Role of salivary miRNAs in the diagnosis of gastrointestinal disorders: a mini-review of available evidence

Abstract

MiRNAs are short, non-coding RNA molecules, which are involved in the regulation of gene expression and which play an important role in various biological processes, including inflammation and cell cycle regulation. The possibility of detecting their extracellular expression, within body fluids, represented the main background for their potential use as non-invasive biomarkers of various diseases. Salivary miRNAs particularly gained interest recently due to the facile collection of stimulated/unstimulated saliva and their stability among healthy subjects. Furthermore, miRNAs seem to represent biomarker candidates of gastrointestinal disorders, with miRNA-based therapeutics showing great potential in those conditions. This review aimed to highlight available evidence on the role of salivary miRNAs in different gastrointestinal conditions. Most salivary-based miRNA studies available in the literature that focused on pathologies of the gastrointestinal tract have so far been conducted on pancreatic cancer patients and delivered reliable results. A few studies also showed the diagnostic utility of salivary miRNAs in conditions such as esophagitis, esophageal cancer, colorectal cancer, or inflammatory bowel disease. Moreover, several authors showed that salivary miRNAs may confidently be used as biomarkers of gastric cancer, but the use of salivary miRNA candidates in gastric inflammation and pre-malignant lesions, essential stages of Correa’s cascade, is still put into question. On the other hand, besides miRNAs, other salivary omics have shown biomarker potential in gastro-intestinal conditions. The limited available data suggest that salivary miRNAs may represent reliable biomarker candidates for gastrointestinal conditions. However, their diagnostic potential requires validation through future research, performed on larger cohorts.

1 Introduction

MiRNAs represent short, non-coding RNA molecules that are able to regulate gene expression at post-transcriptional level, by targeting the 3′ untranslated region (3′-UTR) of messenger RNAs (mRNAs) (O’Brien et al., 2018; Dexheimer and Cochella, 2020). Specific, stable miRNA interactions with 5′-UTR have also been reported (Broughton et al., 2016). It is important though to acknowledge that miRNAs have multiple mRNA targets, detaining multiple binding sites and thus regulating gene expression in a complex manner (Bartel, 2009; Friedman et al., 2009). Most miRNAs are involved in gene expression suppression, also known as “gene silencing,” which is mediated by the interaction between the miRNA-induced silencing complex (miRISC) and the ribonucleoprotein (RNP) effector (Makarova et al., 2016). Given that miRISC-RNP interaction has been discovered in several cellular compartments, questions were raised about their function extension beyond gene expression modulation (Makarova et al., 2016). At the same time, miRISC-RNP complexes also seem to be able to stimulate gene expression at posttranscriptional levels, with miRNA-mediated effects being highly dependent upon factors such as cellular conditions, RNA sequence, or complementarity degree (Vasudevan, 2012). Thus, miRNAs represent fine tuners of gene expression, as schematically represented in Figure 1A.

FIGURE 1

MiRNAs are involved in various biological processes, including hematopoietic cell differentiation, cell growth, or epigenetic regulation of malignant transformation-associated pathways (Chen et al., 2004; Wang and Sen, 2011; Wang et al., 2016). Furthermore, miRNAs seem to substantially contribute to normal developmental processes, by modulating trophoblast cell proliferation and apoptosis. Thus, they function as part of the placental development, neuron, astrocyte, muscle cell development, or bone formation (Fu et al., 2013; Ivey and Srivastava, 2015). Their essential role in embryogenesis, cell development, hemostasis and differentiation has also been reported by several studies conducted on different animal species (He et al., 2022; Khanal et al., 2022; Luo et al., 2022). Given their involvement in numerous physiological processes, it is unsurprising that miRNAs and their aberrant expression have been regarded as potential diagnostic biomarkers in a variety of diseases (Hayes et al., 2014; Tüfekci et al., 2014; Huang, 2017). The quest for miRNA signatures is still ongoing, but multiple miRNAs might be validated as future biomarkers in malignant pathologies, viral infections, cardiovascular, renal or neurological disorders (Wang et al., 2016). The possibility of depicting stable, extracellular miRNAs in body fluids such as urine, blood or saliva, and their aberrant expression, which is sometimes similar to tissular analogues, gives the upperhand of potential non-invasiveness to the biomarker status (Huang, 2017; Fellizar et al., 2022).

2 Salivary miRNAs

As in all body fluids, circulating miRNAs are found in saliva in lipid/lipoprotein vesicular complexes such as exosomes (Leal-Galvan et al., 2022). Exosomes protect miRNA from degradation, ensuring adequate function of the transported molecular information (Théry et al., 2002; Théry et al., 2009). This translates into stability, circulating, exosomal plasma miRNAs being regarded as highly stable in healthy subjects (Sanz-Rubio et al., 2018). In similar fashion, exosomal salivary miRNAs seem to be easily isolated and quantified within the healthy population, constituting promising, easily available biomarkers (Michael et al., 2010). Some theories suggest that miRNAs could also be produced locally in oral fluids, arousing from apoptosis and cell necrosis. A theory based on the possible existence of transcellular and paracellular transport routes into salivary gland tissues has been issued (Yoshizawa et al., 2013). Moreover, salivary endogenous miRNAs seem to degrade at a slower rate than their exogenous homologues, according to a study which aimed to discover and validate miRNAs in the saliva of healthy subjects (Park et al., 2009).

