Tumour Suppressor

Tumour Suppressor Genes: Key Players in Cancer Prevention

PTEN: A Multifunctional Tumour Suppressor

The PTEN gene is a critical tumour suppressor that is conserved across species from humans to worms. PTEN functions as a phospholipid phosphatase, acting on proteins and 3-phosphorylated phosphoinositides, such as phosphatidylinositol (3,4,5)-trisphosphate. This activity allows PTEN to modulate signal-transduction pathways involving lipid second messengers, particularly influencing the serine/threonine kinase AKT/PKB, which is crucial for cell survival signaling . Loss of PTEN function is frequently observed in various cancers, highlighting its importance in maintaining genomic stability, regulating cell survival, migration, proliferation, and metabolism.

Tumour Suppressor Functions in the Nervous System

Tumour suppressors play diverse roles depending on the cell type and tissue context. In the nervous system, mutations in tumour-suppressor genes can lead to unique outcomes compared to other organs. These differences are closely related to the specific cell types and developmental stages affected by the mutations. Understanding the tissue-specific functions of tumour suppressors in the nervous system can provide insights into cancer-relevant signaling pathways and potential therapeutic implications.

MicroRNAs as Tumour Suppressors: The Case of miR-655

MicroRNAs (miRNAs) are small non-coding RNAs that can function as tumour suppressors. In oesophageal squamous cell carcinoma (ESCC), low levels of miR-655 in plasma are associated with lymphatic invasion, lymph node metastasis, and advanced cancer stages. Overexpression of miR-655 in ESCC cells inhibits cell proliferation, migration, invasion, and epithelial-mesenchymal transition, suggesting that restoring miR-655 levels could be a therapeutic strategy to inhibit tumour and lymphatic progression.

Post-Translational Modifications of Tumour Suppressor Genes

Tumour suppressor genes such as retinoblastoma (Rb), p53, and PTEN are regulated by post-translational modifications (PTMs) including phosphorylation, SUMOylation, and acetylation. These modifications act as switches to control cell states, influencing cell survival and the cell cycle. PTMs create a complex network of interactions among tumour suppressor genes, which is crucial for maintaining normal cellular functions and preventing tumorigenesis. Understanding these modifications can lead to new therapeutic strategies targeting these regulatory networks.

TUSC2: A Novel Tumour Suppressor

Tumour suppressor candidate 2 (TUSC2), also known as FUS1, is located on chromosome 3p21.3 and is frequently deleted in malignant pleural mesothelioma. TUSC2 regulates G1 cell cycle progression, apoptosis, calcium homeostasis, and the activity of various kinases. Loss of TUSC2 expression is observed in several cancers, and its restoration has shown promise as an anti-cancer therapy in preclinical models and clinical trials. Combining TUSC2-nanoparticles with EGFR inhibitors like erlotinib is currently being evaluated for its efficacy in treating TUSC2-deficient cancers.

The Immunosuppressive Tumour Microenvironment

The tumour microenvironment (TME) includes myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells, which promote T-cell dysfunction and tumour progression. Elevated levels of these suppressor cells correlate with increased tumour burden. Recent studies suggest that natural killer T (NKT) cells can convert immunosuppressive MDSCs into immunity-promoting antigen-presenting cells, offering potential pathways for clinical interventions to manipulate the TME and enhance cancer immunotherapy.

The Polyamine-Hypusine Axis in Tumour Suppression

A novel tumour suppressor network involving the polyamine-hypusine axis has been identified. Genes such as adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A) are part of this network and are often co-deleted in human lymphomas. This axis regulates apoptosis, and its disruption promotes lymphomagenesis. Targeting this pathway could provide new therapeutic opportunities for cancers with these specific genetic alterations.

RB: Beyond Cell Cycle Regulation

The retinoblastoma (RB) tumour suppressor is well-known for its role in controlling cell cycle progression. However, recent findings indicate that RB also maintains genomic stability, preventing chromosome instability (CIN) and aneuploidy. Loss of RB function is associated with differential responses to various therapeutic agents, making RB status a critical factor in directing cancer treatment regimens .

Conclusion

Tumour suppressor genes are essential for preventing cancer by regulating various cellular processes. Understanding their diverse functions, regulatory mechanisms, and interactions within the cellular environment can provide valuable insights into cancer biology and lead to the development of targeted therapies. From PTEN and miR-655 to TUSC2 and the polyamine-hypusine axis, ongoing research continues to uncover the complexities of tumour suppression and its implications for cancer treatment.

Summary

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