HAb18G/CD147 Promotes pSTAT3-Mediated Pancreatic Cancer Development via CD44s
| Autor: | Jiayuh Lin, Theodore S. Lawrence, Xiaojie Meng, James R. Fuchs, Xiaoqing Wu, Zhi-Nan Chen, Xiaotan T. Qiao, Liang Xu, Diane M. Simeone, David Karnak, Ling Li, Wenhua Tang, Xinbao Hao, Yongmin Li, Rachel Thompson |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
STAT3 Transcription Factor Cancer Research Pancreatic disease Carcinogenesis Kaplan-Meier Estimate medicine.disease_cause Article Mice Cancer stem cell Cell Line Tumor Pancreatic cancer Survivin medicine Animals Humans Clonogenic assay Aged biology CD44 Cancer Middle Aged medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Pancreatic Neoplasms Hyaluronan Receptors Oncology Tissue Array Analysis Basigin biology.protein Cancer research Female Signal Transduction |
| Zdroj: | Clinical Cancer Research. 19:6703-6715 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Signal transducer and activator of transcription 3 (STAT3) plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 has failed clinically. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate the potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo. Experimental Design: The expression of HAb18G/CD147, pSTAT3, and CD44s was determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 were assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot assay, immunofluorescence staining, immunoprecipitation, and in vivo tumor formation using loss or gain-of-function strategies. Results: Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. Cyclophilin A (CyPA), a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147-dependent mechanisms. HAb18G/CD147 was associated and colocalized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high coexpression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer. Conclusions: We identified HAb18G/CD147 as a novel upstream activator of STAT3, which interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest that HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies. Clin Cancer Res; 19(24); 6703–15. ©2013 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|