Advanced Search
WEI Yu, ZHANG Zhouhua, LI Zhifang, ZHANG Li. SerpinA5 Inhibits Malignant Biological Behavior of Esophageal Squamous Cell Carcinoma by Regulating Fn/Integrin-β1 Signaling Pathway[J]. Cancer Research on Prevention and Treatment, 2025, 52(4): 290-296. DOI: 10.3971/j.issn.1000-8578.2025.24.0949
Citation: WEI Yu, ZHANG Zhouhua, LI Zhifang, ZHANG Li. SerpinA5 Inhibits Malignant Biological Behavior of Esophageal Squamous Cell Carcinoma by Regulating Fn/Integrin-β1 Signaling Pathway[J]. Cancer Research on Prevention and Treatment, 2025, 52(4): 290-296. DOI: 10.3971/j.issn.1000-8578.2025.24.0949

SerpinA5 Inhibits Malignant Biological Behavior of Esophageal Squamous Cell Carcinoma by Regulating Fn/Integrin-β1 Signaling Pathway

Funding: 

Natural Science Foundation of Xinjiang Uygur Autonomous Region (No. 2021D01C352)

undefined

More Information
  • Corresponding author:

    ZHANG Li, E-mail: 18799131188@163.com

  • Received Date: September 25, 2024
  • Revised Date: February 18, 2025
  • Accepted Date: February 20, 2025
  • Available Online: February 25, 2025
  • Objective 

    To investigate the effect of SerpinA5 on the malignant biological behavior of esophageal squamous cell carcinoma (ESCC) and its molecular mechanism.

    Methods 

    The expression levels of the SerpinA5 gene in various tumors and adjacent normal tissues were analyzed by using the TIMER2.0 database. The expression levels of SerpinA5 in the ESCC cell line and esophageal epithelial cells were detected through Western blot analysis. Stably transfected KYSE150 cell line with overexpression of SerpinA5 was constructed through lentiviral transfection, and overexpression efficiency was detected via Western blot analysis. The effects of SerpinA5 overexpression on the proliferation, apoptosis, migration, and invasion of ESCC cells were detected by employing the CCK8, plate cloning, flow cytometry, wound healing, and Transwell invasion assays. The nude mice subcutaneous xenograft model with SerpinA5 overexpression was constructed. Tumor growth was observed, and tumor volume and mass were measured. The cell proliferation level of the subcutaneous xenograft tumors in nude mice was detected via immunohistochemistry (IHC). Coimmunoprecipitation (Co-IP) was employed to determine the interaction between SerpinA5 and Fn. Western blot analysis was applied to detect the expression levels of proteins (Fn, Integrin-β1, FAK, and p-FAK) related to the Fn/Integrin-β1 signaling pathway in transplanted tumors.

    Results 

    SerpinA5 was expressed at low levels in ESCC tissues and cell lines. In ESCC cells, SerpinA5 overexpression can considerably inhibit cell proliferation, migration, and invasion and promote cell apoptosis. In the subcutaneous xenograft experiment on nude mice, the tumor volume and weight of the SerpinA5 overexpression group were lower than those of the negative control group. IHC results demonstrated that SerpinA5 overexpression significantly inhibited the proliferation of ESCC cells in tumor tissues. Co-IP confirmed the interaction between SerpinA5 and Fn. Western blot analysis results showed that the expression levels of Fn, Integrin-β1, and p-FAK in the Fn/Integrin-β1 signaling pathway of ESCC cells in the subcutaneous xenograft tumors of nude mice significantly decreased after SerpinA5 overexpression.

    Conclusion 

    Serpin A5 may inhibit proliferation, migration, and invasion and promote apoptosis of ESCC cells by regulating the Fn/Integrin-β1 signaling pathway.

  • Competing interests: The authors declare that they have no competing interests.

  • [1]
    Ferlay J, Ervik M, Lam F, et al. Globocan 2022 (version 1.1) [EB/OL]. https://gco.iarc.who.int/today/en/dataviz/bars?mode=cancer&group_populations=1&populations=900&types=1&sort_by=value0&key=total. –[2024-02-08].
    [2]
    Xu QL, Li H, Zhu YJ, et al. The treatments and postoperative complications of esophageal cancer: a review[J]. J Cardiothorac Surg, 2020, 15(1): 163-173. doi: 10.1186/s13019-020-01202-2
    [3]
    郑荣寿, 陈茹, 韩冰峰, 等. 2022年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2024, 46(3): 221-231. [Zheng RS, Chen R, Han BF, et al. Cancer incidence and mortality in China, 2022[J]. Zhonghua Zhong Liu Za Zhi, 2024, 46(3): 221-231.] doi: 10.3760/cma.j.cn112152-20240119-00035

    Zheng RS, Chen R, Han BF, et al. Cancer incidence and mortality in China, 2022[J]. Zhonghua Zhong Liu Za Zhi, 2024, 46(3): 221-231. doi: 10.3760/cma.j.cn112152-20240119-00035
    [4]
    Thrift AP. The epidemic of oesophageal carcinoma: Where are we now?[J]. Cancer Epidemiol, 2016, 41: 88-95. doi: 10.1016/j.canep.2016.01.013
    [5]
    Zeng H, Chen W, Zheng R, et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries[J]. Lancet Glob Health, 2018, 6(5): e555-e567. doi: 10.1016/S2214-109X(18)30127-X
    [6]
    陈星. SERPINA5预测食管鳞癌放化疗疗效及预后的价值[D]. 乌鲁木齐:新疆医科大学, 2020. [Chen X. The value of SERPINA5 in predicting the efficacy and prognosis of radiotherapy and chemotherapy in esophageal squamous cell carcinoma[D]. Urumqi: Xinjiang Medical University, 2020.]

