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Oncogenic CD44 is essential for pancreatic cancer tumorigenesis: A novel targeted therapeutic strategy
Yu-Xi Liu, Na-Na Zheng, Xiao-Xiao Wang, Quan-Sheng Zhou, Mei Meng
Yu-Xi Liu, Quan-Sheng Zhou, Mei Meng, Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou 215123, Jiangsu Province, China
Na-Na Zheng, National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Soochow University, Suzhou 215123, Jiangsu Province, China
Xiao-Xiao Wang, Institute of Medical Biotechnology, Suzhou Vocational Health College, Suzhou 215123, Jiangsu Province, China
Quan-Sheng Zhou, Mei Meng, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, Jiangsu Province, China
Quan-Sheng Zhou, Mei Meng, National Clinical Research Center for Hematologic Diseases, The Affiliated Hospital of Soochow University, Suzhou 215123, Jiangsu Province, China
Quan-Sheng Zhou, Mei Meng, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, Jiangsu Province, China
Co-first authors: Yu-Xi Liu and Na-Na Zheng.
Co-corresponding authors: Quan-Sheng Zhou and Mei Meng.
Author contributions: Liu YX, Zheng NN and Wang XX - data curation, formal analysis, investigation, methodology, writing-original draft; Liu YX - data curation, investigation, methodology; Zheng NN and Wang XX - funding acquisition; Meng M and Zhou QS - conceptualization, funding acquisition, writing, and editing of the manuscript. Liu YX and Zheng NN contributed equally to this work as co-first authors. Both authors made significant contributions to the study design, data collection and analysis. Specifically, author Meng M was responsible for conceiving and designing the research framework and actively participated in experimental work and data analysis. Zhou QS organized and analyzed the data, providing crucial academic guidance and suggestions throughout the drafting process. In recognition of their equal contributions to the research, both authors have been designated corresponding authors. This arrangement better reflects their shared responsibility and contributions. It will also enable readers to contact either author when necessary, ensuring smooth and efficient communication.
Supported by National Natural Science Foundation of China, No. 82473211 and No. 82200168; Suzhou Municipal Applied Basic Research (Medical and Health) Science and Technology, No. SYWD2024241; National Clinical Research Center for Hematologic Diseases, No. 2020ZKMB04; Suzhou Vocational Health College, No. SZWZY202421; and Natural Science Foundation of Jiangsu Province, No. BK20220247.
Institutional review board statement: This study was approved by the Ethics Committee of Soochow University (Approval No. SUDA20251118A08).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Soochow University (Protocol No. 202206A0253).
Conflict-of-interest statement: The authors declare no conflicts of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
Corresponding author: Mei Meng, Manager, Research Associate, Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, No. 199 Renai Road, Suzhou 215123, Jiangsu Province, China.
mmeng@suda.edu.cn
Received: October 24, 2025
Revised: November 12, 2025
Accepted: December 10, 2025
Published online: March 15, 2026
Processing time: 141 Days and 10.7 Hours
BACKGROUND
CD44, also known as differentiation antigen 44, is a key marker for cancer stem cells and an indicator of poor prognosis in cancer patients. Currently, there are no cancer therapies that specifically target CD44 in clinical practice. Pancreatic cancer has an extremely high mortality rate, and there are few effective treatment options. The effects of CD44 gene knockout on pancreatic cancer have not been previously reported.
AIM
To investigate the impact of CD44 gene knockout on pancreatic tumorigenesis and treatment.
METHODS
CRISPR/Cas9 technology was used to disrupt CD44 gene exons in PaTu-8988 and Panc-1 pancreatic cancer cells to establish CD44 knockout cell lines. The effects of CD44 gene disruption on tumorigenesis in pancreatic cancer cells were then investigated at the molecular, cellular, and animal levels.
RESULTS
CD44 disruption inhibited tumor formation and pancreatic cancer cell migration and invasion capabilities. It increased DNA damage and sensitivity to the chemotherapeutic agent cisplatin, while also suppressing tumor growth in syngeneic mouse xenografts. Mechanistically, CD44 knockout revealed a novel oncogenic axis in cancer cells marked by a 35-fold reduction in promoter activity of the X-chromosome inactivation-specific transcription factor. Furthermore, CD44 knockout suppressed the expression of multiple other oncogenes, weakened the pro-tumor AKT and ERK signaling pathways, and simultaneously activated the tumor-suppressing p38 and p53 pathways.
CONCLUSION
Oncogenic CD44 plays a pivotal role in pancreatic cancer cell carcinogenesis, and CD44 knockout presents a promising therapeutic target for pancreatic cancer treatment. These findings demonstrate the central role of CD44 in pancreatic cancer and provide new therapeutic strategies for its management.
Core Tip: This study employed CRISPR/Cas9-mediated gene editing to knock out the CD44 gene, elucidating its critical role in pancreatic cancer progression. CD44 deficiency significantly suppressed cell proliferation, migration, and invasion, while simultaneously enhancing sensitivity to cisplatin treatment. Furthermore, we identified a novel regulatory axis involving CD44 and X-inactive-specific transcript. Mechanistically, CD44 knockout inhibited the AKT/ERK signaling pathway while activating the p38/p53 pathway. Collectively, these findings indicate that targeting CD44 through CRISPR/Cas9-based gene editing may represent a promising therapeutic strategy for pancreatic cancer.
