Rac1促进异质型细胞叠套结构的形成
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国家自然科学基金(82072287,32100608)


Rac1 promotes the formation of heterotypic cell-in-cell structure
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    摘要:

    异质型细胞叠套结构(heterotypic cell-in-cell structure,heCICs)与肿瘤发生和发展密切相关,在生命科学研究中的重要性逐渐显露。Ras相关C3肉毒毒素底物1(Ras-related C3 botulinum toxin substrate 1,Rac1)属于经典的Rho GTP酶,在细胞骨架以及细胞运动中起到关键调控作用。为研究Rac1在heCICs形成中的作用和机制,利用活细胞示踪剂cell-tracker分别标记肿瘤细胞和免疫杀伤细胞,建立heCICs模型。利用Rac1抑制剂NSC23766抑制Rac1活性后发现,肿瘤细胞与免疫杀伤细胞之间的heCICs形成率显著降低。通过分子克隆技术获得重组质粒pQCXIP-Rac1-EGFP,进行病毒包装感染肿瘤细胞获得Rac1过表达细胞系。进一步检测Rac1过表达对heCICs形成能力的影响,结果表明,Rac1表达水平升高后,heCICs形成率显著升高。本研究显示Rac1具有促进heCICs形成的作用,这为Rac1作为细胞叠套相关疾病的药物治疗靶点奠定了研究基础。

    Abstract:

    Heterotypic cell-in-cell structures (heCICs) are closely related to tumor development and progression, and have become a new frontier in life science research. Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the classic Rho GTPase, which plays a key role in regulating the cytoskeleton and cell movement. To investigate the role and mechanism of Rac1 in the formation of heCICs, tumor cells and immune killer cells were labeled with cell-tracker, respectively, to establish the heCICs model. Upon treatment with the Rac1 inhibitor NSC23766, the formation of heCICs between tumor and immune cells was significantly reduced. The plasmid pQCXIP-Rac1-EGFP constructed by gene cloning was packaged into pseudoviruses that subsequently infect tumor cells to make cell lines stably expressing Rac1. As a result, the formation of heCICs was significantly increased upon Rac1 overexpression. These results demonstrated a promotive role of Rac1 in heCICs formation, which may facilitate treating cell-in-cell related diseases, such as tumors, by targeting Rac1.

