Roles of ribosomal proteins in hematologic disorders and cancers: a review : Emergency and Critical Care Medicine

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Roles of ribosomal proteins in hematologic disorders and cancers: a review

Wang, Jiea; Yan, Fengb,∗

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Emergency and Critical Care Medicine 3(1):p 23-31, March 2023. | DOI: 10.1097/EC9.0000000000000014
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The ribosome is responsible for translating the information contained in the mRNA into protein, which is the final step of the genetic program. Ribosomes that synthesize cellular proteins include ribosomal RNA (rRNA) and ribosomal proteins, which are assembled by a process called ribosome biogenesis.[1] The cytoplasmic 80S ribosome in eukaryotic cells consists of two subunits: a large 60S subunit and a small 40S subunit. The 60S subunit includes 28S, 5.8S, and 5S rRNA and 47 ribosomal proteins, whereas the 40S subunit consists of 18S rRNA and 33 different ribosomal proteins. Ribosome biogenesis is a complex biological process involving energy consumption and careful arrangement.[2]

Ribosome biogenesis occurs mainly in a specific intercellular compartment, the nucleolus. The process can be divided into the following steps: synthesis of preribosomal RNA (pre-rRNA) and ribosomal proteins, pre-rRNA base modification, folding and assembly with ribosomal proteins, and removal of transcribed spacers from pre-rRNA. In addition to RNA polymerases, rRNA, ribosomal proteins, approximately 500 different ribosome assembly factors and 300 small nucleolar RNAs (snoRNAs) are involved in eukaryotic ribosomal biogenesis.

Three RNA polymerases play different roles in ribosome biogenesis: Pol I synthesizes 47S pre-rRNA in the nucleolus, pol III synthesizes 5S rRNA in the nucleolus, Pol II synthesizes snoRNAs and mRNAs in the nucleus. Moreover, Pol II encodes ribosomal proteins in the cytoplasm.[3] The 47S pre-rRNA and 5S rRNA are co-transcribed and assembled with ribosomal proteins imported from the cytoplasm into the 90S processome.[4]

The mature 28S, 5.8S, with 18S rRNA are produced by cleavage and specific modifications of 47S pre-rRNA. Ribosomal proteins are imported into the nucleolus to form the pre-60S ribosomal subunit and 28S, 5.8S, and 5S rRNA and form a pre-40S ribosomal subunit with 18S rRNA.[5] Finally, after modification, the mature 40S and 60S subunits are exported from the nucleus to the cytoplasm through the nuclear pore complexes (NPCs), forming ribosomes with translation functions (see Fig. 1).[6]

Figure 1:
Overview of eukaryotic ribosome biogenesis.

Ribosomal proteins are important components of ribosomes, are ubiquitously present in every cell, and are abundant in content. At present, there are approximately 80 types of ribosomal proteins found in eukaryotic cells that are widely distributed in various tissues, which together with rRNA, form ribosomes to perform protein synthesis. In addition to protein biosynthesis, ribosomal proteins also have functions independent of ribosomes called the extra-ribosomal functions, which include participation in DNA repair, regulation of cell proliferation, apoptosis, and differentiation. Due to the rapid renewal, growth, and differentiation of various cells in the human body, many ribosomal proteins are required to participate in protein biosynthesis and regulation of cell growth. Therefore, changes in ribosomal protein function are associated with the occurrence and development of various diseases. This article reviews the problems associated with ribosomal protein abnormalities and various related diseases.

Naming of ribosomal proteins

The term “ribosomal protein” first appeared in the mid-1960s after which several research groups began to purify and identify ribosomal proteins in E. coli. Each laboratory had designed its own naming system, rendering the naming very confusing. In 1971, this confusion ended[7] when people reached an agreement on the standard experimental methods and naming system for identifying these proteins. Since then, ribosomal proteins of small subunits are named SX, whereas those from large subunits are named LY, where X and Y are integers.

