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Original Article
ALYREF-Mediated Regulation of TBL1XR1 and KMT2E Synergistically Upregulates APOC1, Contributing to Oxaliplatin Resistance in Esophageal Cancer
Jie Hu1orcid , Qilong Liu2, Bi Feng1, Yanling Lu1, Kai Chen1orcid

DOI: https://doi.org/10.4143/crt.2024.1091 [Accepted]
Published online: February 4, 2025
1Department of Medical Oncology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
2Department of Gastroenterology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
Corresponding author:  Kai Chen
Tel: 86-13570289193 Email: chenk6@mail.sysu.edu.cn
Received: 15 November 2024   • Accepted: 3 February 2025
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Purpose
Esophageal cancer (EC) is a rapidly progressing malignancy characterized by a low survival rate and limited treatment success, largely due to late-stage detection, frequent recurrence, and a high propensity for metastasis, despite ongoing advances in therapeutic strategies. While oxaliplatin (L-OHP) is a potent chemotherapeutic agent that induces apoptosis in EC cells, its effectiveness is significantly hindered by the development of resistance.
Materials and Methods
The assessment of gene and protein expression was conducted through a combination of RT-qPCR, Western blot, and IHC staining. Cell viability was assessed using the CCK-8 assay. The interactions among ALYREF, TBL1XR1, KMT2E, and APOC1 were investigated through RIP, ChIP, ChIP-reChIP, RNA pulldown, and dual-luciferase assays. An in vivo mouse model of EC was established.
Results
Expression levels of both APOC1 and ALYREF were elevated in L-OHP-resistant EC tissues and cell lines, and their silencing enhanced sensitivity to L-OHP. TBL1XR1 and KMT2E synergistically upregulated APOC1 expression. Moreover, ALYREF recognized the m5C sites on TBL1XR1 and KMT2E mRNAs, stabilizing these transcripts and promoting APOC1 expression. The regulatory role of these interactions was further validated in vivo.
Conclusion
This study demonstrated that ALYREF interacted with the m5C sites on TBL1XR1 and KMT2E mRNAs, enhancing their stability and leading to increased transcription of APOC1, which in turn contributed to L-OHP resistance in EC. These findings suggest that targeting APOC1 could be a promising strategy for overcoming L-OHP resistance in EC.

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    ALYREF-Mediated Regulation of TBL1XR1 and KMT2E Synergistically Upregulates APOC1, Contributing to Oxaliplatin Resistance in Esophageal Cancer
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