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Fragile Histidine Triad–Mediated Tumor Suppression of Lung Cancer by Targeting Multiple Components of the Ras/Rho GTPase Molecular Switch
- Source :
- Cancer Research. 67:10379-10388
- Publication Year :
- 2007
- Publisher :
- American Association for Cancer Research (AACR), 2007.
-
Abstract
- The fragile histidine triad (FHIT) gene has been shown to function as a tumor suppressor gene in vitro and in vivo. However, the mechanism of its action is still largely unknown. To elucidate the molecular mechanism and biological pathway in FHIT-mediated tumor suppression, we used a complementary gene and protein expression profiling with DNA microarray and ProteinChip technologies to quantitatively monitor cellular changes in gene and protein expression and discover the molecular targets of FHIT in non–small cell lung carcinoma (NSCLC) cells. The Ras/Rho signaling pathway was identified as one of the unique biological pathways associated with FHIT activity. A significantly down-regulated expression of genes and proteins of multiple key components in the Ras/Rho GTPases molecular switch, including Ran, Rab, Rac, Rap, and Ral, was observed on gene and protein expression profiles and further validated by Western blot analysis. Ectopic activation of FHIT in FHIT-deficient H1299 cells also significantly reduced the invasive potential of tumor cells by down-regulating expression of RhoC, a potential marker of tumor cell invasion and metastases. A simultaneous knockdown of the expression of several key Ras/Rho signaling molecules using gene-specific small interfering RNAs (RHO-siRNA) targeting selected Rab11, Rac1, and Rap1 genes significantly inhibited tumor cell growth and induced apoptosis in NSCLC cells in vitro, and a local injection of RHO-siRNAs complexed with N-[1-(2,3-dioleoyloxyl)propyl]-N,N,N-trimethylammoniummethyl sulfate:cholesterol nanoparticles inhibited tumor growth in A549 tumor xenografts in mice, mimicking the AdFHIT-mediated tumor-suppressing effect. These results suggest a new role of FHIT in down-regulating the Ras/Rho GTPase-associated oncogenic signaling pathway. [Cancer Res 2007;67(21):10379–88]
- Subjects :
- rho GTP-Binding Proteins
Cancer Research
Lung Neoplasms
Tumor suppressor gene
Blotting, Western
Protein Array Analysis
RhoC
Apoptosis
RAC1
GTPase
Biology
Biological pathway
Mice
FHIT
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Animals
Humans
Neoplasm Invasiveness
RNA, Small Interfering
neoplasms
Gene knockdown
Tumor Suppressor Proteins
Acid Anhydride Hydrolases
Neoplasm Proteins
Genes, ras
Oncology
biology.protein
Cancer research
Female
Rap1
Signal Transduction
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 67
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....e4dbef4c13069ea66c4ea94d4e6b1c8e