Huang Shenq-Shyang, Liao Wen-Ying, Hsu Chung-Chi, Chan Tze-Sian, Liao Tai-Yan, Yang Pei-Ming, Chen Li-Tzong, Sung Shian-Ying, Tsai Kelvin K
Graduate Program of Biotechnology in Medicine, Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan.
Front Oncol. 2021 May 31;11:638311. doi: 10.3389/fonc.2021.638311. eCollection 2021.
Stem-like cancer cells or cancer stem cells (CSCs) may comprise a phenotypically and functionally heterogeneous subset of cells, whereas the molecular markers reflecting this CSC hierarchy remain elusive. The glycolytic enzyme alpha-enolase (ENO1) present on the surface of malignant tumor cells has been identified as a metastasis-promoting factor through its function of activating plasminogen. The expression pattern of surface ENO1 (sENO1) concerning cell-to-cell or CSC heterogeneity and its functional roles await further investigation.
The cell-to-cell expression heterogeneity of sENO1 was profiled in malignant cells from different types of cancers using flow cytometry. The subcellular localization of sENO1 and its functional roles in the invadopodia formation and cancer cell invasiveness were investigated using a series of imaging, molecular, and and functional studies.
We showed here that ENO1 is specifically localized to the invadopodial surface of a significant subset (11.1%-63.9%) of CSCs in human gastric and prostate adenocarcinomas. sENO1 CSCs have stronger mesenchymal properties than their sENO1 counterparts. The subsequent functional studies confirmed the remarkable pro-invasive and pro-metastatic capacities of sENO1 CSCs. Mechanistically, inhibiting the surface localization of ENO1 by downregulating caveolin-1 expression compromised invadopodia biogenesis, proteolysis, and CSC invasiveness.
Our study identified the specific expression of ENO1 on the invadopodial surface of a subset of highly invasive and pro-metastatic CSCs. sENO1 may provide a diagnostically and/or therapeutically exploitable target to improve the outcome of patients with aggressive and metastatic cancers.
干细胞样癌细胞或癌症干细胞（CSCs）可能构成细胞表型和功能上异质性的亚群，而反映这种CSC层级结构的分子标志物仍不明确。恶性肿瘤细胞表面存在的糖酵解酶α-烯醇化酶（ENO1）通过激活纤溶酶原的功能已被确定为一种促转移因子。表面ENO1（sENO1）关于细胞间或CSC异质性的表达模式及其功能作用有待进一步研究。
使用流式细胞术分析不同类型癌症的恶性细胞中sENO1的细胞间表达异质性。通过一系列成像、分子和功能研究，研究sENO1的亚细胞定位及其在侵袭性足体形成和癌细胞侵袭性中的功能作用。
我们在此表明，ENO1特异性定位于人胃腺癌和前列腺腺癌中相当一部分（11.1%-63.9%）CSCs的侵袭性足体表面。sENO1⁺ CSCs比sENO1⁻对应细胞具有更强的间充质特性。随后的功能研究证实了sENO1⁺ CSCs具有显著的促侵袭和促转移能力。机制上，通过下调小窝蛋白-1的表达抑制ENO1的表面定位会损害侵袭性足体的生物发生、蛋白水解和CSC的侵袭性。
我们的研究确定了ENO1在一部分高侵袭性和促转移性CSCs的侵袭性足体表面特异性表达。sENO1可能为改善侵袭性和转移性癌症患者的预后提供一个可用于诊断和/或治疗的靶点。
