Gut microbiota dysbiosis promotes the development of epithelial ovarian cancer via regulating Hedgehog signaling pathway

ABSTRACT

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, which remains a threat to female health at all ages. Hypotheses for EOC development include the continuous presence of inflammation, in which microbiota and inflammatory cytokines participate in cancer-related signaling pathway activation. Hedgehog (Hh) signaling is prominent for EOC progression, and interacts with inflammation response related to gut microbiota (GM). However, the precise roles of GM during this process are unknown. Here, we showed that the GM from patients with EOC differed from that of healthy women and had GM dysbiosis. We found that EOC modeling may lead to GM changes in mice, and it restored after the administration of GM from healthy controls, while GM from patients with EOC further exacerbated GM dysbiosis. Furthermore, we found that GM from EOC markedly promoted tumor progression and activated Hh signaling; meanwhile, it increased the extent of inflammation and activated NF-κB signaling, but GM from healthy controls improved them. Our results demonstrate how GM dysbiosis promoted EOC progression by activating Hh signaling mediated by TLR4/NF-κB signaling. We anticipate our assay to be a new thought for exploring the role of GM in EOC development. Furthermore, improving GM dysbiosis is a novel therapeutic approach for delaying EOC development.

KEYWORDS:

• Epithelial ovarian cancer
• cancer progression
• gut microbiota
• Hedgehog signaling pathway
• NF-κB signaling pathway

Acknowledgments

This research was supported by grants from National Natural Science Foundation of China (Grant no. 82260507 to Q.C., 82060638 to T.C.), and Jiangxi Provincial Department of Science and Technology (20202ACB206008 to Q.C., Double Thousand Talents Program to T.C.). Thanks for all the reviewers and editor for the support of publication of our manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

T.C. contributed Conceptualization; X.H. and Q.C. contributed methodology; X.H. contributed software; Q.C. and T.C. contributed validation; T.C. contributed formal analysis; X.X., S.W., H.J., Y.T. and G.C. contributed investigation; Q.C. and J.W. contributed resources; X.H. contributed data curation; T.C., X.H., and X.Z. contributed writing – original draft preparation; T.C., Q.C., X.H., and X.X. contributed writing – review and editing; X.H. and X.X. contributed visualization; T.C. and Q.C. contributed supervision; T.C. contributed project administration; Q.C. contributed funding acquisition. All authors have read and agreed to the published version of the manuscript.

Data availability statement

The data used to support the findings of this study are available from the corresponding author upon request, and the raw data of 16S rRNA sequencing generated in this study has been deposited under NCBI SRA BioProject numbers PRJNA900393 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA900393) and PRJNA900513 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA900513).

Institutional review board statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) on medical research of the Second Affiliated Hospital of Nanchang University (Examination and approval No. is Review [2020] No. (016)).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2221093

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [82260507, 82060638]; Key R&D Project of Jiangxi Science and Technology Department [20202ACB206008]; Jiangxi Province “Double Thousand Talents Program” (Science and Technology Innovation High-level Talents Program)