RSPO1-LGR4 axis drives cervical cancer progression via activation of the EGFR/Src/ERK/AKT signaling pathway.
5 affiliations
- 1School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
- 2Hangzhou Xixi Hospital, Hangzhou Sixth People's Hospital, Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310023, China.
- 3Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
- 4Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- 5School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: [email protected].
Abstract
Cervical cancer (CCa) is a leading cause of cancer-associated mortality among women globally, posing a substantial health burden, particularly in low- and middle-income countries where HPV vaccination coverage remains limited. Therefore, identifying novel therapeutic targets to improve clinical outcomes is an urgent clinical need. R-spondin 1 (RSPO1) is a potent activator of Wnt/β-catenin signaling and has emerged as a potential driver of tumorigenesis, yet its biological function in cervical cancer remains poorly understood. In this study, we found that RSPO1 expression is upregulated in cervical cancer tissues, and its expression level is significantly associated with adverse clinical phenotypes in cervical cancer patients. Both in vitro and in vivo experiments demonstrate that overexpression of RSPO1 markedly enhances the proliferation, migration, invasion, and tumorigenic potential of cervical cancer cells. RSPO1 promotes cervical cancer progression by activating the EGFR/Src/ERK/AKT signaling axis in an LGR4-dependent manner. Mechanistically, the RSPO1-LGR4 complex facilitates plasma membrane recruitment of EGFR and Src for activation. Meanwhile, the RSPO1-promoted interaction between LGR4 and EGFR competitively blocks c-Cbl-mediated ubiquitination and subsequent degradation of EGFR. This dual regulatory mechanism mediates sustained activation of the EGFR/Src complex and its downstream ERK/AKT signaling cascades, ultimately driving progression of cervical cancer. In conclusion, our findings demonstrate that the RSPO1-LGR4 signaling axis plays a critical role in malignant progression of cervical cancer, suggesting that targeting this axis may be a promising therapeutic strategy for cervical cancer intervention.
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BibTeX
@article{lu2026rspo1lgr4,
title = {{RSPO1-LGR4 axis drives cervical cancer progression via activation of the EGFR/Src/ERK/AKT signaling pathway.}},
author = {Liting Lu and Xiduan Wei and Sai Liu and Suting Lei and Qing Ji and Xiaoqi Wu and Qingyuan Zhuang and Rulu Pan and Chen Zheng and Yangyang Fu and Xincheng Lu},
journal = {Neoplasia (New York, N.Y.)},
year = {2026},
month = oct,
doi = {10.1016/j.neo.2026.101374},
url = {https://europepmc.org/article/MED/42843207},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - RSPO1-LGR4 axis drives cervical cancer progression via activation of the EGFR/Src/ERK/AKT signaling pathway.
AU - Liting Lu
AU - Xiduan Wei
AU - Sai Liu
AU - Suting Lei
AU - Qing Ji
AU - Xiaoqi Wu
AU - Qingyuan Zhuang
AU - Rulu Pan
AU - Chen Zheng
AU - Yangyang Fu
AU - Xincheng Lu
PY - 2026
DA - 2026/10/07
JO - Neoplasia (New York, N.Y.)
DO - 10.1016/j.neo.2026.101374
UR - https://europepmc.org/article/MED/42843207
AB - Cervical cancer (CCa) is a leading cause of cancer-associated mortality among women globally, posing a substantial health burden, particularly in low- and middle-income countries where HPV vaccination coverage remains limited. Therefore, identifying novel therapeutic targets to improve clinical outcomes is an urgent clinical need. R-spondin 1 (RSPO1) is a potent activator of Wnt/β-catenin signaling and has emerged as a potential driver of tumorigenesis, yet its biological function in cervical cancer remains poorly understood. In this study, we found that RSPO1 expression is upregulated in cervical cancer tissues, and its expression level is significantly associated with adverse clinical phenotypes in cervical cancer patients. Both in vitro and in vivo experiments demonstrate that overexpression of RSPO1 markedly enhances the proliferation, migration, invasion, and tumorigenic potential of cervical cancer cells. RSPO1 promotes cervical cancer progression by activating the EGFR/Src/ERK/AKT signaling axis in an LGR4-dependent manner. Mechanistically, the RSPO1-LGR4 complex facilitates plasma membrane recruitment of EGFR and Src for activation. Meanwhile, the RSPO1-promoted interaction between LGR4 and EGFR competitively blocks c-Cbl-mediated ubiquitination and subsequent degradation of EGFR. This dual regulatory mechanism mediates sustained activation of the EGFR/Src complex and its downstream ERK/AKT signaling cascades, ultimately driving progression of cervical cancer. In conclusion, our findings demonstrate that the RSPO1-LGR4 signaling axis plays a critical role in malignant progression of cervical cancer, suggesting that targeting this axis may be a promising therapeutic strategy for cervical cancer intervention.
SN - 1522-8002
SN - 1476-5586
ER -