Saliva collection, although characterized by non-invasiveness, is being subject to various debates. Type of saliva collection has been miscellaneous so far in various reports. Some authors have proposed collection of unstimulated saliva samples, while others have successfully isolated miRNA molecules from saliva collected after citric acid stimulation (Yoshizawa and Wong, 2013; Xie et al., 2015). Saliva composition seems to be influenced by various factors, including meal schedule, diet, time of the day, age or sex (Koopaie et al., 2021). Time of collection and amount of fasting time required prior to collection is still debated and varies from one study protocol to another. Furthermore, administration of agents such as citric acid for stimulation of saliva secretion, prior to its collection, still remains at the liberty of researchers (Setti et al., 2020). Saliva storage tubes vary in volume, with some subjects reporting difficulty in collecting saliva in smaller sized tubes (Urbizu et al., 2023). Isolation can be achieved both from whole saliva and supernatant, obtained after centrifugation, with identification of high resolution miRNA information (Patel et al., 2011). Centrifugation seems to be helpful in case of viscous saliva samples, but the performance rate should be adapted accordingly, in order to avoid mechanical rupture of cellular components (St John et al., 2004).

Due to their non-invasiveness, salivary miRNAs have emerged as promising biomarkers in the diagnosis and prognosis of various conditions, including neoplastic diseases, such as oral cancer, hepatic cancer, breast cancer or pancreatic cancer (Xie et al., 2015; Koopaie et al., 2021; Mariam et al., 2022; Scholtz et al., 2022), as well as inflammatory conditions, including endometriosis, inflammatory bowel disease, periodontitis or eosinophilic esophagitis (Schaefer et al., 2015; Bhardwaj et al., 2020; Lee et al., 2020; Bendifallah et al., 2022). Furthermore, salivary miRNAs seem to present altered expressions in relation to various types of injuries (Hicks et al., 2021; Hicks et al., 2022). Still, the question of similitude between the expression of miRNAs depicted in the saliva and their tissular or circulating homologues is raised. A few studies have tried to simultaneously assess the biomarker role of the same miRNA type in both saliva and blood or saliva and tissue (Nik Mohamed Kamal et al., 2020; Sembler-Møller et al., 2020). A clear view of the reliability of salivary miRNAs in comparison with miRNAs identified among tissue or other body fluids is still subject to future research.

3 Salivary miRNAs and gastrointestinal conditions

The quest for biomarkers in gastrointestinal disorders has gained more attention recently and research on the subject bloomed after miRNA-based therapeutics showed a great potential in treatment of various diseases of the gastrointestinal tract (Hossian et al., 2019). Most of the studies conducted so far have focused on the role of miRNA in the diagnosis of gastric cancer, as miRNA expression profile seems to be altered in different stages of Correa’s gastric precancerous cascade (Zheng et al., 2011; Deng et al., 2013; Sugiyama et al., 2016; Lario et al., 2018). However, miRNAs have been usually identified from gastric cellular lines, gastric or esophageal mucosa specimens or depicted in the serum or plasma (Matsushima et al., 2011; Sreedharan et al., 2017; Lario et al., 2018; Ohtsuka et al., 2021; Vasapolli et al., 2021). Studies analyzing the role of salivary miRNAs in gastrointestinal conditions are so far limited in number, but those available so far have shown promising results in terms of delivering non-invasive biomarkers. Therefore, this review aims to highlight available evidence on the role of salivary miRNAs in different gastrointestinal conditions.

3.1 Salivary miRNAs, esophagitis and esophageal cancer

Salivary miRNAs distinguished themselves as potential markers of eosinophilic esophagitis. In one pediatric study, in which 56 salivary miRNAs were detected, six different miRNAs (miR-26b-5p, miR-27b-3p, Let-7i-5p, miR-142-5p, miR-30a-5p and miR-205-5p) presented upregulation, quantified through variable importance projection (VIP) scores in subjects with eosinophilic esophagitis. The highest differences between the two study groups were obtained for miR-205-5p, but good sensitivity and specificity parameters were reported for each of the 6 miRNAs (Jhaveri et al., 2023). A similar outcome was described within an adult study, in which miR-4668 emerged as a biomarker candidate that can identify subjects with eosinophilic esophagitis and is correlated with the number of aeroallergens. According to the authors, the same miR-4668 can be used as a response predictor to topical corticosteroids, which suggests that this miRNA could be used as a marker of other allergic disorders as well (Bhardwaj et al., 2020).

More attention has been so far given to the role of miRNAs in the diagnosis and characterization of esophageal cancer. Saliva identifiable miRNAs such as miR-144, miR-451, miR-98, miR-10b and miR-363 might be able to modulate target genes involved in esophageal cancer, according to Du and Zhang (2017). Hoshino et al. describe the high diagnostic performance of miR-1246 in esophageal squamous cell carcinoma, when determined from blood, urine and saliva. Still, variations in salivary miR-1246 levels were found, in relation to saliva collection timing, and its expression differed among the three body fluid samples (Hoshino et al., 2021). On the other hand, plasmatic and salivary miR-21 expressions presented a positive, significant correlation, and comparable diagnostic value in esophageal cancer (Ye et al., 2014). Moreover, high expression of miR-144 was identified in the whole saliva and saliva supernatant of patients with esophageal cancer. Thus, Wu et al. (2013) proposed miR-144 as an early marker of esophageal cancer, with moderate diagnostic performance indices, based on sensitivity and specificity parameters. miRNA identification and expression might though differ between whole saliva and saliva supernatant samples. Hence, Xie et al. found that in subjects with esophageal cancer, three different miRNAs (miR-10b*, miR-144 and miR-451) were upregulated in the whole saliva samples, whereas four of the six identified miRNAs were upregulated (miR-10b*, miR-144, miR-21 and miR-451) within saliva supernatant (Xie et al., 2012; Xie et al., 2013). miR-196a has also been regarded as a suitable salivary biomarker for esophageal squamous cell carcinoma, as its salivary upregulation correlated with the expression augmentation seen in biopsy samples taken from neoplastic tissue, as opposed to the healthy adjacent mucosa (Fendereski et al., 2017).

