Genes defined canonically have dual functions, which are manifested at multiple levels: (1) Different mRNAs, regulatory RNAs, protein isoforms and protein modifications derived from the same genomic locus may function differently and even oppositely; (2) Genes may interact at different levels, such as by forming chimeric RNAs and by forming different protein complexes to exert different and even opposite functions in different situations; (3) High levels of tumor-suppressor genes in normal cells drive proliferation of cancer progenitor cells in the same organ or tissue by imposing compensatory proliferation pressure, which presents the functional duality of genes as a cell-cell interaction at the tissue level. This "mito-inhibition-resistant phenotype" principle can be further tested if one day technology allows the manipulation of genes specifically in cancer progenitor cells without affecting their normal surrounding cells in the same organ or tissue. All these manifestations can find tangible examples along the CCND-CDK4/6-RB axis. The dual-function nature of genes, which often creates confusion to hamper our understanding of tumor biology, may be a main reason behind the heterogeneity of cancer cells in individual patients. Redefining "gene" by considering each of the RNAs, proteins or protein modifications from the same genomic locus as an individual "gene" should help us in clearing up much of the confusion on tumor biology and in selecting target molecules for treatment of different subpopulations of cancer cells in individual patients.
Bibliographical noteFunding Information:
We also want to thank Fred Bogott, MD, PhD, at Austin Medical Center, Austin, Minnesota, for his excellent English editing of this manuscript. This work was supported by a grant from the Department of Defense of United States (DOD Award W81XWH-11-1-0119) to D.J. Liao. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Cyclin D1
- Radiation therapy
- Targeted chemotherapy
- Tumor-suppressor genes