    参考文献
    [1] HUMBLE JG, JAYNE WHW, PULVERTAFT RJV. Biological interaction between lymphocytes and other cells[J]. British Journal of Haematology, 1956, 2(3):283-294.
    [2] FAIS S. Cannibalism:a way to feed on metastatic tumors[J]. Cancer Letters, 2007, 258(2):155-164.
    [3] KRAJCOVIC M, OVERHOLTZER M. Mechanisms of ploidy increase in human cancers:a new role for cell cannibalism[J]. Cancer Research, 2012, 72(7):1596-1601.
    [4] TCHERNOV D, KVITT H, HARAMATY L, BIBBY TS, GORBUNOV MY, ROSENFELD H, FALKOWSKI PG. Apoptosis and the selective survival of host animals following thermal bleaching in zooxanthellate corals[J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(24):9905-9909.
    [5] TSUNODA R, NAKAYAMA M, HEINEN E, MIYAKE K, SUZUKI K, SUGAI N, KOJIMA M. Emperipolesis of lymphoid cells by human follicular dendritic cells in vitro[J]. Virchows Archiv B, 1992, 62(1):69-78.
    [6] WAN QW, LIU J, ZHENG Z, ZHU HB, CHU XG, DONG Z, HUANG S, DU QS. Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism:entosis without matrix detachment[J]. Molecular Biology of the Cell, 2012, 23(11):2076-2091.
    [7] OVERHOLTZER M, MAILLEUX AA, MOUNEIMNE G, NORMAND G, SCHNITT SJ, KING RW, CIBAS ES, BRUGGE JS. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion[J]. Cell, 2007, 131(5):966-979.
    [8] LIANG JQ, NIU ZB, ZHANG B, YU XC, ZHENG Y, WANG CX, REN H, WANG MN, RUAN BZ, QIN HQ, ZHANG X, GU SZ, SAI XY, TAI YH, GAO LH, MA L, CHEN ZL, HUANG HY, WANG XN, SUN Q. p53-dependent elimination of aneuploid mitotic offspring by entosis[J]. Cell Death & Differentiation, 2021, 28(2):799-813.
    [9] MACKAY HL, MOORE D, HALL C, BIRKBAK NJ, JAMAL-HANJANI M, KARIM SA, PHATAK VM, PIÑON L, MORTON JP, SWANTON C, Le QUESNE J, MULLER PAJ. Publisher correction:genomic instability in mutant p53 cancer cells upon entotic engulfment[J]. Nature Communications, 2018, 9:3540.
    [10] BENSELER V, WARREN A, VO M, HOLZ LE, TAY SS, Le COUTEUR DG, BREEN E, ALLISON AC, van ROOIJEN N, McGUFFOG C, SCHLITT HJ, BOWEN DG, McCAUGHAN GW, BERTOLINO P. Hepatocyte entry leads to degradation of autoreactive CD8 T cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(40):16735-16740.
    [11] FAIS S, OVERHOLTZER M. Cell-in-cell phenomena in cancer[J]. Nature Reviews Cancer, 2018, 18(12):758-766.
    [12] WANG XL, LI YL, LI JT, LI L, ZHU H, CHEN H, KONG R, WANG G, WANG YW, HU JS, SUN B. Cell-in-cell phenomenon and its relationship with tumor microenvironment and tumor progression:a review[J]. Frontiers in Cell and Developmental Biology, 2019, 7:311.
    [13] SUN Q, LUO TZ, REN YX, FLOREY O, SHIRASAWA S, SASAZUKI T, ROBINSON DN, OVERHOLTZER M. Competition between human cells by entosis[J]. Cell Research, 2014, 24(11):1299-1310.
    [14] SUN Q, CIBAS ES, HUANG HY, HODGSON L, OVERHOLTZER M. Induction of entosis by epithelial cadherin expression[J]. Cell Research, 2014, 24(11):1288-1298.
    [15] WANG MN, NIU ZB, QIN HQ, RUAN BZ, ZHENG Y, NING XK, GU SZ, GAO LH, CHEN ZL, WANG XN, HUANG HY, MA L, SUN Q. Mechanical ring interfaces between adherens junction and contractile actomyosin to coordinate entotic cell-in-cell formation[J]. Cell Reports, 2020, 32(8):108071.
    [16] WANG MN, NING XK, CHEN A, HUANG HY, NI C, ZHOU CX, YU KT, LAN SC, WANG QW, LI SC, LIU H, WANG XN, CHEN ZL, MA L, SUN Q. Impaired formation of homotypic cell-in-cell structures in human tumor cells lacking alpha-catenin expression[J]. Scientific Reports, 2015, 5:12223.
    [17] RUAN BZ, WANG CX, CHEN A, LIANG JQ, NIU ZB, ZHENG Y, FAN J, GAO LH, HUANG HY, WANG XN, SUN Q. Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation[J]. BMB Reports, 2018, 51(8):412-417.
    [18] LIANG JQ, FAN J, WANG MN, NIU ZB, ZHANG ZR, YUAN L, TAI YH, CHEN ZL, SONG ST, WANG XN, LIU XQ, HUANG HY, SUN Q. CDKN2A inhibits formation of homotypic cell-in-cell structures[J]. Oncogenesis, 2018, 7(6):50.
    [19] WANG S, LI LM, ZHOU YG, HE Y, WEI YS, TAO AL. Heterotypic cell-in-cell structures in colon cancer can be regulated by IL-6 and lead to tumor immune escape[J]. Experimental Cell Research, 2019, 382(1):111447.
