Dataset Information

The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers.

ABSTRACT:

Background

Studies of familial cancers have found that only a small subset of tissues are affected by inherited mutations in a given tumour suppressor gene (TSG) or proto-oncogene (POG), even though the mutation is present in all tissues. Previous tests have shown that tissue specificity is not due to the presence vs absence of gene expression, as TSGs and POGs are expressed in nearly every type of normal human tissue. Using published microarray expression data we tested the related hypothesis that tissue-specific expression of a TSG or POG is highest in tissue where it is of oncogenic importance.

Methods

We tested this hypothesis by examining whether individual TSGs and POGs had higher expression in the normal (noncancerous) tissues where they are implicated in familial cancers relative to those tissues where they are not. We examined data for 15 TSGs and 8 POGs implicated in familial cancer across 12 human tissue types.

Results

We found a significant difference between expression levels in susceptible vs nonsusceptible tissues. It was found that 9 (60%, P<0.001) of the TSGs and 5 (63%, P<0.001) of the POGs had their highest expression level in the tissue type susceptible to their oncogenic effect.

Conclusions

This highly significant association supports the hypothesis that mutation of a specific TSG or POG is likely to be most oncogenic in the tissue where the gene has its highest level of expression. This suggests that high expression in normal tissues is a potential marker for linking cancer-related genes with their susceptible tissues.

SUBMITTER: Muir B

PROVIDER: S-EPMC4506389 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Publications

The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers.

Muir Brian B Nunney Leonard L

British journal of cancer 20150616 2

<h4>Background</h4>Studies of familial cancers have found that only a small subset of tissues are affected by inherited mutations in a given tumour suppressor gene (TSG) or proto-oncogene (POG), even though the mutation is present in all tissues. Previous tests have shown that tissue specificity is not due to the presence vs absence of gene expression, as TSGs and POGs are expressed in nearly every type of normal human tissue. Using published microarray expression data we tested the related hypo ...[more]

PMID: 26079304

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Project description:Prostate cancer is the commonest male cancer in Europe and the USA. The androgen receptor is a key transcription factor contributing to the development of all stages of the disease. In addition, other transcription factors have been associated with poor prognosis in prostate cancer, amongst which c-Myc is a well-established oncogene in many other cancers. We have previously reported that a role for the androgen receptor in prostate cancer is to promote glycolysis and anabolic metabolism. Many of these metabolic pathways are also c-Myc-regulated in other cancers. In this study we report that de novo purine biosynthesis is a c-Myc-dependent pathway in prostate cancer cells as determined by commensurate changes in the levels of enzymes in the pathway in response to siRNA knockdown of c-Myc and inducible overexpression of c-Myc. In addition c-Myc is recruited to the promoters of genes in the pathway as determined by chromatin immunoprecipitation. Using immunohistochemistry and real-time transcript detection we show that two enzymes (PAICS and IMPDH2) within the pathway are overexpressed in prostate cancers. An inhibitor of IMPDH2 reduces cell proliferation and significantly reduces the levels of guanosine triphosphate within treated cells. This imposes nucleolar stress on cells as determined by significant reductions in the levels of guanine nucleotide binding protein-like 3 (GNL3). In addition the levels of c-Myc, p53 and the androgen receptor are affected and the expression of tumour suppressive microRNA-34b is increased. Combining the IMPDH2 inhibitor with anti-androgens results in a combinatorial inhibition of cell proliferation. In conclusion we propose using enzymes within the de novo purine biosynthesis as cancer biomarkers and applying drugs to alter the flux through this pathway may represent an effective means of stratifying patients for therapy and sensitising some to AR-targeted therapies. Total RNA of three biological replicates for each condition was extracted using the RNeasy kit (Qiagen), conditions are: 5 h vehicle, 5 h Doxycycline, 12 h vehicle, 12 h Doxycyline

Dataset Information

The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers.

Background

Methods

Results

Conclusions

Publications

The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers.

Similar Datasets

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