Given the paucity of studies analyzing the role of salivary miRNAs in the diagnosis of esophageal cancer, and their miscellaneous sensitivity and specificity rates, one meta-analysis was performed and suggested that blood-based miRNAs are more accurate than those identified within saliva samples in detecting esophageal squamous cell carcinoma (Wang et al., 2014). The same conclusion was driven by Li et al., who suggested that both serum and plasma miRNAs are appropriate biomarkers for esophageal cancer (Li et al., 2017). However, Wan et al. claimed that type of body samples from which miRNAs were depicted did not constitute a source of heterogenicity among different miRNA-based studies of esophageal cancer (Wan et al., 2016).

3.2 Salivary miRNAs, Helicobacter pylori infection and gastric cancer

MiRNAs play a pivotal role in the modulation of host immune response and inflammation triggered by Helicobacter pylori (H. pylori) (Săsăran et al., 2021). A few studies have identified an upregulation of tissular and serum miRNAs such as miR-146a, miR-155, miR-127-5p, miR-181 in relation to H. pylori-induced chronic gastritis, while others failed to identify a significant variation from healthy subjects in the expression of miR-155 (Chung et al., 2017; Cortés-Márquez et al., 2018; Zabaglia et al., 2018; Mahboobi et al., 2022; Oana et al., 2022). However, only one study so far assessed the role of salivary miRNAs in aiding the identification of H. pylori infection, which included children with pulpitis. The authors found a downregulation of miR-204 in pulp tissue, serum and saliva of subjects who were concomitantly infected with H. pylori, as opposed to those in whom the bacterial infection was absent. At the same time, expression reduction of miR-204 was correlated with an upregulation of MMP-9, which is known to be influenced by inflammation, possibly caused by both pulpitis and H. pylori infection (Zhou and Xu, 2019). Similarly, downregulation of miR-204, in association with upregulation of MMP-9, was reported in patients with H. pylori-associated gastric ulcer (Li et al., 2016). Given the proven involvement of miRNAs in the regulation of inflammatory pathways related to H. pylori infection, as well as the alteration of miRNA expression in the setting of pre-neoplastic lesions, miRNAs were considered promising biomarkers for early gastric cancer detection, as well as potential therapeutic targets in this malignant setting (Shin and Chu, 2014; Vidal et al., 2016; Khayam et al., 2021). After tissular detection of miRNAs which showed biomarker potential, a search for non-invasive miRNAs, available in accessible body fluids was started (Adami et al., 2019; Zhang et al., 2019; Quirico and Orso, 2020; Lopes et al., 2023). Most of the studies available so far have assessed expression of multiple miRNAs among serum and plasma samples (Lopes et al., 2023). However, only two studies have investigated so far the biomarker potential of salivary miRNAs in gastric cancer individuals. Li et al. discovered and validated a panel of multiple extracellular, salivary miRNAs which were associated with gastric cancer. Among them, a significant downregulation of two miRNA candidates, namely, miR-140-5p and miR-301a, was noted in gastric cancer patients when compared to healthy controls (Li et al., 2018). miRNA panel of two whole saliva- identified miRNAs, miR-140 and miR-301a, might ensure early, non-invasive identification of gastric cancer subjects, according to Kaczor-Urbanowicz et al. However, the authors point out that the performance of these biomarkers, assessed with the help of receiver operating characteristic (ROC) curve, differs among ethnicities (Kaczor-Urbanowicz et al., 2022).

Besides salivary miRNAs, salivary microbiota starts to gain more and more popularity as potential biomarkers of H. pylori infection and gastric cancer. The alteration of the gastric microbiome trigerred by H. pylori impairs the oral-gut axis and leads to specific changes in salivary microbial community structure (Ji et al., 2020; Chen et al., 2022). In addition, an accumulation of pro-inflammatory bacteria has been noted in relation to gastric cancer, with a particular abundance of Neisseria species (Kageyama et al., 2019; Huang et al., 2021). Furthermore, salivary microbiome imbalance has been found in relation to chronic gastric inflammation, even in the absence of H. pylori infection (Contaldo et al., 2021).

3.3 Salivary miRNAs and differential diagnosis of inflammatory bowel disease (IBD)

The overlapping of clinical symptoms between Crohn’s disease and ulcerative colitis makes an accurate IBD diagnosis challenging, in the absence of endoscopic investigations and microscopic assessment of tissue biopsies. Peripheral blood miRNAs were firstly regarded as non-invasive biomarkers which can distinguish the two main IBD types, with 10 miRNAs presenting a significant upregulation and one miRNA an important expression decrease in the blood of active ulcerative colitis patients, when compared to Crohn’s disease patients (Wu et al., 2011). A panel of salivary miRNAs might be useful in the differential diagnosis of Chron’s disease and ulcerative colitis. In the study of Schaefer et al., expression of miR-101 was altered in the saliva of Chron’s disease patients, whereas miR-21, miR-31, miR-142-3p, and miR-142-5p presented particular expression variation patterns among patients with ulcerative colitis (Schaefer et al., 2015). No other studies have managed so far to evaluate differential expression of salivary miRNAs in IBD patients.

