Novel Molecular Targeting of a Tumor-Specific Oncogenic Mutant Receptor in Human Prostate Cancer

摘要

EGFRvIII is a ligand-independent, constitutively active variant of the epidermal growth factor receptor. Its expression has detected in many human cancers, including prostate cancer, but has never been detected in normal tissue. In this report, we demonstrated that 35% (74/208) prostate cancer patient specimens detected EGFRvIII-co-expression with ErbB-2. To delineate the biological significance of EGFRvIII in human prostate cancer, we expressed EGFRvIII in Tsu and Dul45 prostate cancer cells. Expression of EGFRvIII in Tsu and DUl45 cells revealed enhancement of proliferation in vitro and increased tumorigenicity in nude mouse. We also designed and generated a tumor specific ribozyme targeted at the fusion junction of EGFRvIII. This specific EGFRvIII ribozyme is able to effectively cleave EGFRvIII mRNA under physiological conditions in a cell-free system. While expressing this EGFRvIII-ribozyme in 32D/EGFRvIII cell, EGFRvIII-ribozyme is capable of down-regulating EGFRvIII expression. However, this ribozyme has not effect on wild-type EGFRmRNA and protein levels. These results suggested that we have generated a tumor-specific biologically functional ribozyme. These results provide the first evidence that EGFRvIII plays a role in human prostate cancer tumorigenesis.