L-cysteine contributes to destructive activities of odontogenic cysts/tumor

Ji Li, Chunyu Feng, Xiaochan Pang, Xiang Li, Xinyu Dou, Erhui Jiang, Zhengjun Shang
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Abstract

Background

Odontogenic cysts/tumor can cause severe bone destruction, which affects maxillofacial function and aesthetics. Meanwhile, metabolic reprogramming is an important hallmark of diseases. Changes in metabolic flow affect all aspects of disease, especially bone-related diseases. At present, the researches on pathogenesis of odontogenic cysts/tumor are mainly focused on the level of gene regulation, but the effects of metabolic alterations on odontogenic cysts/tumor have still underexplored.

Materials and methods

Imaging analysis was used to evaluate the lesion size of different odontogenic lesions. Tartrate resistant acid phosphatase (TRAP) and immunohistochemistry (IHC) assays were utilized to detect the differences in bone destruction activity in odontogenic cysts and tumors. Furthermore, metabolomics and weighted gene co-expression network analysis (WGCNA) were conducted for the metabolomic features and key metabolite screening, respectively. The effect of ferroptosis inhibition on bone destruction was confirmed by IHC, immunofluorescence, and malondialdehyde colorimetric assay.

Results

The bone destruction activity of ameloblastoma (AM) was the strongest and the weakest in odontogenic cysts (OC). High-throughput targeted metabolomics was used to map the metabolomic profiles of OC, odontogenic keratocyst (OKC) and AM. WGCNA and differential analysis identified L-cysteine in OKC and AM. Cystathionine γ-lyase (CTH) was further screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The functions of L-cysteine were further validated. Finally, we confirmed that CTH affected destructive activities by regulating the sensitivity of epithelial cells to ferroptosis.

Conclusion

High-throughput targeted metabolomics performed on diseased tissue confirmed the unique alteration of metabolic profiles in OKC and AM. CTH and its metabolite L-cysteine are the key factors regulating destructive activities.

Abstract Image

L-半胱氨酸有助于牙源性囊肿/肿瘤的破坏活动
背景牙源性囊肿/肿瘤可导致严重的骨质破坏,影响颌面部功能和美观。同时,代谢重编程是疾病的一个重要特征。代谢流的变化会影响疾病的各个方面,尤其是与骨相关的疾病。目前,关于牙源性囊肿/肿瘤发病机制的研究主要集中在基因调控层面,但代谢改变对牙源性囊肿/肿瘤的影响仍未得到充分探索。利用酒石酸耐酸性磷酸酶(TRAP)和免疫组化(IHC)检测牙源性囊肿和肿瘤中骨破坏活性的差异。此外,代谢组学和加权基因共表达网络分析(WGCNA)分别用于代谢组学特征和关键代谢物的筛选。结果 骨髓母细胞瘤(AM)的骨破坏活性最强,而牙源性囊肿(OC)的骨破坏活性最弱。利用高通量靶向代谢组学绘制了OC、牙源性角化囊肿(OKC)和AM的代谢组图谱。WGCNA和差异分析确定了OKC和AM中的L-半胱氨酸。通过京都基因和基因组百科全书(KEGG)分析,进一步筛选出胱硫醚γ-裂解酶(CTH)。进一步验证了 L-半胱氨酸的功能。结论对病变组织进行的高通量靶向代谢组学研究证实,OKC 和 AM 的代谢谱发生了独特的变化。CTH及其代谢产物L-半胱氨酸是调节破坏活动的关键因素。
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