3.4 Salivary miRNAs and pancreatic cancer

The search for reliable biomarkers which can identify initial stages of pancreatic cancer has been of crucial importance in the last years, in light of the very low 1-year survival rates that characterize patients with this type of advanced malignancy (Burris et al., 1997). Humeau et al. identified 4 salivary miRNA candidates, namely, miR-21, miR-23a, miR-23b and miR-29c, which were upregulated in pancreatic cancer patients compared to controls, with these miRNAs presenting good sensitivity and excellent specificity. Moreover, miR-23a and miR-23b were already differentially expressed in precursor lesions of pancreatic cancer, while miR-216 was overexpressed in pancreatic cancer subjects when compared to pancreatitis patients (Humeau et al., 2015). Two miRNA candidates, miR-940 and miR-3679-5p, were upregulated and downregulated, respectively, in pancreatic cancer patients when compared to a study group consisting of subjects diagnosed with benign pancreatic tumors and healthy controls. Moreover, these two miRNAs could reliably identify individuals with resectable pancreatic cancer, according to ROC results (Xie et al., 2015). miR-1246 and miR-4644, detected among salivary exosomes, were other two miRNAs which exhibited a significant expression augmentation in pancreatobiliary tract cancer patients when compared to controls. The best area under the curve was calculated for the combined use of the two miRNAs, which suggested their concomitant panel utility for pancreatobiliary tract cancer diagnosis (Machida et al., 2016). On the other hand, another study concluded that whilst miR-1246 is upregulated within the serum and urine of pancreatic cancer patients, its salivary expression in the same individuals did not differ significantly from the one of healthy controls (Ishige et al., 2020).

3.5 Salivary miRNAs and colorectal cancer

MiRNAs constitute key players in the pathogenesis of colorectal adenocarcinoma, through their involvement in the regulation of mRNA expression, with eight different miRNAs which act on their mRNA targets being reported as having a differential expression in this malignant setting (miR-141, miR-19a, miR-20a, miR-19b-1, miR-19b-2, miR-16, miR-590 and miR-335) (Wang et al., 2017). Moreover, miR-21 has been particularly intensely studied in colorectal cancer. Circulating miR-21 seems to be a useful tool in the diagnosis of colorectal cancer, whereas tissular miR-21 emerged as a marker of prognosis in subjects with the same malignant condition (Peng et al., 2017). In both plasma and saliva, miR-21 has managed to accurately identify patients with colorectal cancer. Salivary miR-21 presented even higher sensitivity and specificity than plasma miR-21 in supporting colorectal cancer screening (Sazanov et al., 2017). Furthermore, Rapado-Gonzalez et al. proposed a panel of five salivary miRNAs (miR-186-5p, miR-29a-3p, miR-29c-3p, miR-766-3p, and miR-491-5p) for the non-invasive diagnosis of colorectal cancer, which presented significant upregulation in relation to this malignancy (Rapado-González et al., 2019).

4 Discussions

Salivaomics, which include proteome, transcriptome, metabolome, microbiome, as well as miRNAs, might represent revolutionary non-invasive tools for the diagnosis of multiple disorders, and especially for the early detection of neoplastic conditions (Wong, 2012). Salivary miRNAs first gained attention as biomarkers of oral pathologies, including periodontal disease or pre-neoplastic lesions or malignancies of the oral cavity (Martina et al., 2020; Kapoor et al., 2021; Manzano-Moreno et al., 2021). Non-coding RNAs, including miRNAs, circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) have been known to be involved in several important hallmarks of gastrointestinal cancers such as esophageal, gastric, pancreatic, colorectal cancer or hepatocellular carcinoma (Dragomir et al., 2020). Still, data on the biomarker utility of salivary miRNAs in conditions of the gastrointestinal tract is scarce, but research is continuously expanding. Igaz et al., who provided an update regarding the recent reported utility of fecal, biliary, salivary and urinary miRNAs, acknowledge the potential of these biomarkers in revolutionizing early diagnosis of malignancies of the gastrointestinal tract, but at the same out point out towards the need of spreading research on larger cohorts and using uniform methodological approaches (Igaz and Igaz, 2015). Through this review, we aimed to highlight current evidence available regarding the use of salivary miRNAs in various gastrointestinal pathologies. An overview of current studies adhering to our review objective, which suggested that miRNAs might serve as biomarker candidates in various types of conditions, has been provided through Table 1. In addition to salivary miRNAs, a synopsis of other, currently available salivary biomarkers in gastro-intestinal conditions has been provided through Figure 1B, based on recent literature data (Zhang et al., 2010; Xiao et al., 2016; Wang et al., 2017; Asai et al., 2018; Bel’skaya et al., 2020; Deutsch et al., 2020; Xu and Jiang, 2020; Huang et al., 2021; Eftekhari et al., 2022; Koopaie et al., 2022; Patel et al., 2022; Lopes et al., 2023).

