Dr. Xiaoran YinAssociate Professor and Deputy Chief Physician
Oncology Department, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi’an, China
Speech Title: LGR5+/CD44+ cells endow cancer stemness and EMT property through WNT/TGF-β crosstalk predicting poor prognosis in gastric adenocarcinoma
Abstract: Background: Gastric cancer is the fifth most common and the fourth most lethal cancer worldwide. Cancer stem cells (CSCs) account for proliferation, invasion, metastasis and drug resistance with the potential to be an effective target for evaluation, diagnosis and treatment of cancer. Our study evaluated the roles of LGR5 as a valuable marker of CSCs in the diagnosis and prognosis of gastric adenocarcinoma.
Methods: Transcription profiles and survival information of 1035 patients with gastric adenocarcinoma were obtained from the GEO (Gene Expression Omnibus) and The Cancer Genome Atlas (TCGA) databases. LGR5, CD24 and CD44 expressions were measured by immunohistochemical on pathological specimens of gastric adenocarcinoma patients in our hospital. Diagnostic and survival information was analysed between different LGR5/CD44 expression level groups by χ2 test and Kaplan-Meier method. The serum-free culture was performed to obtain CSCs from gastric adenocarcinoma cell lines. LGR5, WNT/β-catenin pathway and epithelial-mesenchymal transition (EMT) related expressions were examined by Western-blot and immunofluorescence.
Results: The co-expression of LGR5 and CD44 is associated with poor differentiation and prognosis in gastric adenocarcinoma patients. Serum-free culture purified CSCs showed upregulated expression of LGR5 and CD44. Further investigation revealed that elevated LGR5 expression was accompanied by the activation of WNT/β-catenin and TGF-β/Smads, except for Smad4 downregulation. Immunofluorescence exhibited an increase of p-Smad3 under GSK-3β inhibition, suggesting the crosstalk between the LGR5/β-catenin pathway and the TGF-β/Smads pathway by activating GSK-3β and inhibiting Smad4 to maintain the stemness and EMT characteristics.
Conclusion: LGR5+/CD44+ marks CSCs of gastric adenocarcinoma, indicating poor differentiation and prognosis. LGR5 activates the WNT/β-catenin pathway and forms the crosstalk with the TGF-β/Smads pathway, maintaining the stemness of CSCs. LGR5 can be a diagnostic and therapeutic target of CSCs for the theranostics on gastric adenocarcinoma.
Keywords: LGR5, gastric adenocarcinoma, cancer stem cell, EMT, WNT/TGF-β crosstalk
Acknowledgements: This study was supported by the National Natural Science Foundation of China (NSFC) (81802453), the Key Research and Development Program of Shaanxi Province (2019SF-093), and the Basic Scientific Research Interdisciplinary and Cooperation Project of Xi'an Jiaotong University (1119293853).
Biography: Dr. Xiaoran Yin is an associate chief physician/associate professor of oncology promoted in 2015 from the Second Affiliated Hospital of Xi'an Jiaotong University of China. She specializes in precision diagnosis and treatment, immunotherapy, comprehensive cancer treatment and whole-course management of lung cancer, gastrointestinal cancer and breast cancer. She worked at Massachusetts General Hospital of Harvard Medical School from 2019 as a visiting associate professor and visiting scholar for one and a half years. Her particular interest is to develop novel nanomedicines for cancer theranostics, especially cancer stem cells. She has published more than 50 articles in English and Chinese, including Advanced Material, ADDR, Theranostics, IJMS etc., and she has achieved more than 540 citations, H-index=13. She is a chief guest editor for the Frontiers in immunology/Frontiers in oncology and a reviewer for more than ten scientific journals.