A novel E-cadherin/SOX9 axis regulates cancer stem cells in multiple myeloma by activating Akt and MAPK pathways
Tóm tắt
Cancer stem cells (CSCs) have been identified in multiple myeloma (MM) and are widely regarded as a key driver of MM initiation and progression. E-cadherin, in addition to its established role as a marker for epithelial-mesenchymal transition, also plays critical roles in controlling the aggressive behaviors of various tumor cells. Here, we show that depletion of E-cadherin in MM cells remarkably inhibited cell proliferation and cell cycle progression, in part through the decreased prosurvival CD138 and Bcl-2 and the inactivated Akt and MAPK pathways. CSC features, including the ability of the cells to form clonogenic colonies indicative of self-renewal and side population, were greatly suppressed upon the depletion of E-cadherin and subsequent loss of SOX9 stem-cell factor. We further provide evidence that SOX9 is a downstream target of E-cadherin-mediated CSC growth and self-renewal—ectopic re-expression of SOX9 in E-cadherin-depleted cells rescued its inhibitory effects on CSC-like properties and survival signaling. Collectively, our findings unveil a novel regulatory mechanism of MM CSCs via the E-cadherin/SOX9 axis, which could be important in understanding the long-term cell survival and outgrowth that leads to relapsed/refractory MM.
Tài liệu tham khảo
Hernández-Rivas J, Ríos-Tamayo R, Encinas C, Alonso R, Lahuerta JJ. The changing landscape of relapsed and/or refractory multiple myeloma (MM): fundamentals and controversies. Biomark Res. 2022;10(1):1.
Gao M, Kong Y, Yang G, Gao L, Shi J. Multiple myeloma cancer stem cells. Oncotarget. 2016;7(23):35466–77.
Soncin F, Ward CM. The function of E-cadherin in stem cell pluripotency and self-renewal. Genes. 2011;2(1):229–59.
Karpowicz P, Willaime-Morawek S, Balenci L, DeVeale B, Inoue T, van der Kooy D. E-cadherin regulates neural stem cell self-renewal. J Neurosci. 2009;29(12):3885–96.
Sharma A, Kaur H, De R, Srinivasan R, Pal A, Bhattacharyya S. Knockdown of E-cadherin induces cancer stem-cell-like phenotype and drug resistance in cervical cancer cells. Biochem Cell Biol. 2021;99(5):587–95.
Padmanaban V, Krol I, Suhail Y, Szczerba BM, Aceto N, Bader JS, et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019;573(7774):439–44.
Wang L, Liu H, He J, Li Y, Xu Y, Chen B. E-cadherin expression and its clinical significance in 41 cases of spinal plasma cell myeloma. J Med Coll PLA. 2009;24(1):56–62.
Rapanotti MC, Franceschini L, Viguria TMS, Ialongo C, Fraboni D, Cerretti R, et al. Molecular expression of bone marrow angiogenic factors, cell-cell adhesion molecules and matrix-metallo-proteinases in plasmacellular disorders: a molecular panel to investigate disease progression. Mediterr J Hematol Infect Dis. 2018;10(1):e2018059.
Samart P, Luanpitpong S, Rojanasakul Y, Issaragrisil S. O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination. J Exp Clin Cancer Res. 2021;40(1):100.
McCarron MJ, Park PW, Fooksman DR. CD138 mediates selection of mature plasma cells by regulating their survival. Blood. 2017;129(20):2749–59.
Lentzsch S, Chatterjee M, Gries M, Bommert K, Gollasch H, Dörken B, et al. PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia. 2004;18(11):1883–90.
Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1(5):2315–9.