In 2012, Strasbourg et al. proposed that ribosomal proteins should be named in the same way as those in yeast ribosomes.[8] In 2013, Strasbourg’s proposal was discussed at a ribosome conference in Napa, California where the idea of prefixing a protein name with a letter appeared, but no consensus was attained.

Subsequently, a new ribosomal protein nomenclature system was proposed in 2014. The aim was to eliminate the confusion caused by the fact that ribosomal proteins of different species were assigned the same name despite their unrelated structures and functions. The authors thought that homologous macromolecules with the same function in different organisms should be given the same name. Ban et al. described the proposed ribosomal protein nomenclature system, which showed the equivalence between this system and other nomenclature systems currently used. This was a modest amendment to the proposal of the Strasbourg group for the first time.[9]

The ribosomal proteins of E. coli were first isolated, sequenced, and described by several studies. Therefore, the scientific standard priority practices required that their archaeal and eukaryotic homologs be named as ribosomal proteins of E. coli. The proteins found in the ribosomes of all three domains were prefixed with “u” (for universal), followed by their E. coli names. Bacterial ribosomal proteins without eukaryotic (or archaeal) homologs are represented by the prefix “b” (bacteria). Similarly, the prefix “a” (archaea) should be used to identify archaeal ribosomal proteins without homologs in eubacterial and eukaryotic ribosomes; however, none has yet been found. Eukaryotic ribosomal proteins without eubacterial homolog, which were first sequenced in rats, are given the names assigned to them by Wool and his colleagues,[10] whereas others first sequenced in the yeast community are named using the system described in 1997.[11] By adding the letter “e” (for eukaryotic) before the name of ribosomal proteins only in eukaryotes, the problem caused by the accidental overlap in protein numbering scheme is avoided, and the reader is reminded that the proteins in question are not homologous to eubacteria.[9]

The role of ribosomal proteins in cells

Ribosomes are organelles that are necessary for protein synthesis in all living cells. Ribosomal proteins are the main components of ribosomes which combine with RNA to form ribosomes and perform protein synthesis as well as extra-ribosomal functions.[12] Warner et al.[12] proposed that the extra-ribosomal functions of ribosomal proteins can be roughly divided into three aspects according to their scope of action: (1) in the ribosome system, regulation of the balance of ribosome assembly units and maintenance of the integrity of the ribosome; (2) outside the ribosome system, recognizing the nucleolus stress response and mediating cell cycle arrest or apoptosis in the G1 phase; and (3) the specific or nonspecific function of ribosomal proteins. It can be seen that ribosomal proteins are not only active in the ribosomal system, but also interact with other nonribosomal components to regulate the physiological functions of the cell.[13]

Ribosomal proteins and blood system diseases

Clinical and experimental evidence has shown that the abnormal expression of ribosomal protein genes affects the protein translation process, causes abnormal cell development, growth arrest, or death, and causes various diseases. At present, it has been confirmed that some diseases of the blood system are related to abnormalities in ribosomal proteins. Due to the rapid renewal, growth, and differentiation of bone marrow hematopoietic cells, many ribosomal proteins are required to participate in protein biosynthesis and cell growth regulation. Therefore, the blood system is more susceptible to abnormal expression of ribosomal proteins. Mutations in genes encoding ribosomal proteins or abnormal expression of ribosomal proteins caused by other factors affect the normal proliferation and differentiation of bone marrow hematopoietic cells, inducing a clonal advantage causing hematological malignancies.[14] The following sections briefly introduce the relationship between ribosomal proteins and several blood system diseases.

Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is congenital aplastic anemia with erythrocytopenia, wherein the blood system is mainly manifested as macrocytic anemia, reduction of bone marrow erythroid precursor cells, and malignant transformation tendency.[15,16] In 1997, Gustavsson et al.[17] first discovered that DBA is a rare hereditary bone marrow failure syndrome. It causes developmental disorders in multiple systems of the body, which mostly occur before the age of 2. Approximately 40% of cases have developmental malformations. Deformities most often involve the head and neck (cleft palate, oval cleft palate, reticular appearance of neck, microphthalmos, loss of lower eyelashes, malformation of the external ear, and micrognathism), limbs (three thumbs, multiple fingers, and syndactyly), urogenital tract, heart, and spinal cord.[14]

Approximately half of the DBA patients have mutations and deletions in the ribosomal protein gene. Global studies involving a large number of patients have found that the frequency of RPS19 mutations in DBA patients is approximately 25%.[18,19] Moreover, mutations in RPL5 (7% of DBA cases), RPS26 (7%), RPL11 (5%), RPL35A (3.5%), RPS10 (3%), RPS24 (2.4%), and RPS17 (1%) genes have also been identified in patients with DBA.[20–26] However, RPS19 is the most frequently mutated gene. In a very small subset of DBA patients, other ribosomal protein gene mutations have been found: RPS7, RPS15, RPS27, RPS27A, RPS28, RPS29, RPL9, RPL15, RPL18, RPL26, RPL27, and RPL31, with each gene affecting <1% of DBA patients.[19] Some DBA patients have no ribosomal protein gene mutations, and the genes associated with the DBA-like phenotype include GATA1, TSR2, EPO, and ADA2. Up-to-date, no mutation has been found in 20% of patients with DBA. In this case, exome or whole genome sequencing should be performed to identify DBA-related genes that have not yet been screened.[19]

Hamaguchi et al.[27] reported that when RPS19 cDNA was introduced into the bone marrow CD34+ cells of DBA patients through the RPS19 gene retroviral recombinant expression plasmid, the apoptosis rate was reduced, and the erythroid colony formation rate was significantly increased. After Rps19Dsk mice were treated with P53 heterozygous inactivation, their red blood cell counts in the peripheral blood increased, and the mean red blood cell volume (MCV) decreased. In contrast, the anemia of RPS19 mutant mice treated with P53 homozygous inactivation could be completely relieved.[28] Aspesi et al.[15] used Ranking-PCA and other technologies to screen for changes in the gene expression profile of CD34+ bone marrow hematopoietic cells knocked out by RPS19. In addition to the genes involved in pro-apoptosis, such as the upregulation of PYCARD, they also participate in maintaining intracellular oxidation. Genes that restore homeostasis, such as SOD2 and TXNRD1, have increased expression levels, suggesting that cells with RPS19 deletion are more sensitive to cellular oxidative stress. Therefore, ribosome deletion can participate in ribosome stress by changing the expression of multiple functional genes in the cell.[13]


The 5q-syndrome is a unique subtype of myelodysplastic syndrome (MDS). The World Health Organization (WHO) defines it as refractory anemia with unique karyotypic abnormalities, that is, the deletion of the long arm of chromosome 5 (5q-). Compared with other types of MDS, 5q-syndrome shows severe macrocytic anemia, normal/high platelet count, micromegakaryocyte dysplasia, and rarely progresses to acute myeloid leukemia (AML).[29]

Haploid deficiency of RPS14 has been identified as a major genetic abnormality in patients with 5q-syndrome.[30] The deficiency of RPS14 leads to an erythroid deficiency. Ebert et al.[30] performed RNAi screening on all genes in the commonly deleted region (CDR) of HSC in patients with 5q-syndrome and found that the lack of RPS14 haplotype might lead to maturity barriers of red blood cells in 5q-syndrome. Experiments have shown that the use of RNA interference technology to decrease the expression of RPS14 in normal artificial hematopoietic progenitor cells may inhibit the hematopoietic differentiation of bone marrow erythroid cells and result in the appearance of a large number of megaloblasts, which is very close to the characteristic of anemia of 5q-syndrome.[31] Although P53, which is a tumor suppressor, is upregulated in cells where RPS14 is absent, 5q-patients still have a tendency for malignant transformation, which suggests that other pathway abnormalities do not depend on P53 are involved. Studies have shown that as a negative regulator of C-MYC, RPS14 can prevent C-MYC from recruiting its transcriptional costimulatory molecule TRRAP and inhibiting the transcriptional activation of C-MYC on its target genes. In 5q-patients, RPS14 is missing, and C-MYC is unregulated, inducing uncontrolled cell proliferation and malignant transformation of the disease.[13,32]