As presented within the former chapters, most salivary-based miRNA studies available in the literature that focused on pathologies of the gastro-intestinal tract have been conducted on patients with pancreatic cancer. One meta-analysis which included the formerly described studies revealed that salivary miRNAs facilitate diagnosis of pancreatic cancer, with good performance indices such as pooled sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratio. Hence, these have been proposed as biomarkers of early pancreatic cancer (Koopaie et al., 2021). The discriminatory power of salivary miRNAs in the detection of esophageal cancer cannot be foreseen, in spite of only a few available studies (Xie et al., 2012; Xie et al., 2013; Wu et al., 2013; Ye et al., 2014; Fendereski et al., 2017). The use of non-blood based liquid biopsies for timely detection of gastric cancer is another hot topic of current research, but the small number of available studies still raise the need for further research and validation (Lopes et al., 2023). Particular beneficial results could be obtained from the identification of initial stages of Correa’s cascade, which so far has been accomplished through plasmatic and tissular miRNAs (Lario et al., 2018; Kim et al., 2020). In colorectal cancer, the use of fecal miRNAs has so far been considered the ultimate non-invasive screening method, with only a few studies showing the biomarker characteristics of salivary miRNAs (Link et al., 2010; Sazanov et al., 2017; Rapado-González et al., 2019). Some studies offer though encouraging results, in spite of their unicity on the subject. For example, one recent study proved for the first time that salivary miRNA signatures could be used in the early identification of hepatocellular carcinoma (HCC). After identifying an impressive number of 4,565 precursor and mature miRNAs, the authors found that 283 of these were downregulated in patients with HCC (Mariam et al., 2022). Hence, abundance of miRNA candidates in the saliva calls for expansion of future research, in light of the limited data available.

In conclusion, salivary miRNAs may represent reliable biomarker candidates for gastrointestinal conditions. Their diagnostic potential has so far been underlined by a limited number of studies, but future research assessing salivary identifiable miRNAs, performed on larger cohorts, might validate or infirm their biomarker status in a multitude of gastrointestinal disorders, particularly in the early identification of malignancies.

References

• 1

  AdamiB.TabatabaeianH.GhaediK.TalebiA.AzadehM.DehdashtianE. (2019). miR-146a is deregulated in gastric cancer. J. Cancer Res. Ther.15, 108–114. 10.4103/jcrt.JCRT_855_17

  • CrossRef
  • Google Scholar

• 2

  AsaiY.ItoiT.SugimotoM.SofuniA.TsuchiyaT.TanakaR.et al (2018). Elevated polyamines in saliva of pancreatic cancer. Cancers (Basel)10, 43. 10.3390/cancers10020043

  • CrossRef
  • Google Scholar

• 3

  BartelD. P. (2009). MicroRNAs: Target recognition and regulatory functions. Cell136, 215–233. 10.1016/j.cell.2009.01.002

  • CrossRef
  • Google Scholar

• 4

  Bel’skayaL. V.SarfE. A.ShalyginS. P.PostnovaT. V.KosenokV. K. (2020). Identification of salivary volatile organic compounds as potential markers of stomach and colorectal cancer: A pilot study. J. Oral Biosci.62, 212–221. 10.1016/j.job.2020.05.002

  • CrossRef
  • Google Scholar

• 5

  BendifallahS.SuisseS.PucharA.DelbosL.PoilblancM.DescampsP.et al (2022). Salivary MicroRNA signature for diagnosis of endometriosis. J. Clin. Med.11, 612. 10.3390/jcm11030612

  • CrossRef
  • Google Scholar

• 6

  BhardwajN.SenaM.GhaffariG.IshmaelF. (2020). MiR-4668 as a novel potential biomarker for eosinophilic esophagitis. Allergy Rhinol. Provid.11, 2152656720953378. 10.1177/2152656720953378

  • CrossRef
  • Google Scholar

• 7

  BroughtonJ. P.LovciM. T.HuangJ. L.YeoG. W.PasquinelliA. E. (2016). Pairing beyond the seed supports MicroRNA targeting specificity. Mol. Cell64, 320–333. 10.1016/j.molcel.2016.09.004

  • CrossRef
  • Google Scholar

• 8

  BurrisH. A.MooreM. J.AndersenJ.GreenM. R.RothenbergM. L.ModianoM. R.et al (1997). Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J. Clin. Oncol.15, 2403–2413. 10.1200/JCO.1997.15.6.2403

  • CrossRef
  • Google Scholar

• 9

  ChenC.-Z.LiL.LodishH. F.BartelD. P. (2004). MicroRNAs modulate hematopoietic lineage differentiation. Science303, 83–86. 10.1126/science.1091903

  • CrossRef
  • Google Scholar

• 10

  ChenX.WangN.WangJ.LiaoB.ChengL.RenB. (2022). The interactions between oral-gut axis microbiota and Helicobacter pylori. Front. Cell Infect. Microbiol.12, 914418. 10.3389/fcimb.2022.914418

  • CrossRef
  • Google Scholar

• 11

  ChungJ.-W.JeongS. H.LeeS. M.PakJ. H.LeeG. H.JeongJ.-Y.et al (2017). Expression of MicroRNA in host cells infected with Helicobacter pylori. Gut Liver11, 392–400. 10.5009/gnl16265

  • CrossRef
  • Google Scholar

• 12

  ContaldoM.FuscoA.StiusoP.LamaS.GravinaA. G.ItroA.et al (2021). Oral microbiota and salivary levels of oral pathogens in gastro-intestinal diseases: Current knowledge and exploratory study. Microorganisms9, 1064. 10.3390/microorganisms9051064

