Alternative pre-mRNA Splicing and Cancer
Tumours can emerge as a result of a change in the splicing pattern of single gene.
A change in the splicing pattern of a gene can affect different steps in the life of a cell. This can be cell growth, adhesion, migration, invasion and cell death. Additionally splicing regulation can be altered leading to subsequent tumour formation. One example of a changed splicing pattern causing cancer is the Ron protein. Ron is a cellular receptor which regulates several cellular activities, cell growth and motility among them. In the case of human gastric carcinoma, mistakes in splicing cause the production of different protein called ‘Delta Ron’ (ΔRon) (Collesi et al., 1996).
Alterations in splicing regulators and inactivation of tumour suppressors can cause cancer.
In normal cells the proteins that control alternative splicing are present in normal amounts and there are other proteins (called tumour suppressors), which keep cell growth in check. When things go wrong with either of these, cancer can result.
Alternative splicing is regulated by a huge number of factors. Alterations in the balance of these splicing regulators play a role for example in human ovarian cancer and in mouse models of breast cancer development.
Additionally, cancer can emerge as a result of the inactivation of tumour suppressors. FHIT, a putative tumour suppressor has been detected in human tumours (including gastric, cervical, thyroid and testicular germ-cell tumours) in many different alternatively spliced forms, which stop the protein working properly.
Probably the most famous tumour suppressor is p53, which is mutated in many cancers. Different alternative splicing forms of p53 are expressed in a tissue specific manner and their expression pattern is altered in human breast cancer.
Cancer is a complex process of changes in gene expression and altered regulatory pathways leading to severe changes as tumours develop. Mutations can act in different steps in how cells divide, move, stick together or invade other tissues, all of which contribute to cancer. A better understanding of the processes involved in what can go wrong with splicing will give an important insight into the formation and development of tumours. The identification of cancer-specific splice forms also provides a way of diagnosing the type and stage of cancer and could be targets for treatment.
Alterations in splicing regulatory elements can produce tumour-forming signals that can lead to spreading of cancer cells over to different regions of the body.
A “strategy” of cancer to spread through an organism is to change the normal way cells communicate with one another to a programme which will make normal cells become cancerous. CD44 is a cell-surface glycoprotein that is involved in different cellular mechanisms. Multiple forms of this protein can be generated by including and combining up to 10 variant internal exons. Certain splice variants of this protein are found to be over-expressed in various tumours and play a role in the movement of cells. Thus changes in the normal splicing pattern of CD44 cause the behaviour and movement of cells to change.
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