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Stable alterations of CD44 isoform expression in prostate cancer cells decrease invasion and growth and alter ligand binding and chemosensitivity. BMC Cancer 2010 Jan 14;10:16

Date

01/16/2010

Pubmed ID

20074368

Pubmed Central ID

PMC2820461

DOI

10.1186/1471-2407-10-16

Scopus ID

2-s2.0-76749147900   20 Citations

Abstract

BACKGROUND: Dysregulated CD44 expression characterizes most human cancers, including prostate cancer (PCa). PCa loses expression of CD44 standard (CD44s) that is present in benign epithelium, and overexpresses the novel splice variant isoform, CD44v7-10.

METHODS: Using retroviral gene delivery to PC-3M PCa cells, we expressed luciferase-only, enforced CD44s re-expression as a fusion protein with luciferase at its C-terminus or as a protein separate from luciferase, or knocked down CD44v7-10 by RNAi. Invasion, migration, proliferation, soft agar colony formation, adhesion, Docetaxel sensitivity, and xenograft growth assays were carried out. Expression responses of merlin, a CD44 binding partner, and growth-permissive phospho-merlin, were assessed by western blot.

RESULTS: Compared to luciferase-only PC-3M cells, all three treatments reduced invasion and migration. Growth and soft agar colony formation were reduced only by re-expression of CD44s as a separate or fusion protein but not CD44v7-10 RNAi. Hyaluronan and osteopontin binding were greatly strengthened by CD44s expression as a separate protein, but not a fusion protein. CD44v7-10 RNAi in PC-3M cells caused marked sensitization to Docetaxel; the two CD44s re-expression approaches caused minimal sensitization. In limited numbers of mouse subcutaneous xenografts, all three alterations produced only nonsignificant trends toward slower growth compared with luciferase-only controls. The expression of CD44s as a separate protein, but not a fusion protein, caused emergence of a strongly-expressed, hypophosphorylated species of phospho-merlin.

CONCLUSION: Stable re-expression of CD44s reduces PCa growth and invasion in vitro, and possibly in vivo, suggesting CD44 alterations have potential as gene therapy. When the C-terminus of CD44s is fused to another protein, most phenotypic effects are lessened, particularly hyaluronan adhesion. Finally, CD44v7-10, although it was not functionally significant for growth, may be a target for chemosensitization.

Author List

Yang K, Tang Y, Habermehl GK, Iczkowski KA

Author

Kenneth A. Iczkowski MD Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Cell Adhesion
Cell Movement
Gene Expression Regulation, Neoplastic
Humans
Hyaluronan Receptors
Ligands
Male
Mice
Neoplasm Invasiveness
Neoplasm Transplantation
Phosphorylation
Prostatic Neoplasms
Protein Isoforms
Protein Structure, Tertiary
RNA Interference
Taxoids
jenkins-FCD Prod-406 0f9a74600e4e79798f8fa6f545ea115f3dd948b2