  • CrossRef
  • Google Scholar

• 13

  Cortés-MárquezA. C.Mendoza-ElizaldeS.Arenas-HuerteroF.Trillo-TinocoJ.Valencia-MayoralP.Consuelo-SánchezA.et al (2018). Differential expression of miRNA-146a and miRNA-155 in gastritis induced by Helicobacter pylori infection in paediatric patients, adults, and an animal model. BMC Infect. Dis.18, 463. 10.1186/s12879-018-3368-2

  • CrossRef
  • Google Scholar

• 14

  DengH.GuoY.SongH.XiaoB.SunW.LiuZ.et al (2013). MicroRNA-195 and microRNA-378 mediate tumor growth suppression by epigenetical regulation in gastric cancer. Gene518, 351–359. 10.1016/j.gene.2012.12.103

  • CrossRef
  • Google Scholar

• 15

  DeutschO.HavivY.KriefG.KeshetN.WestreichR.StemmerS. M.et al (2020). Possible proteomic biomarkers for the detection of pancreatic cancer in oral fluids. Sci. Rep.10, 21995. 10.1038/s41598-020-78922-x

  • CrossRef
  • Google Scholar

• 16

  DexheimerP. J.CochellaL. (2020). MicroRNAs: From mechanism to organism. Front. Cell Dev. Biol.8, 409. 10.3389/fcell.2020.00409

  • CrossRef
  • Google Scholar

• 17

  DragomirM. P.KopetzS.AjaniJ. A.CalinG. A. (2020). Non-coding RNAs in GI cancers: From cancer hallmarks to clinical utility. Gut69, 748–763. 10.1136/gutjnl-2019-318279

  • CrossRef
  • Google Scholar

• 18

  DuJ.ZhangL. (2017). Analysis of salivary microRNA expression profiles and identification of novel biomarkers in esophageal cancer. Oncol. Lett.14, 1387–1394. 10.3892/ol.2017.6328

  • CrossRef
  • Google Scholar

• 19

  EftekhariA.Maleki DizajS.SharifiS.SalatinS.KhalilovR.SamieiM.et al (2022). “Chapter six - salivary biomarkers in cancer,” in Advances in clinical chemistry. Editor MakowskiG. S. (Elsevier), 171–192. 10.1016/bs.acc.2022.06.005

  • CrossRef
  • Google Scholar

• 20

  FellizarA.RefuerzoV.RamosJ. D.AlbanoP. M. (2022). Expression of specific microRNAs in tissue and plasma in colorectal cancer. J. Pathol. Transl. Med.57, 147–157. 10.4132/jptm.2022.02.19

  • CrossRef
  • Google Scholar

• 21

  FendereskiM.ZiaM. F.ShafieeM.SafariF.SaneieM. H.TavassoliM. (2017). MicroRNA-196a as a potential diagnostic biomarker for esophageal squamous cell carcinoma. Cancer Invest.35, 78–84. 10.1080/07357907.2016.1254228

  • CrossRef
  • Google Scholar

• 22

  FriedmanR. C.FarhK. K.-H.BurgeC. B.BartelD. P. (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Res.19, 92–105. 10.1101/gr.082701.108

  • CrossRef
  • Google Scholar

• 23

  FuG.BrkićJ.HayderH.PengC. (2013). MicroRNAs in human placental development and pregnancy complications. Int. J. Mol. Sci.14, 5519–5544. 10.3390/ijms14035519

  • CrossRef
  • Google Scholar

• 24

  HayesJ.PeruzziP. P.LawlerS. (2014). MicroRNAs in cancer: Biomarkers, functions and therapy. Trends Mol. Med.20, 460–469. 10.1016/j.molmed.2014.06.005

  • CrossRef
  • Google Scholar

• 25

  HeT.FanY.WangY.LiuM.ZhuA. J. (2022). Dissection of the microRNA network regulating hedgehog signaling in Drosophila. Front. Cell Dev. Biol.10, 866491. 10.3389/fcell.2022.866491

  • CrossRef
  • Google Scholar

• 26

  HicksS. D.OnksC.KimR. Y.ZhenK. J.LoeffertJ.LoeffertA. C.et al (2021). Refinement of saliva microRNA biomarkers for sports-related concussion. J. Sport Health Sci.S2095-2546 (21), 369–378. 10.1016/j.jshs.2021.08.003

  • CrossRef
  • Google Scholar

• 27

  HicksS. D.LeddyJ.LichakB. P.OnksC.DretschM.TennantP.et al (2022). Defining biological phenotypes of mild traumatic brain injury using saliva MicroRNA profiles. J. Neurotrauma39, 923–934. 10.1089/neu.2022.0018

  • CrossRef
  • Google Scholar

• 28

  HoshinoI.IshigeF.IwatateY.GunjiH.KuwayamaN.NabeyaY.et al (2021). Cell-free microRNA-1246 in different body fluids as a diagnostic biomarker for esophageal squamous cell carcinoma. PLoS One16, e0248016. 10.1371/journal.pone.0248016

  • CrossRef
  • Google Scholar

• 29

  HossianA. K. M. N.MackenzieG. G.MattheolabakisG. (2019). miRNAs in gastrointestinal diseases: can we effectively deliver RNA-based therapeutics orally?Nanomedicine (Lond)14, 2873–2889. 10.2217/nnm-2019-0180

