Mutations in the Retinoblastoma-related Gene RB2/p130 in Lung Tumors and Suppression of Tumor Growth in Vivo by Retrovirus-mediated Gene Transfer
2000
The retinoblastoma (Rb) family consists of the tumor suppressor
pRb/p105 and related proteins p107 and pRb2/p130. Recent
immunohistochemical studies of the retinoblastoma family of proteins in
235 specimens of lung cancer show the tightest inverse association
between the histological grading in the most aggressive tumor types and
pRb2/p130. This led us to study a panel of human lung cancers for
mutations in the RB2/p130 gene. Mutations in the
Rb-related gene RB2/p130 were detected in 11 of 14
(78.5%) primary lung tumors by single-strand conformation polymorphism
and sequence analysis. A Moloney leukemia virus-based retroviral system
was set up, and a comparable viral concentration of 1 × 10 7 infectious units/ml was obtained. Retrovirus-mediated
delivery of wild-type RB2/p130 to the lung tumor cell
line H23 potently inhibited tumorigenesis in vitro and
in vivo , as shown by the dramatic growth arrest observed
in a colony assay and the suppression of anchorage-independent growth
potential and tumor formation in nude mice. The tumors transduced with
the RB2/p130 retrovirus diminished in size after a
single injection, and a 12-fold reduction in tumor growth after
RB2/p130 transduction compared with the
Pac -transduced tumors (92% reduction,
P = 0.003) and
lacZ -transduced tumors (93% reduction,
P < 0.001) was found to be statistically
significant. These findings provide the missing confirmation that
RB2/p130 is a “ bona fide ” tumor
suppressor gene and strengthen the hypothesis that it may be a
candidate for cancer gene therapy for lung cancer.
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