    Chen X. The value of SERPINA5 in predicting the efficacy and prognosis of radiotherapy and chemotherapy in esophageal squamous cell carcinoma[D]. Urumqi: Xinjiang Medical University, 2020.
    [7]
    Yang H, Wahlmüller FC, Sarg B, et al. A+-helix of protein C inhibitor (PCI) is a cell-penetrating peptide that mediates cell membrane permeation of PCI[J]. J Biol Chem, 2015, 290(5): 3081-3091. doi: 10.1074/jbc.M114.581736
    [8]
    Wahlmüller FC, Yang H, Furtmüller M, et al. Regulation of the Extracellular SERPINA5(Protein C Inhibitor) Penetration Through Cellular Membranes[J]. Adv Exp Med Biol, 2017, 966: 93-101.
    [9]
    Wakita T, Hayashi T, Nishioka J, et al. Regulation of carcinoma cell invasion by protein C inhibitor whose expression is decreased in renal cell carcinoma[J]. Int J Cancer, 2004, 108(4): 516-523. doi: 10.1002/ijc.11594
    [10]
    Song Y, Ye L, Tan Y, et al. Therapeutic exosomes loaded with SERPINA5 attenuated endometrial cancer cell migration via the integrin β1/FAK signaling pathway[J]. Cell Oncol (Dordr), 2022, 45(5): 861-872.
    [11]
    Jing Y, Jia D, Wong CM, et al. SERPINA5 inhibits tumor cell migration by modulating the fibronectin-integrin β1 signaling pathway in hepatocellular carcinoma[J]. Mol Oncol, 2014, 8(2): 366-377. doi: 10.1016/j.molonc.2013.12.003
    [12]
    Morgan E, Soerjomataram I, Gavin A T, et al. International trends in oesophageal cancer survival by histological subtype between 1995 and 2014[J]. Gut, 2021, 70(2): 234-242.
    [13]
    Asanuma K, Yoshikawa T, Hayashi T, et al. Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity[J]. Int J Cancer, 2007, 121(5): 955-965. doi: 10.1002/ijc.22773
    [14]
    Bijsmans Ingrid TGW, Smits Kim M, de Graeff Pauline, et al. Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors[J]. Mod Pathol, 2011, 24: 463-470.
    [15]
    Palmieri D, Lee JW, Juliano RL, et al. Plasminogen activator inhibitor-1 and -3 increase cell adhesion and motility of mda-mb-435 breast cancer cells[J]. J Biol Chem, 2002, 277(43): 40950-40957. doi: 10.1074/jbc.M202333200
    [16]
    Fan M, Xiong X, Han L, et al. Serpina5 promotes tumour cell proliferation by modulating the pi3k/akt/mtor signalling pathway in gastric cancer[J]. J Cell Mol Med, 2022, 26(18): 4837-4846. doi: 10.1111/jcmm.17514
    [17]
    Zhang L, Hu S, Korteweg C, et al. Expression of immunoglobulin G in esophageal squamous cell carcinomas and its association with tumor grade and Ki67[J]. Hum Pathol, 2012, 43(3): 423-434. doi: 10.1016/j.humpath.2011.05.020
    [18]
    Ma H, Wang J, Zhao X, et al. Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation[J]. Cell Rep, 2020, 30(3): 793-806. e6.
    [19]
    Kuonen F, Surbeck I, Sarin KY, et al. TGFβ, Fibronectin and Integrin α5β1 Promote Invasion in Basal Cell Carcinoma[J]. J Invest Dermatol, 2018, 138(11): 2432-2442. doi: 10.1016/j.jid.2018.04.029
    [20]
    Vega ME, Schwarzbauer JE. Collaboration of Fibronectin Matrix with other Extracellular Signals in Morphogenesis and Differentiation[J]. Curr Opin Cell Biol, 2016, 42: 1-6. doi: 10.1016/j.ceb.2016.03.014
    [21]
    Strohmeyer N, Bharadwaj M, Costell M, et al. Fibronectin-bound α5β1 integrins sense load and signal to reinforce adhesion in less than a second[J]. Nat Mater, 2017, 16(12): 1261-1270.
    [22]
    Li K, Zhao G, Ao J, et al. ZNF32 induces anoikis resistance through maintaining redox homeostasis and activating Src/FAK signaling in hepatocellular carcinoma[J]. Cancer Lett, 2019, 442: 271-278. doi: 10.1016/j.canlet.2018.09.033
    [23]
    Zhao G, Gong L, Su D, et al. Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1[J]. J Clin Invest, 2019, 129(3): 971-987.

Catalog

    Figures(8)

    Article views (1516) PDF downloads (126) Cited by()

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return