmacol，2022，12：784801.
[7] Yang B，Teng F，Chang L，et al. Tumor-derived exosomal circ RNA_102481 contributes to EGFR-TKIs resistance via the miR-30a-5p/ROR1 axis in non-small cell lung cancer [J]. Aging （Albany NY），2021，13（9）：13264-13286.
[8] Yang C，Shi J，Wang J，et al. Circ_0006988 promotes the pro- liferation，metastasis and angiogenesis of non-small cell lung cancer cells by modulating miR-491-5p/MAP3K3 axis [J]. Cell Cycle，2021，20（13）：1334-1346.
[9] Yang C，Zhang Y，Lin S，et al. Suppressing the KIF20A/NUAK1/Nrf2/GPX4 signaling pathway induces ferroptosis and enhances the sensitivity of colorectal cancer to oxaliplatin [J]. Aging （Albany NY），2021，13（10）：13515-13534.
[10] Wang C，Chen S，Guo H，et al. Forsythoside a mitigates Alzheimer’s-like pathology by inhibiting ferroptosis-mediated neuroinflammation via Nrf2/GPX4 axis activation [J]. Int J Biol Sci，2022，18（5）：2075.
[11] Wang J，Zhu Q，Wang Y，et al. Irisin protects against sepsis-associated encephalopathy by suppressing ferroptosis via activation of the Nrf2/GPX4 signal axis [J]. Free Radic Biol Med，2022，187：171-184.
[12] 杨盛翔，孟繁成，白吉林.长链非编码RNA在神经胶质瘤的研究进展[J].中国微侵袭神经外科杂志，2021，26（2）：94-96.
[13] van Zonneveld AJ，K?觟lling M，Bijkerk R，et al. Circular RNAs in kidney disease and cancer [J]. Nat Rev Nephrol，2021， 17（12）：814-826.
[14] Qian Y，Li Y，Li R，et al. circ-ZNF609：A potent circRNA in human cancers [J]. J Cell Mol Med，2021，25（22）：10349- 10361.
[15] Lei G，Zhang Y，Hong T，et al. Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity [J]. Oncogene，2021，40（20）：3533-3547.
[16] Liao P，Wang W，Wang W，et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 [J]. Cancer Cell，2022，40（4）：365-378.
[17] 向亮，何东，曹科，等.铁死亡在恶性肿瘤治疗中的研究进展[J].中国肿瘤，2021，30（4）：300-308.
[18] Wei R，Zhao Y，Wang J，et al. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells [J]. Int J Biol Sci，2021，17（11）：2703- 2717.
[19] Pandrangi SL，Chittineedi P，Chikati R，et al. Role of dietary iron revisited：in metabolism，ferroptosis and pathophysiology of cancer [J]. Am J Cancer Res，2022，12（3）：974- 985.
[20] Cheng Z，Akatsuka S，Li GH，et al. Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis [J]. Cancer Sci，2022， 113（1）：65-78.
[21] Zazueta C，Jimenez-Uribe AP，Pedraza-Chaverri J，et al. Genetic Variations on Redox Control in Cardiometabolic Diseases：The Role of Nrf2 [J]. Antioxidants （Basel），2022， 11（3）：507-514.
[22] Basu P，Averitt DL，Maier C，et al. The Effects of Nuclear Factor Erythroid 2 （NFE2）-Related Factor 2 （Nrf2） Activation in Preclinical Models of Peripheral Neuropathic Pain [J]. Antioxidants （Basel），2022，11（2）：430-451.
[23] 李春燕，孙传政，宋鑫.肿瘤细胞死亡的一种新形式——铁死亡[J].中国生物化学与分子生物学报，2019， 35（11）：1208-1214.
[24] Ge MH，Tian H，Mao L，et al. Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway [J]. CNS Neurosci Ther，2021，27（9）：1023-1040.
[25] Chen X，Li J，Kang R，et al. Ferroptosis：machinery and regulation [J]. Autophagy，2021，17（9）：2054-2081.
京公网安备 11010502046598号