In addition, RPS14 deficiency results in impaired 18S RNA processing, which leads to decreased 40S subunit levels.[30] The loss of heterozygosity of chromosome 5q is very large, and haploidy deficiency of other genes may also lead to the phenotype of 5q-.[33] For example, insufficient haplotypes of miR-145 and miR-146a may be responsible for thrombocytosis in this disease.[34,35] However, in vivo (mouse) and in vitro models, erythroid deficiency, which is the most similar phenotype to DBA, has been proven to result from haploid deficiency of RPS14.[30,36]

Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with clinical manifestations of bone marrow failure, exocrine pancreatic dysfunction, skeletal abnormalities, and a tendency to transform MDS or leukemia. In 2003, the gene mutation of Shwachman-Bodian-Diamond syndrome (SBDS) was reported by Boocock et al., and the name of Shwachman Bodian Diamond was reported for the first time.[37] Approximately 90% of patients were found to have biallelic mutations in the SBDS gene.[37] Recently, three more genes (NAJC21, EFL1, and SRP54) related to ribosome assembly or protein translation have been associated with the SDS phenotype.[38–41] Although the exact function of these genes is still unclear, there is evidence that they play a role in ribosomal biogenesis and ribosomal processing.[42]

SBDS plays a role in ribosome synthesis by promoting the release of eukaryotic initiation factor 6 (eIF6) through direct interaction with EFL1. NAJC21 stabilizes ribosomes, and SRP54 promotes protein transport. Studies have shown that many ribosomal protein genes in SDS cells are poorly expressed, including RPS9, RPS20, RPL6, RPL15, RPL22, RPL23, and RPL29, as well as genes involved in rRNA and mRNA processing.[43]

Dyskeratosis congenita

Dyskeratosis congenita (DKC) is a rare progressive bone marrow failure syndrome with an autosomal recessive/ dominant or X-linked recessive inheritance pattern. Its clinical manifestations include reticular skin pigmentation, nail dystrophy, and oral leukoplakia. Hematological abnormalities usually occur in early adulthood. Early death is commonly associated with bone marrow failure, infection, fatal pulmonary complications, or malignancies.[44]

The disease is associated with several telomerase-shortening genes with multiple genetic patterns. DKC1 (encoding dyskerin), TERC, TERT (encoding telomerase), and NOP10, are associated with the pathogenesis of DKC. We found that in DKC cases, the pathogenic mutation occurs in the telomerase complex, which is composed of telomerase reverse transcriptase (TERT), telomerase RNA (TERC), and dyskerin. It adds specific DNA sequences to the ends of chromosomes and resists the normal shortening during DNA replication.[45] Compared with autosomal dominant DKC, the phenotype of X-linked recessive DKC is more severe, and the mutation occurs in the DKC1 gene, which encodes dyskerin.[46] Dyskerin is a part of the telomerase complex and is also involved in rRNA modification (rRNA pseudouridine). However, the functional consequences of rRNA pseudouracil deficiency remain unclear. Some studies have shown that in addition to telomerase complex mutations, rRNA modification defects may play an important role in the clinical manifestations of DKC.

Cartilage hair hypoplasia

Cartilage hair hypoplasia (CHH) is a rare autosomal recessive genetic disease that leads to chondrodysplasia, hair hypoplasia, short limb dwarfism, anemia, and increased cancer risk. This is related to T-cell and B-cell immunodeficiencies. In addition to lymphopenia, hematological abnormalities may also include large-cell anemia. Stem cell transplantation was the only treatment option. Although transplantation cannot cure bone abnormalities, it is especially suitable for patients with severe T cell deficiency.[47]

