CXCL12 promotes EMT-mediated malignant transformation of endometriosis-associated ovarian cancer via PI3K/Akt signaling: An integrated transcriptomic and clinical study
Abstract
Background
Endometriosis-associated ovarian cancer (EAOC) is a distinct form of epithelial ovarian cancer that arises from the malignant transformation of benign endometriotic lesions. While epithelial-mesenchymal transition (EMT) is acknowledged as a crucial process in the progression of EAOC, the upstream regulatory mechanisms and key molecular drivers are not fully understood. This study focuses on the chemokine CXCL12, its biological function, molecular mechanisms, and clinical prognostic significance in the transition from endometriosis to EAOC.
Methods
Differentially expressed genes (DEGs) between benign endometriosis and EAOC tissues were identified using Gene Expression Omnibus (GEO) datasets. CXCL12 emerged as a candidate regulator. To further elucidate the functional role of CXCL12, we conducted in vitro studies by establishing cell models with either CXCL12 overexpression or knockdown. Additionally, we investigated the underlying mechanism of CXCL12's function, focusing on its interaction with the PI3K/Akt signaling pathway and its regulation of downstream EMT-associated proteins. A retrospective analysis of clinical data from 38 EAOC patients was performed to evaluate the association between CXCL12 expression levels and patient prognosis.
Results
CXCL12 expression was significantly elevated in EAOC tissues compared to benign endometriosis samples and was closely associated with EMT-related phenotypes. In vitro functional assays demonstrated that CXCL12 enhanced cellular migratory and invasive capacities. Mechanistically, CXCL12 was found to induce EMT by activating the PI3K/Akt signaling pathway. Clinical analysis further revealed that high CXCL12 expression was associated with reduced overall survival and increased recurrence risk in EAOC patients. Multivariate Cox regression analysis identified CXCL12 as an independent adverse prognostic factor in EAOC.
Conclusion
This study is the first to systematically define the critical role of CXCL12 in the malignant transformation of endometriosis to EAOC.Our findings demonstrate that CXCL12 promotes tumor cell invasion and metastasis through PI3K/Akt-mediated induction of EMT. These results provide novel insights into the pathogenesis of EAOC and highlight CXCL12 as a promising biomarker for early diagnosis and a potential therapeutic target, offering new avenues for precision management of EAOC.