Article Dans Une Revue PLoS ONE Année : 2025

Frizzled 7 drives amplification of cancer stem-cell subpopulations and the aggressiveness and poor differentiation of human hepatocellular carcinoma

Janick Selves
  • Fonction : Auteur
Jean-Marie Peron
  • Fonction : Auteur

Résumé

FZD7 is one of the key players in the subset of WNT-TGFβ-activated hepatocellular carcinomas (HCC), but the consequences of its abnormal expression on hepatocarcinogenesis remain to be better understood. Herein, we aimed to investigate the role of the FZD7-mediated signaling in immature phenotype and aggressiveness of HCC.

Firstly, 499 human HCCs were used for clinical and molecular comparisons regarding the expression of FZD7 and stemness-associated markers. We showed that FZD7 overexpression was associated with poor differentiation and, in combination with CD133, predicted a poor outcome of patients with aggressive recurrence. Next, the impact of WNT3/FZD7 signaling on the differentiation of hepatic cells was assessed in HCC cell lines, as well in the non-transformed progenitor HepaRG cell line and in primary human hepatocytes, transduced with WNT3 and FZD7-expressing lentiviruses. We demonstrated that the ectopic expression of WNT3 and FZD7 inhibited the differentiation behavior of HepaRG cells and human primary hepatocytes, amplified the pool of EpCAM (+) , CD90 (+) and CD133 (+) subsets of HCC cell lines, and increased their cancer stem cell features. Moreover, we found that WNT3/FZD7-mediated stemness properties of cancer cells were independent of the stemness-associated marker NANOG. In conclusion, we identified the FZD7 (+) /CD133 (+) signature as a potential prognosis marker and molecular therapeutic target, and we strengthened the hypothesis for the involvement of FZD7 in the enrichment of a cancer stem cell pool in HCC.

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hal-05308248 , version 1 (10-10-2025)

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Anaïs Lopez, Alexia Paturel, Nadim Fares, Floriane Pez, Guanxiong Wang, et al.. Frizzled 7 drives amplification of cancer stem-cell subpopulations and the aggressiveness and poor differentiation of human hepatocellular carcinoma. PLoS ONE, 2025, 20, ⟨10.1371/journal.pone.0332768⟩. ⟨hal-05308248⟩
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