Genetic defects in cartilage hair dysplasia have been identified as mutations in the RMRP gene.[48] RMRP is a ribonucleoprotein that exists in the nucleus and mitochondria. RMRP is involved in the cleavage of RNA and pre-RNA in mitochondrial DNA synthesis.[49] RMRP is necessary for cell growth, which is consistent with the observation that T cells, B cells, and fibroblasts have common defects in cell growth. In 2005, a study found that the level of cyclin B2 mRN A in CHH cells with RMRP mutation was increased.[50] It is well known that cyclin B2 causes chromosomal instability through mitotic spindle checkpoint changes, which provides another explanation for bone marrow dysfunction.[51]

Table 1 summarizes related altered genes, clinical manifestations, blood tests, and therapeutic methods for hematological diseases relevant to changes in ribosomal proteins or ribosomes.

Table 1 - The Features of Ribosome-related Hematologic Disorders
Name of Disease Related Genes Clinical Manifestation Blood Test Therapeutic Method
Diamond-Blackfan anemia RPS19, RPL5, RPS26, RPL11, RPL35A, RPS10, RPS24, RPS17, RPS7, RPS15, RPS27, RPS27A, RPS28, RPS29, RPL9, RPL15, RPL18, RPL26, RPL27, RPL31 Head and neck deformities, genitourinary tract and heart damage Macrocytic anemia, erythrocytopenia (<5% of bone marrow erythrocytes) Corticosteroid hormone, bone marrow transplantation
5q-syndrome RPS14 Pallor, progression to AML (10%) Macrocytic anemia, platelets were normal/elevated, micromegakaryocytes dysplasia Medication
Shwachman-Diamond syndrome SBDS, NAJC21, EFL1, SRP54, RPS9, RPS20, RPL6, RPL15, RPL22, RPL23, RPL29 Bone marrow failure, exocrine pancreatic dysfunction, skeletal abnormalities and tendency to transform MDS or leukemia. Neutropenia, thrombocytopenia, aplastic anemia Trypsin, replacement therapy
Dyskeratosis congenita DKC1, TERC, TERT, NOP10 Reticular skin pigmentation, nail dystrophy, oral leukoplakia Telomere length shortening, peripheral blood pancytopenia Symptomatic treatment
Cartilage hair hypoplasia RMRP Chondrodysplasia, hair hypoplasia, short limb dwarfism, anemia and increased risk of cancer Neutropenia, lymphopenia, hypogammaglobulinemia Enhance immunity, thymus transplantation

Ribosomal proteins and tumors

Early studies believe that it is necessary to maintain high-efficiency protein synthesis through an increase in ribosome biosynthesis to meet the continuous growth requirements of tumor cells. However, an increasing number of studies have shown that ribosome biosynthesis is abnormal in tumors. Changes in the modification may affect the occurrence of tumors.[6] Therefore, ribosome biosynthesis is closely associated with the occurrence and development of tumors. Due to the vigorous metabolism of tumor cells and the enhanced growth and proliferation ability, abnormal ribosomal biosynthesis frequently occurs in tumors. These abnormal processes in ribosomal biosynthesis include rDNA instability, abnormal rRNA synthesis, mutations in ribosomal protein genes, and imbalances in ribosomal protein expression. The abnormality of ribosomal biosynthesis in tumors depends on various factors, including changes in proto-oncogenes and tumor suppressor genes and the activation of specific signaling pathways in cells. Ribosome biosynthesis is strictly regulated by many key cell growth and proliferation signaling pathways,[52] including RAS/RAF/MEK/ERK, MYC, and PI3K/AKT/mTOR. These pathways form a complex network that regulates cell growth and proliferation.[53] Therefore, ribosomal proteins play an important role in protein biosynthesis in cancer cells. Tumor suppressor genes and oncogenes have been shown to regulate ribosomal protein biosynthesis and ribosomal translation. MYC is a proto-oncogene that regulates the biogenesis of mature ribosomes by modifying the factor genes necessary for ribosome assembly. Its overexpression in tumor cells increases the expression and activity of ribosomal components. Therefore, regulating protein synthesis may be an important mechanism by which MYC regulates cell growth and initiates tumorigenesis.[54] PTEN is a tumor suppressor that regulates the formation of mature ribosomes by inhibiting the activity of RPS6K.[55] These data suggest that the disorder of ribosomal protein biosynthesis may be an important factor in carcinogenesis.

