Background:Liver cancer stem cells(LCSCs)are recognized as pivotal drivers of hepatocellular carcinoma(HCC)progression;however,the molecular mechanisms maintaining their stem-like phenotype remain largely unresolved.T...Background:Liver cancer stem cells(LCSCs)are recognized as pivotal drivers of hepatocellular carcinoma(HCC)progression;however,the molecular mechanisms maintaining their stem-like phenotype remain largely unresolved.This work investigates the role of prefoldin subunit 6-like protein(PFDN6L)in shaping LCSC traits and promoting or restraining HCC progression.Methods:PFDN6L,a cytoskeleton-associated chaperone,was studied using multiple in vitro assays—cell growth evaluation,cell cycle profiling,and spheroid culture—alongside analyses of stemness-associated markers(SOX2,CD133,CD44).Tumorigenic capacity was assessed in xenograft mouse models,and signaling pathway interrogation was performed to define underlying mechanisms.Results:In patient samples,higher PFDN6L expression correlated with improved survival outcomes.Forced expression of PFDN6L induced G2/M arrest,diminished sphere formation,and reduced pluripotency marker expression,whereas knockdown accelerated in vivo tumor formation.Mechanistic experiments demonstrated that PFDN6L suppressesmalignancy by simultaneously dampening AKT and ERK1/2 activation,thereby impairing oncogenic signaling cascades.Conclusion:PFDN6L acts as a negative regulator of LCSC-driven tumorigenesis.Its dual blockade of AKT and ERK pathways forms the mechanistic basis of its tumor-suppressive action,supporting its potential as a prognostic biomarker and therapeutic target in HCC.展开更多
基金supported by the National Natural Science Foundation of China(Grant Numbers 82350117,82160476,32360046,82260462)First-Class Discipline Team of Kunming Medical University 2024XKTDYS07,Yunnan Provincial Department of Science and Technology Key Research and Development Plan for Social Development Special Projects(202403AC100022)+4 种基金The Fundamental Research Project of Yunnan Provincial Department of Science and Technology(202301AT070129)the Joint Special Funds for the Department of Science and Technology of Yunnan Province KunmingMedical University(Grant Number 202401AY070001-360)the Yunnan Provincial Department of Education Science Research Fund Project(Grant Number 2023Y0655,2024Y234)Yunnan Province Science and Technology Talents and Platform Plan Project(202305AF150067)Beijing Sci-Tech Innovation Medical Development Foundation KC2023-JX-0288-PM94.
文摘Background:Liver cancer stem cells(LCSCs)are recognized as pivotal drivers of hepatocellular carcinoma(HCC)progression;however,the molecular mechanisms maintaining their stem-like phenotype remain largely unresolved.This work investigates the role of prefoldin subunit 6-like protein(PFDN6L)in shaping LCSC traits and promoting or restraining HCC progression.Methods:PFDN6L,a cytoskeleton-associated chaperone,was studied using multiple in vitro assays—cell growth evaluation,cell cycle profiling,and spheroid culture—alongside analyses of stemness-associated markers(SOX2,CD133,CD44).Tumorigenic capacity was assessed in xenograft mouse models,and signaling pathway interrogation was performed to define underlying mechanisms.Results:In patient samples,higher PFDN6L expression correlated with improved survival outcomes.Forced expression of PFDN6L induced G2/M arrest,diminished sphere formation,and reduced pluripotency marker expression,whereas knockdown accelerated in vivo tumor formation.Mechanistic experiments demonstrated that PFDN6L suppressesmalignancy by simultaneously dampening AKT and ERK1/2 activation,thereby impairing oncogenic signaling cascades.Conclusion:PFDN6L acts as a negative regulator of LCSC-driven tumorigenesis.Its dual blockade of AKT and ERK pathways forms the mechanistic basis of its tumor-suppressive action,supporting its potential as a prognostic biomarker and therapeutic target in HCC.
