Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview
Li-Hui Wang1, Chun-Fu Wu1, Nirmal Rajasekaran2
1Department of Pharmacology, Shenyang Pharmaceutical University College of Life Science and Biopharmaceutical, Shenyang, China.
Abstract:
Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson's two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.
Insights
Cancer arises from genetic and epigenetic changes in tumor suppressor genes (TSGs). This review revises the two-hit model to a multiple-hit model, incorporating novel inactivation mechanisms for identifying new cancer biomarkers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer development involves genetic and epigenetic alterations in tumor suppressor genes (TSGs) and proto-oncogenes.
- Knudson's two-hit model explains TSG inactivation via biallelic deletion or mutation.
- Emerging evidence shows TSGs can be inactivated through mechanisms beyond biallelic hits.
Purpose of the Study:
- To review and integrate novel mechanisms of TSG inactivation.
- To propose a revised multiple-hit model for TSG inactivation.
- To facilitate the identification of novel TSGs as cancer biomarkers.
Main Methods:
- Literature review of studies on TSG inactivation mechanisms.
- Analysis of genetic and epigenetic alterations in cancer.
- Synthesis of existing models with newly identified inactivation pathways.
Main Results:
- TSG inactivation occurs through epigenetic silencing, proteasomal degradation, altered cellular localization, and transcriptional dysregulation.
- These mechanisms complement traditional biallelic inactivation.
- A revised multiple-hit model is proposed.
Conclusions:
- The revised multiple-hit model provides a more comprehensive framework for understanding TSG inactivation.
- This model aids in identifying novel TSGs with prognostic and predictive potential.
- Further research can leverage this model for targeted cancer therapies and biomarker discovery.
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