REVIEW Small Nucleolar RNAs in Solid Tumors: A Brief Review of the Literature on These Potential Biomarkers

Objective: The objective of this study was to conduct an integrative review, addressing the key findings, biological functions, and clinical significance of these biomolecules in solid tumors. Methods: This document analyzes the main data on the involvement of snoRNAs in solid tumors. For this, Pubmed and Science direct were used, with keywords. Additionally


Introduction
Solid tumors are considered one of the leading causes of cancer-related deaths, due to their rapid tumor growth and local or distant metastasis.They pose critical challenges due to physiological characteristics and limitations in treatment options [1,2].Among the markers that have been extensively studied in these types of tumors are non coding RNAs (ncRNAs).There are several families of ncRNAs in mammals, some of which are: microRNAs (miRNAs), small interfering RNAs (siRNAs), piwi-interacting RNAs Small Nucleolar RNAs in Solid Tumors: A Brief Review of the Literature on These Potential Biomarkers be divided into two subtypes, according to the motif present in the molecule: H/ACA (SNORA) and C/D box (SNORD).A third group is the SCARNA, discovered in 2002, which has presents both C/D and H/ACA domains and accumulates in Cajal bodies [5].In vertebrates, most snoRNAs are encoded in intronic regions of coding genes or long non-coding RNAs (lncRNAs), and a small group of snoRNAs originate from intergenic regions [6].
Since their discovery, the functional role of snoRNAs under normal and pathological conditions has been investigated.SnoRNA expression can be modified by a variety of genetic alterations changes such as: a) overexpression; b) translocation; c) mutations; and d) copy number variations [7].Epigenetic mechanisms can also alter gene expression such as: a) DNA methylation; and b) histone modification [7,8].Historically, the first snoRNAassociated human disease described is Prader-Willi syndrome (PWS), a rare genetic disorder characterized by hypotonia and hyperphagia [9,10].Currently, snoRNAs are known to be participate in a wide range of human diseases, including, congenital heart defects, and cancer [11,10].
The demonstration that snoRNA expression varies in cancerous tissues challenges the old dogma, according to which snoRNAs only function maintaining of ribosome biogenesis [8,12].In recent years, several studies have presented promising data on the involvement of these biomolecules in different types of malignant neoplasms, through the regulation of several molecular pathways [13,14].In this context, the objective of this work was to carry out an integrative review addressing the main results, such as biological functions and clinical significance of these biomolecules in solid tumors.

Snornas in Lung Cancer
Works with snoRNAs in lung cancer began in 2010 when Liao et al. [15] observed that six snoRNAs (SNORA80E, SNORA73B, SNORD33, SNORD66, SNORD76 and SNORD78) were overexpressed compared to tissue samples from individuals without cancer.Of these six snoRNAs, three (SNORD33, SNORD66, and SNORD76) had a sensitivity of 81.1% and a specificity of 95.8% in distinguishing lung cancer patients from normal individuals.
Subsequently, Mei et al. [16] demonstrated in 64 samples from patients with stage I lung cancer that SNORA42 genomic amplification resulted in an overexpression of tumor stem cells.Silencing of this small nucleolar RNA reduces the transcript levels of genes associated with pluripotency, such as OCT4, SOX2, NOTCH1, NANOG, SMO, and ABCG2.These results suggest that SNORA42 is essential for the expression of transcription factors in tumor stem cells.
Dysregulation of other snoRNAs such as SNORA21, SNORD28, SNORA47, SNORD66, SNORA68, and SNORA78 was associated with worse overall survival, in addition to allowing differentiation between patients with stage I lung cancer and normal tissue [17].SNORD46 knockdown results in decreased cell viability, inhibition of invasion, and migration capacity [13].
Recently, two studies have addressed the identification of these biomolecules in non-invasive samples.In the first one, Dong et al. [18] observed that the expression of SNORD55 was decreased in both plasma and tissue of patients in the early stages of the disease.Similar data were observed by Wang et al. [19] when investigating the expression of SNORD83A.These data support the potential of snoRNAs as biomarkers the early detection of lung cancer (Table 1).Another snoRNA, SNORA38B, was significantly expressed, and associated with poorer worse prognostic factors, including proliferation, migration, and cellular invasion, correlated with advanced disease stages, and decreased survival, thus representing a potential therapeutic target [20].
Two snoRNAs, SNORD42B and SNORD111, could serve as promising non-invasive biomarkers for earlystage lung cancer, as they were shown to have good sensitivity and specificity [39].Finally, Wan et al. [21] observed six snoRNAs (SNORD14A, SNORD59A, SNORD99, SNORD100, SNORD63, and SNORD19) which are related to infiltration into the tumor immune microenvironment, thus predicting the prognosis and responsiveness to immunotherapy in lung cancer patients.

