N-钙黏蛋白与Wnt/β-catenin通路在骨髓间充质干细胞与白血病干细胞中的耐药机制研究<sup>*</sup>

doi:10.3969/j.issn.1671-7171.2024.05.013

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摘要【目的】探讨N-钙黏蛋白(N-cadherin)与Wnt/β-catenin通路在骨髓间充质干细胞(MSC)与白血病干细胞(LSC)中的耐药机制研究。【方法】65例急性髓系白血病(AML)患者,完全缓解41例,未缓解24例,比较两组CD34⁺CD38^-干细胞中N-cadherin的表达差异。根据不同MSC或去甲氧柔红霉素(IDA)处理下将CD34⁺CD38^- Kg1α细胞分为6组,检测细胞增殖和凋亡情况及N-cadherin、β-catenin水平,检测细胞黏附及抗凋亡能力。【结果】未缓解患者的N-cadherin表达水平高于完全缓解者(P<0.01);LSC+IDA组(B组)细胞凋亡率显著高于LSC与MSC直接共培养+IDA组(D组)(P<0.05);在IDA浓度为100 nmol/L、200 nmol/L时, B组的细胞增殖抑制率显著高于D组(P<0.05);B 组的集落形成率显著低于D组(P<0.05)。Western blot结果显示:N-cadherin及β-catenin在MSC直接接触培养条件下表达高于单独培养或分离培养;LSC在MSC共培养条件下,N-cadherin及β-catenin表达水平上升,伴随细胞核内β-catenin水平上升。【结论】骨髓微环境的MSC可以通过N-cadherin与LSC的黏附作用支持LSC的增殖能力,同时促进LSC Wnt/β-catenin通路的激活,对化疗药物产生耐药性。

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关键词 ：白血病,髓样,急性, 钙结合蛋白质类, 抗药性,肿瘤

Abstract：【Objective】To explore the molecular mechanisms of the N-cadherin and the Wnt/β-catenin pathway facilitate drug resistance in leukemia stem cells (LSC) and mesenchymal stem cells (MSC).【Methods】The study included 65 patients with acute myeloid leukemia (AML), of whom 41 achieved complete remission (CR group) and 24 did not (non-remission, NR group). The expression of N-cadherin in CD34⁺CD38^- stem cells was compared between these two groups. The CD34⁺CD38^- Kg1α cells were further divided into six groups based on different treatments with MSC or idarubicin (IDA) that cell proliferation, apoptosis, and levels of N-cadherin and β-catenin were assessed. The cell adhesion and anti-apoptotic capabilities were also evaluated.【Results】The N-cadherin expression in the NR group compared was significantly higher than that in the CR group (P<0.01).The apoptosis rate in the LSC+IDA group (Group B) was significantly higher than that in the LSC and MSC co-culture + IDA group (Group D) (P<0.05). At IDA concentrations of 100 and 200 nmol/L, the proliferation inhibition rate in Group B was significantly higher than that in Group D (P<0.05). The colony formation rate in Group B was significantly lower than that in Group D (P<0.05). The Western blot results showed that the expression levels of both N-cadherin and β-catenin were higher in direct co-culture condition of MSC than in solo cultures or non-contact co-cultures. In co-culture condition with MSC, LSC showed increased expression levels of N-cadherin and β-catenin, along with an increase in nuclear β-catenin level.【Conclusion】MSCs in the bone marrow microenvironment can support the proliferation of LSC through N-cadherin-mediated adhesion and promote the activation of the Wnt/β-catenin pathway in LSC, thereby enabling them to evade the cytotoxic effects of chemotherapy.

Key words： Leukemia, Myeloid, Acute Calcium-Binding Proteins Drug Resistance, Neoplasm

收稿日期: 2024-01-27

中图分类号:

R733.72

基金资助:*龙岩市科技计划项目(2020LYF17028)

通讯作者: **E-mail:yulian-ly@126.com

引用本文:

马小美, 吴爱瑜, 邓嘉仪, 吴维颢, 陈隆天, 黄建清, 余莲. N-钙黏蛋白与Wnt/β-catenin通路在骨髓间充质干细胞与白血病干细胞中的耐药机制研究^*[J]. 医学临床研究, 2024, 41(5): 688-692.
MA Xiaomei, WU Aiyu, DENG Jiayi, et al. The Molecular Mechanisms of the N-cadherin and the Wnt/β-catenin Pathway Facilitate Drug Resistance in Leukemia Stem Cells and Mesenchymal Stem Cells. JOURNAL OF CLINICAL RESEARCH, 2024, 41(5): 688-692.

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http://journal07.magtech.org.cn/yxlcyj/CN/10.3969/j.issn.1671-7171.2024.05.013 或 http://journal07.magtech.org.cn/yxlcyj/CN/Y2024/V41/I5/688

[1] BOLANDI S M,PAKJOO M,BEIGI P, et al.A role for the bone marrow microenvironment in drug resistance of acute myeloid leukemia[J].Cells,202l,10(11):2833.
[2] YAO Y Y,LI F L,HUANG J S,et al. Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development[J].Exp Hematol Oncol,2021,10(1):39.
[3] WONG R S, CHEONG S K. Leukaemic stem cells: drug resistance, metastasis and therapeutic implications[J].Malays J Pathol,2012,34(2):77-88.
[4] 孙俊雅, 江雪杰. 骨髓微环境介导急性髓细胞白血病耐药的研究现状[J].国际输血及血液学杂志,2020,43(2):99-103.
[5] VEROVSKAYA E V, DELLORUSSO P V, PASSEGUE E. Losing sense of self and surroundings:hematopoietic stem cell aging and leukemic transformation[J].Trends Moi Med,2019, 25(6):494-515.
[6] WILLIAMS D A, CANCELAS J A. Leukaemia: niche retreats for stem cells[J].Nature,2006, 444(7121):827-828.
[7] KONOPLEVA M Y, JORDAN C T. Leukemia stem cells and microenvironment: biology and therapeutic targeting[J].J Clin Oncol,2011,29(5):591-599.
[8] MEADS M B, GATENBY R A, DALTON W S. Environment-mediated drug resistance: a major contributor to minimal residual disease[J].Nat Rev Cancer,2009,9(9):665.
[9] RUBTSOVA S N, ZHITNYAK I Y, GLOUSHANKOVA N A,et al.Dual role of E-cadherin in cancer cells[J].Tissue Barriers, 2022,10(4):2005420.
[10] ZHI L, WANG M, RAO Q, et al. Enrichment of N-cadherin and Tie2-bearing CD34⁺/CD38^-/CD123⁺ leukemic stem cells by chemotherapy-resistance[J].Cancer Lett,2010, 296(1):65-73.
[11] 李佳慧,孙振亮.急性髓系白血病干细胞的研究现状和进展[J].中国基层医药,2022, 29(9):1433-1436.
[12] MEAD A J, NEO W H, BARKAS N, et al. Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation[J].J Exp Med,2017, 214(7):2005-2021.
[13] MALHOTRA S, KINCADE P W. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis[J].Cell Stem Cell,2009,4(1):27-36.
[14] ALICJA M G, DEBORA V, MYRIAM A.Wnt signalling in acute myeloid leukaemia[J].Cells,2019,8(11):1403.
[15] RUAN Y, KIM H N, OGANA H, et al.Wnt signaling in leukemia and its bone marrow microenvironment[J].Int J Mol Sci,2020,21(17):6247.