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Clin Cancer Res. 2013 Dec 15;19(24):6703-15. doi: 10.1158/1078-0432.CCR-13-0621. Epub 2013 Oct 16.

HAb18G/CD147 promotes pSTAT3-mediated pancreatic cancer development via CD44s.

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1
Authors' Affiliations: Departments of Radiation Oncology and Surgery, University of Michigan Medical Center; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan; Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an; Department of Hematology/Oncology, Hainan University Medical School, Haikou, Hainan, China; Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, Kansas; Department of Pediatrics, College of Medicine; and Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio.

Abstract

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.

PMID:
24132924
PMCID:
PMC3873783
DOI:
10.1158/1078-0432.CCR-13-0621
[Indexed for MEDLINE]
Free PMC Article
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