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

Sep 24, 2026

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Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and remains a persistent threat across ages. Gut microbiota (GM) dysbiosis, together with chronic inflammation and cytokines, is hypothesized to support EOC-related signaling activation. Hedgehog (Hh) signaling is crucial to EOC progression and links to inflammation, yet GM’s precise role is unclear. Using patient- and control-derived GM, dysbiosis from EOC patients promoted tumor progression, enhanced Hh signaling, and activated NF-κB while healthy GM improved these effects, indicating TLR4/NF-κB–mediated Hh activation as a mechanism.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Introduction

Hedgehog (Hh) signaling in EOC

Inflammation, cytokines, and pathway activation

ARTICLE HISTORY

Keywords

GUT MICROBES 2023, VOL. 15, NO. 1, 2221093 [https://doi.org/10.1080/19490976.2023.2221093](https://doi.org/10.1080/19490976.2023.2221093) Gut microbiota dysbiosis promotes the development of epithelial ovarian cancer via regulating Hedgehog signaling pathway Xinyue Hua, Xuan Xub, Xiangdi Zengb, Rui Jinb, Shengnan Wanga, Huifu Jianga, Yuwen Tanga, Guanxiang Chena, Jing Weib, Tingtao Chen b, and Qi Chena a Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, China; bNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China 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. ARTICLE HISTORY Received 9 December 2022 Revised 25 May 2023 Accepted 30 May 2023 KEYWORDS Epithelial ovarian cancer; cancer progression; gut microbiota; Hedgehog signaling pathway; NF-κB signaling pathway 1. Introduction Epithelial ovarian cancer (EOC) is the most prevalent subtypes of ovarian cancer (OC), which originates from the canceration of ovarian surface epithelium (OSE) or tubal epithelium 1,2. With an estimated 313,959 (1.6%) new cases and 207,252 (2. 1%) deaths worldwide in 2020, EOC remains the leading cause of death from gynecologic cancers3. Primary cytoreductive surgery combined with adjuvant chemotherapy remains the standard front-line regimen forEOC with an unsatisfactory clinical efficacy, due to the fact that EOCs are generally diagnosed at advanced stages asa result of occult onset and followed by rapid progression4. Therefore, exploration of the underlying molecular mechanism of EOC development is urgent and significant for developing novel therapeutic approaches and improving prognosis for EOC. The mechanism of EOC development may be related to genetic mutations, continuous presence of inflammation, and signaling pathway activation5,6. In recent years, more and more researches indicated that Hedgehog (Hh) signaling pathway played a pivotal role in EOC development7. The Hh signaling pathway was initially identified by Nüsslein-Volhard in Drosophila in the early 1980s and contributed to embryonic development and tissue patterning8, while many studies have demonstrated that the aberrantly activated Hh signaling pathway raised the cancer risk and promoted the progression of numerous cancers via enhancing cell proliferation, invasion, and migration9. In our previous studies, the Hh signaling pathway has been proven to extraordinarily activate in EOC compared with normal ovarian tissue. Suppression of Hh signaling such as inhibitor Gli‑antagonist 61 (GANT61) restrained

FAQs

What role does gut microbiota dysbiosis play in epithelial ovarian cancer progression?

EOC-associated gut microbiota dysbiosis promotes tumor progression by activating Hedgehog signaling.

How is Hedgehog signaling connected to inflammation-related pathways in this study?

The results indicate that gut microbiota dysbiosis increases inflammation and activates NF-κB signaling, which mediates Hedgehog activation via TLR4/NF-κB signaling.

How do gut microbiota samples from healthy controls compare with those from EOC patients?

GM from healthy controls improves dysbiosis-related effects, whereas GM from EOC patients further exacerbates dysbiosis and promotes tumor progression and signaling activation.

Sep 24, 2026

Uploaded by Mia