C-Sis Proto-Oncogene

By Dr. Tomislav Meštrović, MD, Ph.D.Reviewed by Deepthi Sathyajith, M.Pharm.

Oncogenes were initially discovered as cancer-causing viruses. However, science soon proved that they are found in all normal cells. In short, they are copies of normal cellular genes but are activated due to certain mutations. Oncogenes are responsible for encoding proteins that have the ability to kick-start cellular transformation either by activating mutations or by over expression.

The activation and alteration of proto-oncogenes to oncogenes results in functions that may be qualitative (e.g. modified product production) or quantitative (e.g. increased production of an unaltered product). As a direct consequence of such changes, activated oncogenes may lead to abnormal cell proliferation and hence tumor development.

Proto-Oncogenes

Cell division is strictly controlled in multicellular organisms. The original and unmutated (wild-type) allele of a certain oncogene is referred to as the proto-oncogene, which has the propensity to promote cell growth and cell division.

For instance, the c-sis oncogene (or proto-oncogene to be more precise) is actively transcribed in the highly invasive and proliferative cytotrophoblastic shell during the first trimester of pregnancy in the human placenta. The c-sis oncogene transcription occurs in parallel with the c-myc transcript distribution. The above represents an autocrine growth regulation model of a developing human placenta in a normal tissue.

There is also normal expression of c-sis oncogene in human and bovine endothelial cells. Its function, however, is still not completely elucidated. It is purported to have a role in the normal vessel wall development and other physiological processes related to vascularization.

However, once a certain tissue or organ has reached the intended size, the growth should automatically stop and the cell division should halt. Any mutation arising in the gene responsible for cell division is potentially disastrous resulting in cancer-causing genetic mutations. Translocation, point mutation, and amplification are some means by which proto-oncogenes are converted to malignant oncogenes.

The Importance of C-Sis Oncogene

Studies have demonstrated that human c-sis proto-oncogene is over expressed in a large number of human tumor cells, establishing an autocrine growth-promoting circuit.

Furthermore, the expression of the normal human c-sis coding sequence may result in cellular transformation when observed in specific experimental conditions. However, additional research work is required to pinpoint the exact factors that are responsible for its oncogenic activity under natural conditions.

One research group has demonstrated the presence of c-sis transcripts in various human breast cancer-cell lines. The activation of the c-sis proto-oncogene (which has a striking homology to platelet-derived growth factor [PDGF]) is linked to the autocrine stimulation of cell growth in the breasts. In addition, the uncontrolled proliferation of stromal fibroblasts in breast tumors with desmoplasia are considered a direct consequence of the over expression of c-sis and similar oncogenes.

With research proving the role of c-sis oncogene in vascularization processes, some researchers also suggest that c-sis oncogene plays a role in the pathogenesis of atherosclerosis. Other non-malignant diseases linked to this oncogene are giant cell arteritis, bronchiolitis obliterans, as well as different fibrotic events. There is also an enhanced expression of c-sis oncogenes in human meningiomas and neurinomas.

With research establishing the fact that human c-sis oncogene is expressed in many types of tumors and carcinomas, efforts have been made to develop appropriate therapy that can stop the overexpression of the c-sis oncogene in pathological conditions. Once such therapy for abnormal proliferation of the c-sis oncogene is the triplex forming oligonucleotides (TFO). TFOs can stop the overexpression of c-sis oncogene by inhibiting the transcriptional activity of the c-sis/PDF-B promoter.

Ongoing research shows a growing emphasis on molecular oncology that will help pave way for developing many more target-specific cancer therapies.

Further Reading

• All Oncogene Content
• What are Oncogenes?
• What are Proto-Oncogenes?
• Ras Genes and Cancer