Hepatocellular carcinoma

The expression of RPS2 was increased in mouse hepatocellular carcinoma. RPS2 is involved in the binding of amino-acyl tRNA to ribosomes, which potentially affects the fidelity of translation. The results showed that the increase in RPS2 level was related to an increase in cell proliferation.[56] Similarly, the expression of RPS8, RPL12, RPL23A, RPL27, and RPL30 ribosomal protein mRNAs was increased in three human hepatocellular carcinoma cell lines (Huh-7, Hep G2, and HLF).[57] The expression of RPL36 was higher in the early stage (stages I and II) of HCC. RPL36 may be related to the early stage of hepatocarcinogenesis and may be used as a prognostic marker for patients with hepatectomy.[58] In a previous study, RPL36A mRNA was preferentially overexpressed in HCC tissues and HCC cell lines. Overexpression of RPL36A enhances the proliferation and colony formation of hepatocellular carcinoma cells.[59] High expression of RPS3A was associated with low tumor immune cell infiltration in hepatocellular carcinoma patients and correlated with poor prognosis.[60] It was found that RPS8 was highly expressed in alcohol-related hepatocellular carcinoma and is related to its progression suggesting that RPS8 may be a new specific biomarker for alcohol-related hepatocellular carcinoma.[61] There was a significant correlation between RPS15A expression and the degree of malignancy and prognosis in hepatocellular carcinoma. RPS15A promoted angiogenesis in hepatocellular carcinoma by increasing the expression of FGF18 via the Wnt/β-catenin pathway.[62]

Colorectal cancer

It has been reported that the expression of ribosomal protein genes, including RPS3, RPS6, RPS8, RPS12, and RPL5, was increased in colorectal cancer.[63] Another study showed that expression of 12 ribosomal proteins RPSA, RPS8, RPS11, RPS12, RPS18, RPS24, RPL7, RPL13A, RPL18, RPL28, RPL32, and RPL35A were different between colorectal cancer tissues and healthy colon mucosa.[64] Immunohistochemistry showed that the expression of RPS11 and RPL7 increased in 18 cases of colorectal cancer compared with normal mucosa.[64] The mRNA expression of specific ribosomal proteins was correlated with the Dukes stage of tumor.[65] The expression of RPL13 mRNA in CRC tissues was higher than that in adjacent normal tissues. Knockout of RPL13 expression can significantly inhibit the growth and tumorigenicity of colon cancer cells.[66] Interestingly, RPL14 and RPS17 may promote colorectal cancer.[67] RPL14 and RPS17 were the few activated genes in colorectal cancer, which correlated with microsatellite instability (MSI) marker and mismatch repair gene inactivation.[67] RPL15 was significantly upregulated in colorectal cancer cell lines, and its overexpression in colorectal cancer is associated with progression.[68] DUOX2 regulates the stability of ribosomal protein RPL3 by affecting RPL3 ubiquitination. The expression of DUOX2 was significantly increased in colorectal cancer tumor samples. Moreover, it promoted the invasion and metastasis of colorectal cancer cells through interaction with RPL3.[69]

Prostate cancer

It was found that the RPL19 gene is significantly overexpressed in prostate cancer cell lines. The study found that the expression of RPL19 was negatively correlated with the survival of patients with prostate cancer.[70] In addition, the knockout of the RPL19 gene eliminated the invasive phenotype of human prostate cancer.[71] RPL19 may be used as an independent prognostic indicator and therapeutic target for prostate cancer. RPS2 protein has been reported as a new therapeutic target for prostate cancer. DNAZYM-1P was developed as a “ribozyme-like” oligonucleotide to knock down RPS2, which could inhibit the growth and induce apoptosis of prostate cancer cells.[72] RPL22L1 and RPS21 are highly expressed in human prostate cancer tissues and participate in the proliferation and invasion of prostate cancer cells.[73]

