下调LAMA3可通过调节Hippo-YAP通路增强结肠癌对奥沙利铂的敏感性。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-01-09 DOI:10.1016/j.bbadis.2025.167665

Jiqiang Li , Yahui Yu , Rong Zeng, Yujiao Zou, Junguo Bu

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引用次数: 0

摘要

背景：奥沙利铂是结肠癌（CC）患者的一线化疗药物。然而，其耐药性限制了其治疗效果。方法：通过生物信息学方法鉴定GSE42387和GSE227315数据集中的奥沙利铂耐药相关差异表达基因（DEGs）。通过体外和体内功能实验，探讨层粘连蛋白亚单位α 3 （LAMA3）在耐药和肿瘤发生中的作用。利用京都基因与基因组百科全书（KEGG）途径富集分析和western blot对下游分子机制进行了探索。结果：共鉴定出6个与奥沙利铂耐药相关的枢纽基因，包括LAMB3、ITGA3、COL4A6、COL12A1、LAMA3和LAMC2，这些基因均在奥沙利铂耐药CC细胞系中高表达。LAMA3敲低使CC细胞对奥沙利铂治疗增敏，进一步抑制CC细胞的增殖、迁移和侵袭，增加凋亡。此外，LAMA3敲低可促进奥沙利铂在CC异种移植肿瘤模型中的治疗效果。在机制上，YAP的过表达显著抵消了LAMA3敲低引起的对奥沙利铂敏感性增强，表明LAMA3通过希波-YAP途径调节CC中奥沙利铂敏感性。结论：LAMA3敲低可通过调节Hippo-YAP通路促进CC对奥沙利铂的敏感性，为CC治疗提供新的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Knockdown of LAMA3 enhances the sensitivity of colon cancer to oxaliplatin by regulating the Hippo-YAP pathway

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Knockdown of LAMA3 enhances the sensitivity of colon cancer to oxaliplatin by regulating the Hippo-YAP pathway

Background

Oxaliplatin is the first-line chemotherapy for patients with colon cancer (CC). However, its resistance limits its therapeutic efficacy.

Methods

Oxaliplatin resistance-associated differentially expressed genes (DEGs) in the GSE42387 and GSE227315 datasets were identified through bioinformatics methods. Functional experiments were conducted both in vitro and in vivo to evaluate the roles of laminin subunit alpha 3 (LAMA3) in drug resistance and tumorigenesis. The downstream molecular mechanisms were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and western blot.

Results

Six hub genes associated with oxaliplatin resistance were identified, including LAMB3, ITGA3, COL4A6, COL12A1, LAMA3, and LAMC2, all of which were highly expressed in oxaliplatin-resistant CC cell lines. LAMA3 knockdown sensitized CC cells to oxaliplatin treatment, resulting in further inhibition of proliferation, migration, and invasion, as well as an increase in apoptosis in CC cells. Additionally, LAMA3 knockdown promoted the therapeutic efficacy of oxaliplatin in the CC xenograft tumor models. Mechanistically, overexpression of YAP notably counteracted the enhanced sensitivity to oxaliplatin caused by LAMA3 knockdown, indicating that LAMA3 modulates oxaliplatin sensitivity in CC through the Hippo-YAP pathway.

Conclusion

LAMA3 knockdown promotes CC sensitivity to oxaliplatin via modulating the Hippo-YAP pathway, providing new therapeutic targets for the CC treatment.

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.