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

Anaïs Lopez, Alexia Paturel, Nadim Fares, Floriane Pez, Guanxiong Wang, Patricia Gifu, Lydie Lefrançois, Jihed Chouaref, Pierre Saintigny, Janick Selves, Jean-Marie Peron, Michel Rivoire, Philippe Merle and Claude Caron de Fromentel

PLOS ONE, 2025, vol. 20, issue 10, 1-16

Abstract: 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0332768

DOI: 10.1371/journal.pone.0332768

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