  • CrossRef
  • Google Scholar

• 30

  HuangK.GaoX.WuL.YanB.WangZ.ZhangX.et al (2021). Salivary microbiota for gastric cancer prediction: An exploratory study. Front. Cell Infect. Microbiol.11, 640309. 10.3389/fcimb.2021.640309

  • CrossRef
  • Google Scholar

• 31

  HuangW. (2017). MicroRNAs: Biomarkers, diagnostics, and therapeutics. Methods Mol. Biol.1617, 57–67. 10.1007/978-1-4939-7046-9_4

  • CrossRef
  • Google Scholar

• 32

  HumeauM.Vignolle-VidoniA.SicardF.MartinsF.BournetB.BuscailL.et al (2015). Salivary MicroRNA in pancreatic cancer patients. PLoS One10, e0130996. 10.1371/journal.pone.0130996

  • CrossRef
  • Google Scholar

• 33

  IgazI.IgazP. (2015). Diagnostic relevance of microRNAs in other body fluids including urine, feces, and saliva. Exp. Suppl.106, 245–252. 10.1007/978-3-0348-0955-9_11

  • CrossRef
  • Google Scholar

• 34

  IshigeF.HoshinoI.IwatateY.ChibaS.ArimitsuH.YanagibashiH.et al (2020). MIR1246 in body fluids as a biomarker for pancreatic cancer. Sci. Rep.10, 8723. 10.1038/s41598-020-65695-6

  • CrossRef
  • Google Scholar

• 35

  IveyK. N.SrivastavaD. (2015). microRNAs as developmental regulators. Cold Spring Harb. Perspect. Biol.7, a008144. 10.1101/cshperspect.a008144

  • CrossRef
  • Google Scholar

• 36

  JhaveriP. B.LambertK. A.BogaleK.LehmanE.AlexanderC.IshmaelF.et al (2023). Salivary microRNAs in pediatric eosinophilic esophagitis. Allergy Asthma Proc.44, 145–152. 10.2500/aap.2023.44.220102

  • CrossRef
  • Google Scholar

• 37

  JiY.LiangX.LuH. (2020). Analysis of by high-throughput sequencing: Helicobacter pylori infection and salivary microbiome. BMC Oral Health20, 84. 10.1186/s12903-020-01070-1

  • CrossRef
  • Google Scholar

• 38

  Kaczor-UrbanowiczK. E.SaadM.GroganT. R.LiF.HeoY. J.ElashoffD.et al (2022). Performance of salivary extracellular RNA biomarker panels for gastric cancer differs between distinct populations. Cancers (Basel)14, 3632. 10.3390/cancers14153632

  • CrossRef
  • Google Scholar

• 39

  KageyamaS.TakeshitaT.TakeuchiK.AsakawaM.MatsumiR.FurutaM.et al (2019). Characteristics of the salivary microbiota in patients with various digestive tract cancers. Front. Microbiol.10, 1780. 10.3389/fmicb.2019.01780

  • CrossRef
  • Google Scholar

• 40

  KapoorP.ChowdhryA.BaggaD. K.BhargavaD.AishwaryaS. (2021). MicroRNAs in oral fluids (saliva and gingival crevicular fluid) as biomarkers in orthodontics: Systematic review and integrated bioinformatic analysis. Prog. Orthod.22, 31. 10.1186/s40510-021-00377-1

  • CrossRef
  • Google Scholar

• 41

  KhanalS.ZancanelaB.PeterJ.FlyntA. (2022). The small RNA universe of Capitella teleta. FASEB J.36 (Suppl. 1). 10.1096/fasebj.2022.36.S1.L7428

  • CrossRef
  • Google Scholar

• 42

  KhayamN.NejadH. R.AshrafiF.AbolhassaniM. (2021). Expression profile of miRNA-17-3p and miRNA-17-5p genes in gastric cancer patients with Helicobacter pylori infection. J. Gastrointest. Cancer52, 130–137. 10.1007/s12029-019-00319-5

  • CrossRef
  • Google Scholar

• 43

  KimB.JangJ.HeoY. J.KangS. Y.YooH.SohnI.et al (2020). Dysregulated miRNA in a cancer-prone environment: A study of gastric non-neoplastic mucosa. Sci. Rep.10, 6600. 10.1038/s41598-020-63230-1

  • CrossRef
  • Google Scholar

• 44

  KoopaieM.AbedinejadF.ManifarS.MousaviR.KolahdoozS.ShamshiriA. (2021). Salivary miRNA-21 expression as a potential non-invasive diagnostic biomarker in breast cancer. Gene Rep.25, 101317. 10.1016/j.genrep.2021.101317

  • CrossRef
  • Google Scholar

• 45

  KoopaieM.KolahdoozS.FatahzadehM.AleedawiZ. A. (2022). Salivary noncoding RNA in the diagnosis of pancreatic cancer: Systematic review and meta-analysis. Eur. J. Clin. Invest.52, e13848. 10.1111/eci.13848

  • CrossRef
  • Google Scholar

• 46

  LarioS.Brunet-VegaA.QuílezM. E.Ramírez-LázaroM. J.LozanoJ. J.García-MartínezL.et al (2018). Expression profile of circulating microRNAs in the Correa pathway of progression to gastric cancer. United Eur. Gastroenterol. J.6, 691–701. 10.1177/2050640618759433

