Abstract
Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.
Highlights
In 2018, colorectal cancer (CRC) was ranked the third most frequent cancer world-wide, after lung and prostate cancers in men and lung and breast cancers in women, by the International Agency for Research on Cancer (IARC) [1]
Evidence that the ribosome biogenesis pathway is altered in CRC has markedly increased in recent years
Studies using cellular and animal models largely contributed to establishing that the alterations leading to quantitative increase in ribosome production were linked to colorectal tumorigenesis initiation and/or progression
Summary
In 2018, colorectal cancer (CRC) was ranked the third most frequent cancer world-wide, after lung and prostate cancers in men and lung and breast cancers in women, by the International Agency for Research on Cancer (IARC) [1]. Various approaches have been developed to curb the mortality rate of CRC, in particular to improve the early detection using different analyses such as fecal blood tests and colonoscopy, in-depth enquiry into family history, blood analysis for tumor markers [8,9], and analysis of tumor gene expression [10,11]. These practices are reinforced by a broad panel of imaging methods [12]. Somatic APC mutations are present in almost 80% of sporadic human CRC and frequently occur within the coding sequence, resulting in a truncated defective protein [23]. The aim of this review is to present all aspects of ribosome biogenesis alterations reported in human colorectal cancers and explore the possibility of developing neo/adjuvant therapies based on direct or indirect targeting of ribosome production in CRC
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