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Identification and tissue-level validation of ferroptosis-related genes in small intestinal neuroendocrine neoplasms
Chuang Lv1,2, Zhiqiang Liu1,2, Chengcheng Tong1,2
1Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China.
Background:
Small intestinal neuroendocrine neoplasms (SI-NENs), a subgroup of neuroendocrine tumors originating from neuroendocrine cells in the small intestine, present significant therapeutic challenges, and their relationship with ferroptosis-a regulated form of cell death driven by iron-dependent lipid peroxidation-remains poorly understood. This study aimed to identify the ferroptosis-related genes in SI-NENs and evaluate their clinical relevance.
Methods:
The RNA sequencing data of SI-NENs patients were retrieved from two public datasets (GSE65286 and GSE98894). Machine learning (LASSO regression, a regularization method for selecting key features by reducing redundant genes, and random forest, an ensemble learning algorithm that builds multiple decision trees to improve prediction accuracy) was adopted to identify the core ferroptosis-related genes in SI-NENs. An external cohort consisting of 10 health volunteers and 14 SI-NENs patients was enrolled and intestinal mucosal biopsies were obtained for validation.
Results:
CDCA3, CDC25A, CYP4F8, and MYB were identified as the core ferroptosis-related genes in SI-NENs patients via machine learning. In the external cohort, immunofluorescence (IF) staining confirmed a significantly decreased expression of CYP4F8 and CDCA3 in patients with SI-NENs compared with the health control. Moreover, in G2/3 patients, the expression levels of CYP4F8 and CDCA3 were significantly decreased compared with G1 patients. In contrast, no significant difference in the expression of the four core ferroptosis genes was found across the different tumor locations, the age stratifications, or the abdominal pain statuses. In addition, a statically negative correlation of the expression of CYP4F8 was further detected concerning the tumor diameter and the expression of Ki67.
Conclusion:
Four core ferroptosis-related genes (CDCA3, CDC25A, CYP4F8, and MYB) were identified in SI-NENs patients, which may aid in developing the diagnostic biomarkers and therapeutic targets in the clinic.
Insights
Researchers identified four key ferroptosis-related genes (CDCA3, CDC25A, CYP4F8, and MYB) in small intestinal neuroendocrine neoplasms (SI-NENs). These genes show potential as diagnostic biomarkers and therapeutic targets for SI-NENs.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small intestinal neuroendocrine neoplasms (SI-NENs) are challenging to treat.
- The role of ferroptosis, an iron-dependent cell death, in SI-NENs is not well understood.
Purpose of the Study:
- Identify ferroptosis-related genes in SI-NENs.
- Evaluate the clinical relevance of these genes.
Main Methods:
- Utilized RNA sequencing data from public SI-NENs datasets.
- Applied machine learning (LASSO regression, random forest) to identify core ferroptosis-related genes.
- Validated findings using immunofluorescence on patient biopsies.
Main Results:
- Identified CDCA3, CDC25A, CYP4F8, and MYB as core ferroptosis-related genes in SI-NENs.
- Found decreased expression of CYP4F8 and CDCA3 in SI-NENs patients compared to controls.
- Observed lower CYP4F8 and CDCA3 expression in higher grade (G2/3) SI-NENs.
Conclusions:
- Four core ferroptosis-related genes (CDCA3, CDC25A, CYP4F8, MYB) were identified in SI-NENs.
- These genes may serve as diagnostic biomarkers.
- These genes represent potential therapeutic targets for SI-NENs.
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