Ribosome Biogenesis Rate and Cancer Development

Introduction to Ribosome Biogenesis and Nucleolar Hypertrophy

Ribosome biogenesis is the process of making ribosomes that occurs in the cytoplasm and nucleolus. In mammalian cells, ribosomal genes are transcribed by RNA polymerase I (Pol I) to generate 47S rRNA precursors. Transcription initiation factor I (TIF-I) A, upstream binding factor (UBF), and selectivity factor 1 (SL1) are important factors in ribosomal DNA (rDNA) transcription. During this process, mature ribosomal subunits can be formed through the assembly of rRNA with ribosomal protein (RP).

Studies have shown that nucleolar size is directly related to the degree of cancer malignancy, so that has served as an important parameter predicting the clinical outcome of cancers. Changes in the expression of oncogenes and tumor suppressors can largely influence the function and size of the nucleolus. For example, the oncogene MYC controls multiple steps of ribosome biogenesis, including increasing Pol I activity, increasing Pol II transcription, as well as enhancing Pol III transcription. The overexpression of oncogene MYC may result in an increased ribosome biogenesis rate.

Fig.1 The AgNORs are the sites where rRNA synthesis takes place in the nucleolus. (Penzo, 2019)

Ribosome Biogenesis Rate and Cancer Development

In human cancers, p53 and pRb frequently lose their function and result in loss of control of cell proliferation and up-regulation of rRNA transcriptional activity. In this case, tumors with altered p53 and/or pRb always show significantly enlarged nucleoli. Nucleolar hypertrophy leading to an increased rate of ribosome biosynthesis has been found in many human cells, such as human hepatocytes with chronic inflammatory disease, colonic mucosal epithelial cells with chronic ulcerative disease, as well as pancreatic acinar cells with chronic pancreatitis. These conditions lead to a significant increase in the risk of developing cancer. What’s more, the higher the number of liver cells with hypertrophic nucleoli, the higher the incidence of cancer.

The mechanism between enhanced ribosomal biogenesis and tumorigenesis is that upregulation of rRNA transcription leads to reduced availability of MDM2-inactive ribosomal proteins and a substantial downregulation of p53 protein expression. For example, nucleolar hypertrophy reduced p53 expression, and localized reduction or absence of E-cadherin expression was found in colonic epithelial cells from patients with ulcerative colitis.

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Reference

1. Penzo, M.; et al. The ribosome biogenesis-cancer connection. Cells, 2019, 8(1): 55.