机械拉伸载荷调控肺癌细胞行为的分子机制

doi:10.13418/j.issn.1001-165x.2025.4.13

PDF(3954 KB)

中国临床解剖学杂志 ›› 2025, Vol. 43 ›› Issue (4) : 444-459. DOI: 10.13418/j.issn.1001-165x.2025.4.13

实验研究

机械拉伸载荷调控肺癌细胞行为的分子机制

李祥天¹，温小晖²，王若琳²，成云水³，刘钊汝³ ，吕英³，樊庭宇⁴*，宫凤英³*

作者信息 +

Molecular mechanisms of mechanical stretching in regulating lung cancer cell behavior

Li Xiangtian¹, Wen Xiaohui², Wang Ruolin², Cheng Yunshui³, Liu Zhaoru³, Lv Ying³, Fan Tingyu⁴*, Gong Fengying³*

Author information +

文章历史 +

摘要

目的本研究拟揭示周期性应力刺激与肺癌发生发展的潜在机制。方法本研究通过重分析GEO数据库中的数据集GSE272292，初步探讨了硬基质环境下周期性拉伸应力（15%应变，0.2 Hz，持续7 d）对肺腺癌细胞A549基因表达调控的影响。结果功能富集分析显示，差异基因显著富集于能量代谢的重要场所“线粒体内膜”和“含胶原的细胞外基质”，并筛选出线粒体核糖体蛋白（MRPL13）和V型胶原蛋白（COL5A1）作为调控该双表型的关键候选基因。GSEA分析进一步揭示了“CD22介导的B细胞受体信号调控”通路激活。结论机械信号可能通过调控MRPL13和COL5A1分子介导肺癌细胞的线粒体能量代谢与细胞外基质重塑等表型改变，为肺癌机械生物学研究提供了新视角。

Abstract

Objective To elucidate the potential mechanisms linking cyclic mechanical stress to lung tumorigenesis. Methods The GEO dataset GSE272292 was re-analyzed to investigate the effects of cyclic tensile stress (15% strain, 0.2 Hz, applied for 7 days) on gene expression in A549 lung adenocarcinoma cells under stiff matrix conditions. Results Functional enrichment analysis revealed that differentially expressed genes were significantly enriched in "mitochondrial inner membrane" (a hub for energy metabolism) and "collagen-containing extracellular matrix". Key candidate genes, including mitochondrial ribosomal protein (MRPL13) and collagen type V (COL5A1), were identified as regulators of these dual phenotypes. GSEA further highlighted activation of "CD22-mediated B-cell receptor signaling regulation" pathway. Conclusions These findings suggest that mechanical signals may drive phenotypic alterations in mitochondrial energy metabolism and extracellular matrix (ECM) remodeling via MRPL13 and COL5A1, offering novel insights into lung cancer mechanobiology.

导出引用

李祥天, 温小晖, 王若琳, 成云水, 刘钊汝 , 吕英, 樊庭宇, 宫凤英. 机械拉伸载荷调控肺癌细胞行为的分子机制[J]. 中国临床解剖学杂志. 2025, 43(4): 444-459 https://doi.org/10.13418/j.issn.1001-165x.2025.4.13

Li Xiangtian, Wen Xiaohui, Wang Ruolin, Cheng Yunshui, Liu Zhaoru, Lv Ying, Fan Tingyu, Gong Fengying. Molecular mechanisms of mechanical stretching in regulating lung cancer cell behavior[J]. Chinese Journal of Clinical Anatomy. 2025, 43(4): 444-459 https://doi.org/10.13418/j.issn.1001-165x.2025.4.13

