Open Access

ARTICLE

PFDN6L Gene Predicts Good Prognosis Associated with Its Inhibition of the Stem-Ness Properties in Hepatocellular Carcinoma

Fangyuan Li^1,2,#, Xiaoyuan Hu^1,#, Xiaoge Gao³, Ling Liu³, Tao Li¹, Dan He¹, Jiaxing Cheng¹, Xiaobiao Ma¹, Li Li^1,*, Chunlei Ge^1,*, Hong Yao^1,*

1 Cancer Biotherapy Center & Cancer Research Institute, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, 650118, China
2 Shenzhen Baoan Women’s and Children’s Hospital, Shenzhen, 518100, China
3 Cancer Institute, Xuzhou Medical University, Xuzhou, 221002, China

* Corresponding Authors: Li Li. Email: ; Chunlei Ge. Email: ; Hong Yao. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: New Insights in Drug Resistance of Cancer Therapy: A New Wine in an Old Bottle)

Oncology Research 2025, 33(12), 4029-4048. https://doi.org/10.32604/or.2025.067628

Received 08 May 2025; Accepted 19 August 2025; Issue published 27 November 2025

Abstract

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 suppresses malignancy 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.

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