Transforming Growth Factor-β Modulates Cancer Stem Cell Traits on CD44 Subpopulations in Hepatocellular Carcinoma

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mario Alejandro Aguilar-Chaparro, Sonia Andrea Rivera-Pineda, Hury Viridiana Hernández-Galdámez, Emmanuel Ríos-Castro, Olga Lilia Garibay-Cerdenares, Carolina Piña-Vázquez, Saúl Villa-Treviño
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Abstract

Hepatocellular carcinoma (HCC) is a formidable malignancy, with growing interest in identifying cancer stem cells (CSCs) as potential therapeutic targets. CD44 isoforms have emerged as promising CSC markers in HCC, often associated with epithelial-mesenchymal transition (EMT) induced by transforming growth factor-beta (TGF-β). However, the intricate relationship between CSC traits, CD44 isoforms, and TGF-β effects on CD44 subpopulations in HCC remains unclear. This study aimed to clarify how TGF-β influences proteomic changes and CSC traits in subpopulations expressing standard CD44 isoform (CD44std) and CD44 variant 9 (CD44v9). Treating SNU-423 cells with TGF-β lead to notable morphological changes, resembling a spindle-like phenotype, along with reductions in CD44v9+ subpopulations and differential CD44std expression. Proteomic analysis highlighted significant alterations in signaling pathways, particularly the mitogen-activated protein kinase (MAPK) pathway. Validation experiments demonstrated upregulation in CD44std cells and downregulation in CD44v9 cells post-TGF-β treatment. Furthermore, TGF-β exerted regulatory influence over Sox2 and Nanog expression, resulting in increased colony and spheroid formation in CD44std cells but decreased capabilities in CD44v9 cells. TGF-β also enhanced the migratory and invasive properties of both subpopulations through EMT, alongside increased adhesive abilities in CD44v9 cells. These findings illuminate the dynamic interplay between TGF-β and CD44std/CD44v9 subpopulations, emphasizing the role of MAPK signaling and modulation of CSC traits. This research contributes to understanding the dynamic interplay between CD44 isoforms and TGF-β in HCC.

Abstract Image

转化生长因子-β调节肝细胞癌 CD44 亚群的癌症干细胞特征
肝细胞癌(HCC)是一种可怕的恶性肿瘤,人们越来越关注癌症干细胞(CSCs)作为潜在的治疗靶点。CD44亚型已成为HCC中有希望的CSC标志物,通常与转化生长因子-β (TGF-β)诱导的上皮-间质转化(EMT)有关。然而,CSC特征、CD44亚型和TGF-β对HCC中CD44亚群的影响之间的复杂关系尚不清楚。本研究旨在阐明TGF-β如何影响表达标准CD44亚型(CD44std)和CD44变体9 (CD44v9)亚群的蛋白质组学变化和CSC性状。用TGF-β处理SNU-423细胞导致显著的形态学改变,类似纺锤样表型,同时CD44v9+亚群减少和CD44std表达差异。蛋白质组学分析强调了信号通路的显著改变,特别是丝裂原活化蛋白激酶(MAPK)通路。验证实验表明,tgf -β处理后CD44std细胞上调,CD44v9细胞下调。此外,TGF-β调控Sox2和Nanog的表达,导致CD44std细胞集落和球状体形成增加,而CD44v9细胞集落和球状体形成能力下降。TGF-β还通过EMT增强了这两个亚群的迁移和侵袭特性,同时增加了CD44v9细胞的粘附能力。这些发现阐明了TGF-β与CD44std/CD44v9亚群之间的动态相互作用,强调了MAPK信号传导和CSC性状调节的作用。本研究有助于了解HCC中CD44亚型与TGF-β之间的动态相互作用。
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来源期刊
Journal of cellular biochemistry
Journal of cellular biochemistry 生物-生化与分子生物学
CiteScore
9.90
自引率
0.00%
发文量
164
审稿时长
1 months
期刊介绍: The Journal of Cellular Biochemistry publishes descriptions of original research in which complex cellular, pathogenic, clinical, or animal model systems are studied by biochemical, molecular, genetic, epigenetic or quantitative ultrastructural approaches. Submission of papers reporting genomic, proteomic, bioinformatics and systems biology approaches to identify and characterize parameters of biological control in a cellular context are encouraged. The areas covered include, but are not restricted to, conditions, agents, regulatory networks, or differentiation states that influence structure, cell cycle & growth control, structure-function relationships.
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