中图分类号： R734.2

参考文献

[1] Najrana T, Mahadeo A, Abu-eid R, et al. Mechanical stretch regulates the expression of specific miRNA in extracellular vesicles released from lung epithelial cells [J]. J Cell Physiol, 2020, 235(11): 8210-8223. DOI: 10.1002/jcp.29476.
[2] Roshanzadeh A, Nguyen TT, Nguyen KD, et al. Mechanoadaptive organization of stress fiber subtypes in epithelial cells under cyclic stretches and stretch release [J]. Sci Rep, 2020, 10(1): 18684. DOI: 10.1038/s41598-020-75791-2.
[3] Gong F, Yang Y, Wen L, et al. An overview of the role of mechanical stretching in the progression of lung cancer [J]. Front Cell Dev Biol, 2021, 9: 781828. DOI: 10.3389/fcell.2021.781828.
[4] Wang C, Yang J. Mechanical forces: The missing link between idiopathic pulmonary fibrosis and lung cancer [J]. Eur J Cell Biol, 2022, 101(3): 151234. DOI: 10.1016/j.ejcb.2022.151234.
[5] Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction [J]. Nature, 2011, 474(7350): 179-183. DOI: 10.1038/nature10137.
[6] Douguet D, Honoré E. Mammalian mechanoelectrical transduction: structure and function of force-gated ion channels [J]. Cell, 2019, 179(2): 340-354. DOI: 10.1016/j.cell.2019.08.049.
[7] Nakamura F, Song M, Hartwig JH, et al. Documentation and localization of force-mediated filamin A domain perturbations in moving cells [J]. Nat Commun, 2014, 5: 4656. DOI: 10.1038/ncomms5656.
[8] Pan J, Copland I, Post M, et al. Mechanical stretch-induced serotonin release from pulmonary neuroendocrine cells: implications for lung development [J]. Am J Physiol Lung Cell Mol Physiol, 2006, 290(1): L185-L193. DOI: 10.1152/ajplung.00167.2005.
[9] Chess PR, Toia L, Finkelstein JN. Mechanical strain-induced proliferation and signaling in pulmonary epithelial H441 cells [J]. Am J Physiol Lung Cell Mol Physiol, 2000, 279(1): L43-L51. DOI: 10.1152/ajplung.2000.279.1.L43.
[10]Chaturvedi LS, Marsh HM, Basson MD. Src and focal adhesion kinase mediate mechanical strain-induced proliferation and ERK1/2 phosphorylation in human H441 pulmonary epithelial cells [J]. Am J Physiol Cell Physiol, 2007, 292(5): C1701-C1713. DOI: 10.1152/ajpcell.00529.2006.
[11]Wang WH, Hsu CL, Huang HC, et al. Quantitative phosphoproteomics reveals cell alignment and mitochondrial length change under cyclic stretching in lung cells [J]. Int J Mol Sci, 2020, 21(11): 4074. DOI: 10.3390/ijms21114074.
[12]Lin J, Ou H, Luo B, et al. Capsaicin mitigates ventilator-induced lung injury by suppressing ferroptosis and maintaining mitochondrial redox homeostasis through SIRT3-dependent mechanisms [J]. Mol Med, 2024, 30(1): 148. DOI: 10.1186/s10020-024-00910-y.
[13]Crosas-Molist E, Graziani V, Maiques O, et al. AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration [J]. Nat Commun, 2023, 14(1): 2740. DOI: 10.1038/s41467-023-38292-0.
[14]Dupont S, Wickström SA. Mechanical regulation of chromatin and transcription [J]. Nat Rev Genet, 2022, 23(10): 624-643. DOI: 10.1038/s41576-022-00493-6.
[15]Gruschke S, Gröne K, Heublein M, et al. Proteins at the polypeptide tunnel exit of the yeast mitochondrial ribosome [J]. J Biol Chem, 2010, 285(25): 19022-19028. DOI: 10.1074/jbc.M110.113837.
[16]Krishnamoorthy GP, Davidson NR, Leach SD, et al. EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC [J]. Cancer Discov, 2019, 9(2): 264-281. DOI: 10.1158/2159-8290.CD-18-0606.
[17]Caligiuri G, Tuveson DA. Activated fibroblasts in cancer: Perspectives and challenges [J]. Cancer Cell, 2023, 41(3): 434-449. DOI: 10.1016/j.ccell.2023.02.015
[18]Liu W, Wei H, Gao Z, et al. COL5A1 may contribute the metastasis of lung adenocarcinoma [J]. Gene, 2018, 665: 57-66. DOI: 10.1016/j.gene.2018.04.066.
[19]Zhang H, Dai J, Mu Q, et al. Macrophage heterogeneity and oncogenic mechanisms in lung adenocarcinoma: insights from scRNA-seq analysis and predictive modeling [J]. Front Immunol, 2024, 15: 1491872. DOI: 10.3389/fimmu.2024.1491872.
[20]Alborzian Deh Sheikh A, Akatsu C, Abdu-Allah HHM, et al. The protein tyrosine phosphatase SHP-1 (PTPN6) but not CD45 (PTPRC) is essential for the ligand-mediated regulation of CD22 in BCR-ligated B cells [J]. J Immunol, 2021, 206(11): 2544-2551. DOI: 10.4049/jimmunol.2100109.
鈥�樊庭宇，讲师，E-mail: 526201753@qq.com；宫凤英，副主任医师，E-mail: gfying2011@smu.edu.cn