Gastric cancer

It has been found that RPL15 is upregulated in gastric cancer cell lines and tissues. Moreover, the growth of gastric cancer cells in vitro and tumorigenicity in vivo were suppressed by inhibiting RPL15 expression.[74] The expression of RPS13 is also upregulated in human gastric cancer. Downregulation of RPS13 inhibited the growth of gastric cancer cells, possibly through upregulation of p27, which affects G1 cell cycle arrest.[75] Compared with normal gastric mucosa, RPL6 was upregulated in gastric cancer tissue, and RPL6 promoted cell growth by upregulating cyclin E. RPL6 may be a potential prognostic biomarker in patients with gastric cancer because the level of RPL6 was inversely proportional to the survival time of patients.[76] Ribosomal protein RPL11 was a key factor influencing the sensitivity of gastric cancer to the treatment of 5-Fluorouracil (5-FU), suggesting a potential strategy for solving 5-FU resistance by increasing RPL11 expression.[77] The expression of RPS15A in human gastric cancer was significantly upregulated and correlated with TNM stage and poor survival. The underlying mechanism of gastric cancer progression is the activation of the Akt/ IKKβ/NF-ĸB signaling pathway.[78] The expression of RPL22 decreased in gastric cancer tissues and cells. RPL22 silencing could accelerate the proliferation, migration, and invasion of gastric cancer cells and inhibit apoptosis by activating MDM2-p53. RPL22 may be a potential target for gastric cancer therapy.[79]

Esophageal cancer

The results showed that the expression of RPL14 decreased and that of RPL15 increased in esophageal cancer.[80,81] In addition, RPS6 phosphorylation is increased in patients with esophageal squamous cell carcinoma and is associated with shorter disease-free survival. Importantly, inhibition of RPS6 promoted cell death by reducing cyclin D1 and inhibiting cell migration and invasion by decreasing ERK/JNK phosphorylation. It has been suggested that RPS6 phosphorylation is closely related to the tumor progression of esophageal squamous cell carcinoma and has prognostic significance.[82] It has been confirmed that RPL34 is upregulated in esophageal cancer tissues and cells and has a carcinogenic effect on esophageal cancer cells in vitro.[83] The corresponding long noncoding RNA, RPL34-AS1, inhibited the proliferation, migration, and invasion of esophageal cancer cells by decreasing RPL34 expression.[84]

Other tumors

Single chain ribosome inactivating protein (scRIP), produced from Shiga-like toxin 1 (SLT-1A), has been demonstrated to be capable of killing 7 out of 8 melanoma cell lines and causing better survival of mice receiving human melanoma xenografts with Dacarbazine.[85] The mammalian target of rapamycin (mTOR), which is thought to play a key role in controlling cancer growth, is an important target for cancer therapy. Phosphorylated RPS6 is a marker of mTOR activation, and the expression of phosphorylated RPS6 could predict the early response of tumors to mTOR inhibitors. Patients with high levels of phosphorylated RPS6 showed a better response to mTOR inhibitors, suggesting that this was a promising effective predictor for mTOR inhibitor therapy in sarcoma.[86] The expression of RPS6 was high in diffuse large B-cell lymphomas, and knockdown of RPS6 by shRNAs resulted in a reduced number of actively proliferating cells. It has been shown that RPS6 is associated with multiple mRNAs with a 5’TOP tract to encode the translation machinery.[87]

Although ribosomal protein level changes are considered potential biomarkers of cancer prognosis, most of these studies are descriptive and lack the underlying mechanisms. Further studies are needed to elucidate the functional roles of different ribosomal protein groups in certain cancer types. Ribosomal proteins with altered expression in different cancers are summarized in Table 2.