Colorectal Cancer
Changes in snoRNAs have also been reported in colorectal cancer (CRC) (Table 2), and the data presented demonstrate promising results.showdemonstrate promising results.Among these studies is one by Zhang et al. [22], who observed that the high expression of SNORA71A was statistically significant in patients with TNM stages and lymph node metastases, in addition to playing having a role in the proliferation, migration, and invasion of CRC cells.In the same paper, the functional analysis of genes that are co-expressed with SNORA71A revealed that this snoRNA is involved in the NF-kappa B, Toll-like, Jak-STAT signaling pathways.Therefore, small nucleolar RNAs, in particular SNORA71A, may be involved in one of the hallmarks of cancer, namely immune surveillance.
In another study, SNORA15, SNORA41, and SNORD33 were useful in the identification of cancerous tissue compared to normal tissue, so that the change in the expression of these biomolecules was also associated with Table 5. List of snoRNAs about Their Biological Role and Clinical Significance associated with Other Types of Cancers the presence of metastatic lymph nodes and the degree of differentiation [23].Regarding the identification of these biomolecules in non-invasive samples, SNORD1C showed demonstrated overexpression in the serum of patients with colorectal cancer, in addition to being associated with worse prognostic factors [24].Furthermore, the snoRNAs SNORD15B and SNORA5C were also dysregulated in CRC, and with their expression was being associated with clinical-pathological parameters, including age, lymphatic invasion, and history of colon polyps, suggesting they have oncogenic functions in neoplasia progression and could predict poor patient prognosis [25].
In addition to the above snoRNAs, SNORA21 has been previously implicated in cell proliferation and adhesion [26].High levels of SNORD126 in CRC cells upregulated the PI3K/AKT pathway and increased FGFR2 expression.FGFR2 has attracted considerable attention as a potential therapeutic target in gastric cancer.Therefore, these data suggest that SNORD126, in addition to acting on critical processes of carcinogenesis via PI3/Akt regulation, may be a potential therapeutic target [27].

Prostate Cancer
Prostate cancer is regarded as a multistep disease resulting from the accumulation of genetic alterations, including the activation of oncogenes and the inactivation of tumor suppressor genes.One of the deleted regions is 6q14-22, which encompasses the coding region of snoRNA U50, as observed by Dong et al. [28].The deletion in this region is a candidate tumor suppressor gene.
SNORD50A-SNORD50B has been found deleted in several cancer types, with its loss linked to reduced survival.Furthermore, a microarray screen revealed direct binding of SNORD50A and SNORD50B to K-Ras [61].
Crea et al. [29], showed that trevealed that SNORA55 is upregulated in prostate cancer and was associated with poor a worse prognosis (Table 3), interacting with prooncogenic and inflammatory pathways.Inhibition of this snoRNA, in turn, interfered with the growth of malignant cells, thus preventing their invasion.

Hepatocellular Carcinoma
Another solid neoplasm in which the role of snoRNAs has been investigated is hepatocellular carcinoma (Table 4).SNORA18L5 has already been associated with cell proliferation and tumor growth [30].Meanwhile, SNORA24 was associated with poor patient survival in addition to RAS-mediated oncogenic activity [31].
Aberrant expression of snoU2_19, in turn, facilitated the proliferation of hepatocellular carcionoma cells, inhibited apoptosis, and induced cell cycle progression, *Host gene= https://bioinfo-scottgroup.med.usherbrooke.ca/snoDB/;**Chromosomal location = https://www.genenames.org/such that the knockout of this biomolecule inhibited Wnt/B-catenin signaling by inducing the translocation of B-catenin [44].Alterations in this pathway have also been related to the regulation of SNORD76.In human cancers, the Wnt/β-catenin pathway is positively activated, which has led to the development of several Wnt signaling inhibitors for cancer therapies [33].
Another snoRNA that regulates a key pathway in the carcinogenic process is ACA11.This small nucleolar RNA is capable of promoting cell growth, migration, and invasion through the activation of the PI3K/AKT pathway, and consequently the expression of Cyclin D1 [33].Altered expression of cyclin D1 has been reported to be associated with poor prognostic factors in several types of cancer, as in penile cancer [62].
Recently, the clinical significance of SNORD31 has been observed in hepatocellular carcinomas.This snoRNA is downregulated and this expression pattern has been associated with poorer prognosis and shorter survival characteristics [35].These findings serve as potential prognostic biomarkers and therapeutic targets for patients with hepatocellular carcinoma.

Other Types of Cancers
There are still few studies elucidating the role of snoRNAs in solid tumors.Some relevant data have been observed in gastric cancer, as an per the example of the work described by Wang et al. [37], where 8 snoRNAs (ACA47, E2, ACA10, SNORA58, HBII-316, U70, U8, and U66) were associated with lower survival, with a high predictive value [37].Interesting data were also found for SNORD105B.Positive regulation of the expression of this snoRNA was associated with factors of worse prognosis, such as tumor size, differentiation, and pathological stage, in addition to implying proliferation, migration, invasion, and activation of the c-Myc pathway [38].
For other tumor types, the lack of information is much greater (Table 5).For some cancers, such as ovarian and gallbladder cancer, the literature only reports three studies for ovarian.Moreover, for penile cancer, there are no studies, furthering the need to explore the involvement of these biomolecules.
SnoRNAs may be involved in key processes of solid tumor carcinogenesis through the regulation of important pathways.The use of these biomolecules may pave the way for innovative clinical applications, such as their use in the early detection of neoplasms in non-invasive samples and as therapeutic targets.Therefore, it is essential to expand the investigation of snoRNAs in the field of oncology across different tumor types.

Table 2 .
List of snoRNAs in Terms of Their Biological Role and Clinical Significance associated with Colorectal Cancer

Table 3 .
List of snoRNAs about Their Biological Role and Clinical Significance associated with Prostate Cancer