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Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes
Z Su1, N I Goldstein, P B Fisher
1Departments of Pathology and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Abstract:
The genetic alterations and molecular events mediating human prostate cancer development and progression remain to be defined. Rapid expression cloning and differential RNA display detect a putative oncogene, prostate tumor-inducing gene 1 (PTI-1), that is differentially expressed in human prostate (as well as breast, colon, and small cell lung) cancer cell lines, patient-derived prostate carcinomas, and blood from patients with metastatic prostate cancer. PTI-1 consists of a unique 5' untranslated region (5' UTR) with significant sequence homology to Mycoplasma hyopneumoniae 23S ribosomal RNA juxtaposed to a sequence that encodes a truncated and mutated human elongation factor 1alpha (Trun-EF). Stable expression of a nearly full-length 1.9-kb PTI-1 gene, but not the separate PTI-1 5' UTR or Trun-EF region, in normal rat embryo fibroblast cells, CREF-Trans 6, induces an aggressive tumorigenic phenotype in athymic nude mice. Blocking PTI-1 expression with antisense PTI-1 results in reversion of transformed PTI-1-expressing cells to a more normal cellular morphology with suppression in both anchorage-independent growth and tumorigenic potential in athymic nude mice. These findings document that PTI-1 is indeed an oncogene, and directly blocking PTI-1 expression can nullify cancer phenotypes. In these contexts, PTI-1 not only represents a gene with discriminating diagnostic properties but also may serve as a target for the gene-based therapy of human prostate and other cancers.
Insights
Researchers identified prostate tumor-inducing gene 1 (PTI-1) as a novel oncogene. Blocking PTI-1 expression reversed cancer phenotypes, suggesting its potential as a diagnostic marker and therapeutic target for prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The molecular mechanisms driving prostate cancer development are not fully understood.
- Identifying key genetic alterations is crucial for diagnosis and treatment.
Purpose of the Study:
- To identify and characterize novel oncogenes involved in prostate cancer.
- To evaluate the therapeutic potential of targeting identified oncogenes.
Main Methods:
- Differential RNA display and expression cloning were used to identify PTI-1.
- Stable expression and antisense inhibition of PTI-1 were performed in cell lines and animal models.
- Tumorigenic potential and cellular morphology were assessed.
Main Results:
- Prostate tumor-inducing gene 1 (PTI-1) was identified as differentially expressed in various cancer types, including prostate cancer.
- Stable PTI-1 expression induced a tumorigenic phenotype in normal cells.
- Antisense inhibition of PTI-1 reverted transformed cells, suppressing tumorigenicity.
Conclusions:
- PTI-1 functions as an oncogene in prostate cancer.
- Targeting PTI-1 expression offers potential for cancer diagnosis and gene-based therapy.