    [20] JAFFE AB, HALL A. RHO GTPASES:biochemistry and biology[J]. Annual Review of Cell and Developmental Biology, 2005, 21:247-269.
    [21] ETIENNE-MANNEVILLE S, HALL A. Rho GTPases in cell biology[J]. Nature, 2002, 420(6916):629-635.
    [22] AELST LV, SOUZA-SCHOREY CD. Rho GTPases and signaling networks[J]. Genes & Development, 1997, 11(18):2295-2322.
    [23] GU Y, FILIPPI MD, CANCELAS JA, SIEFRING JE, WILLIAMS EP, JASTI AC, HARRIS CE, LEE AW, PRABHAKAR R, ATKINSON SJ, KWIATKOWSKI DJ, WILLIAMS DA. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases[J]. Science, 2003, 302(5644):445-449.
    [24] CONIGLIO SJ, JOU TS, SYMONS M. Rac1 protects epithelial cells against anoikis[J]. Journal of Biological Chemistry, 2001, 276(30):28113-28120.
    [25] SAHAI E, MARSHALL CJ. RHO-GTPases and cancer[J]. Nature Reviews Cancer, 2002, 2(2):133-142.
    [26] ANDERSON KW, LI WI, CEZEAUX J, ZIMMER S. In vitro studies of deformation and adhesion properties of transformed cells[J]. Cell Biophysics, 1991, 18(2):81-97.
    [27] 王春玲, 张荣芳, 陈峰杰, 周露, 姬颖华. MiR-509靶向Rac1调节人肝癌LM3细胞侵袭和迁移及裸鼠模型的存活[J]. 中国病理生理杂志, 2019, 35(5):813-818. WANG CL, ZHANG RF, CHEN FJ, ZHOU L, JI YH. MiR-509 regulates growth, invasion and migration of human hepatocellular carcinoma LM3 cells and survival of nude mice[J]. Chinese Journal of Pathophysiology, 2019, 35(5):813-818(in Chinese).
    [28] 张璐玢, 邹雪琴, 张鳅丹, 高淑君, 刘雪, 潘玲丽, 赵杨静, 梁秀婷, 王荟, 朱彦玲, 邵启祥. RAC1通过调节紧密连接蛋白1分布影响卵巢癌细胞的迁移和侵袭[J]. 江苏大学学报(医学版), 2020, 30(5):408-413. ZHANG LB, ZOU XQ, ZHANG QD, GAO SJ, LIU X, PAN LL, ZHAO YJ, LIANG XT, WANG H, ZHU YL, SHAO QX. RAC1 inhibits the migration and invasion of human epithelial ovarian cancer cells by regulating the distribution of tight junction protein 1[J]. Journal of Jiangsu University (Medicine Edition), 2020, 30(5):408-413(in Chinese).
    [29] ALMANGUSH A, MÄKITIE AA, HAGSTRÖM J, HAGLUND C, KOWALSKI LP, NIEMINEN P, COLETTA RD, SALO T, LEIVO I. Cell-in-cell phenomenon associates with aggressive characteristics and cancer-related mortality in early oral tongue cancer[J]. BMC Cancer, 2020, 20(1):843.
    [30] LIU JJ, WANG L, ZHANG YX, LI SB, SUN FZ, WANG G, YANG T, WEI D, GUO LX, XIAO HL. Induction of entosis in prostate cancer cells by nintedanib and its therapeutic implications[J]. Oncology Letters, 2019, 17(3):3151-3162.
    [31] MARTÍNEZ-SÁNCHEZ LDC, NGO PA, PRADHAN R, BECKER LS, BOEHRINGER D, SOTERIOU D, KUBANKOVA M, SCHWEITZER C, KOCH T, THONN V, ERKERT L, STOLZER I, GÜNTHER C, BECKER C, WEIGMANN B, KLEWER M, DANIEL C, AMANN K, TENZER S, ATREYA R, et al. Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation[J]. Gut, 2023, 72(2):275-294.
    [32] SAUZEAU V, BEIGNET J, VERGOTEN G, BAILLY C. Overexpressed or hyperactivated Rac1 as a target to treat hepatocellular carcinoma[J]. Pharmacological Research, 2022, 179:106220.
    [33] CANNON AC, URIBE-ALVAREZ C, CHERNOFF J. RAC1 as a therapeutic target in malignant melanoma[J]. Trends in Cancer, 2020, 6(6):478-488.
    [34] PAYAPILLY A, GUILBERT R, DESCAMPS T, WHITE G, MAGEE P, ZHOU C, KERR A, SIMPSON KL, BLACKHALL F, DIVE C, MALLIRI A. TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change[J]. Cell Reports, 2021, 37(6):109979.
    [35] SAXENA S, BEENA KR, BANSAL A, BHATNAGAR A. Emperipolesis in a common breast malignancy[J]. Acta Cytologica, 2002, 46(5):883-886.
    [36] SU Y, HUANG HY, LUO TZ, ZHENG Y, FAN J, REN H, TANG M, NIU ZB, WANG CX, WANG YQ, ZHANG ZR, LIANG JQ, RUAN BZ, GAO LH, CHEN ZL, MELINO G, WANG XN, SUN Q. Cell-in-cell structure mediates in-cell killing suppressed by CD44[J]. Cell Discovery, 2022, 8:35.
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胡涛,冯鹏飞,李浩源,周鲁林,牛祖彪,黄一诺,王小宁,王晨曦,刘惠,吴成君. Rac1促进异质型细胞叠套结构的形成[J]. 生物工程学报, 2023, 39(10): 4123-4134

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  • 收稿日期:2023-02-09
  • 录用日期:2023-03-20
  • 在线发布日期: 2023-10-17
  • 出版日期: 2023-10-25
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