Table 2 - Ribosomal Proteins in Cancers
Cancer Name Ribosomal Proteins with Altered Expressions Ref.
Hepatocellular carcinoma RPS2 56
RPS8, RPL12, RPL23a, RPL27 and RPL30 57
RPL36 58
RPL36A 59
RPS3A, 60
RPS8, 61
RPS15A 62
Colorectal cancer RPS3, RPS6, RPS8, RPS12 and RPL5, 63
RPSA, RPS8, RPS11, RPS12, RPS18, RPS24, RPL7, RPL13A, RPL18, RPL28, RPL32 and RPL35A 64
RPL13 66
RPL14 and RPS17 67
RPL15 68
RPL3 69
Prostate cancer RPL19 70,71
RPS2 72
RPL22L1 and RPS21 73
Gastric cancer RPL15 74
RPS13 75
RPL6 76
RPL11 77
RPS15A 78
RPL22 79
Esophageal cancer RPL14, RPL15 80,81
RPS6 82
RPL34 83,84

Ribosomal protein typing and diseases

At present, there are approximately 80 types of ribosomal proteins found in eukaryotic cells, which are widely distributed in various tissues. In recent years, increasing evidence has shown that many ribosomal proteins form ribosomes and participate in protein biosynthesis, and are also related to certain diseases.[88] RPL6 is associated with congenital heart disease.[89] Mutations in the human RPL10 gene can cause microcephaly.[90] In mammals and Drosophila, RPS3 acts as an endonuclease.[91] In the process of zebrafish pancreatic cancer, RPL36 acts as an effective tumor suppressor.[92] In Drosophila, RPS6 can inhibit tumor.[93] RPS5 connects viruses and ribosomes, regulates cell differentiation and apoptosis, and other ribose functions in vitro. RPS5 gene expression changes in tumor tissues such as nasopharyngeal carcinoma cells, colorectal cancer, and liver cancer. RPL9 is closely related to the occurrence of liver cancer, the assembly of oncogenic mouse mammary tumor virus, and the prevention of brucellosis.[94,95]


Ribosomal proteins were initially considered as “housekeeping” genes involved in ribosome biosynthesis and protein synthesis. Most ribosomal proteins are co-transcribed and assembled with rRNA, and the structure becomes more stable as the assembly progresses. Ribosomal proteins play a key role in bringing together and maintaining the binding of rRNA domains. However, the mechanism of rRNA folding, processing, and assembly with ribosomal proteins is still unclear. Ribosomal proteins are considered to have a variety of extra-ribosomal functions, including cell proliferation, differentiation, and apoptosis, and play an important role in the growth and development of organisms. Abnormalities associated with the overexpression and reduced expression of ribosomal proteins suggest that they are potential therapeutic targets. Ribosomal protein genes may be oncogenes and tumor suppressors, and their role will be a new scientific field. Further studies are needed to understand how aberrations in translation mechanisms and their components lead to the development of hematological diseases and cancers.[96] Up-to-date, the abnormal expression of ribosomal proteins in tumors mostly remain at the level of expression, and the specific mechanistic understanding is not detailed enough. The next step of this research is to carry out specific functional research and clarify whether ribosomal proteins are the cause or result of tumorigenesis, and to actively develop anti-tumor drugs related to ribosomal biogenesis and ribosomal proteins. Through an in-depth study of ribosomal protein genes in diseased tissues, we can further clarify the mechanism of disease occurrence and development and understand the role of ribosomal protein gene abnormalities in various diseases, which can provide a novel insight into genetic diagnosis and gene therapy of diseases.

Conflict of interest statement

The authors declare no conflict of interest.

Author contributions

Wang J participated in the writing of the paper and Yan F participated in the research design.


This work was supported by the National Natural Science Foundation of China (81601721) and the Natural Science Foundation of Shandong Province (ZR2016HB11).

Ethical approval of studies and informed consent

Not applicable.




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Cancers; Extra-ribosomal function; Hematologic diseases; Ribosomal protein; Ribosome

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