  • CrossRef
  • Google Scholar

• 47

  Leal-GalvanB.HarveyC.ThomasD.SaelaoP.Oliva ChavezA. S. (2022). Isolation of microRNAs from tick ex vivo salivary gland cultures and extracellular vesicles. J. Vis. Exp.10.3791/63618

  • CrossRef
  • Google Scholar

• 48

  LeeN. H.LeeE.KimY. S.KimW. K.LeeY. K.KimS. H. (2020). Differential expression of microRNAs in the saliva of patients with aggressive periodontitis: A pilot study of potential biomarkers for aggressive periodontitis. J. Periodontal Implant Sci.50, 281–290. 10.5051/jpis.2000120006

  • CrossRef
  • Google Scholar

• 49

  LiX.-J.WangL.LiG.ZhengX.DuanC. (2016). Expression of miR-204 and MMP-9 in Helicobacter pylori-associated gastric ulcer. Available at: https://www.semanticscholar.org/paper/Expression-of-miR-204-and-MMP-9-in-Helicobacter-Li-Wang/cb8f7e302b16639d0db3010bb82c1a1424253619 (Accessed May 20, 2023).

  • Google Scholar

• 50

  LiM.WuF.JiY.YangL.LiF. (2017). Meta-analysis of microRNAs as potential biomarkers for detecting esophageal carcinoma in Asian populations. Int. J. Biol. Markers32, e375–e383. 10.5301/ijbm.5000296

  • CrossRef
  • Google Scholar

• 51

  LiF.YoshizawaJ. M.KimK.-M.KanjanapangkaJ.GroganT. R.WangX.et al (2018). Discovery and validation of salivary extracellular RNA biomarkers for noninvasive detection of gastric cancer. Clin. Chem.64, 1513–1521. 10.1373/clinchem.2018.290569

  • CrossRef
  • Google Scholar

• 52

  LinkA.BalaguerF.ShenY.NagasakaT.LozanoJ. J.BolandC. R.et al (2010). Fecal MicroRNAs as novel biomarkers for colon cancer screening. Cancer Epidemiol. Biomarkers Prev.19, 1766–1774. 10.1158/1055-9965.EPI-10-0027

  • CrossRef
  • Google Scholar

• 53

  LopesC.ChavesJ.OrtigãoR.Dinis-RibeiroM.PereiraC. (2023). Gastric cancer detection by non-blood-based liquid biopsies: A systematic review looking into the last decade of research. United Eur. Gastroenterol. J.11, 114–130. 10.1002/ueg2.12328

  • CrossRef
  • Google Scholar

• 54

  LuoX.ChenX.LvY.HanY.QuX.ZhangY.et al (2022). MicroRNA-101 regulates oocyte maturation in vitro via targeting HAS2 in porcine cumulus cells. Theriogenology187, 119–126. 10.1016/j.theriogenology.2022.04.025

  • CrossRef
  • Google Scholar

• 55

  MachidaT.TomofujiT.MaruyamaT.YonedaT.EkuniD.AzumaT.et al (2016). miR-1246 and miR-4644 in salivary exosome as potential biomarkers for pancreatobiliary tract cancer. Oncol. Rep.36, 2375–2381. 10.3892/or.2016.5021

  • CrossRef
  • Google Scholar

• 56

  MahboobiR.FallahF.YadegarA.DaraN.Kazemi AghdamM.AsgariB.et al (2022). Expression analysis of miRNA-155 level in Helicobacter pylori related inflammation and chronic gastritis. Iran. J. Microbiol.14, 495–502. 10.18502/ijm.v14i4.10235

  • CrossRef
  • Google Scholar

• 57

  MakarovaJ. A.ShkurnikovM. U.WickleinD.LangeT.SamatovT. R.TurchinovichA. A.et al (2016). Intracellular and extracellular microRNA: An update on localization and biological role. Prog. Histochem Cytochem51, 33–49. 10.1016/j.proghi.2016.06.001

  • CrossRef
  • Google Scholar

• 58

  Manzano-MorenoF. J.Costela-RuizV. J.García-RecioE.Olmedo-GayaM. V.RuizC.Reyes-BotellaC. (2021). Role of salivary MicroRNA and cytokines in the diagnosis and prognosis of oral squamous cell carcinoma. Int. J. Mol. Sci.22, 12215. 10.3390/ijms222212215

  • CrossRef
  • Google Scholar

• 59

  MariamA.Miller-AtkinsG.MoroA.RodarteA. I.SiddiqiS.Acevedo-MorenoL.-A.et al (2022). Salivary miRNAs as non-invasive biomarkers of hepatocellular carcinoma: A pilot study. PeerJ10, e12715. 10.7717/peerj.12715

  • CrossRef
  • Google Scholar

• 60

  MartinaE.CampanatiA.DiotalleviF.OffidaniA. (2020). Saliva and oral diseases. J. Clin. Med.9, 466. 10.3390/jcm9020466

  • CrossRef
  • Google Scholar

• 61

  MatsushimaK.IsomotoH.InoueN.NakayamaT.HayashiT.NakayamaM.et al (2011). MicroRNA signatures in Helicobacter pylori-infected gastric mucosa. Int. J. Cancer128, 361–370. 10.1002/ijc.25348

  • CrossRef
  • Google Scholar

• 62

  MichaelA.BajracharyaS. D.YuenP. S. T.ZhouH.StarR. A.IlleiG. G.et al (2010). Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis.16, 34–38. 10.1111/j.1601-0825.2009.01604.x

  • CrossRef
  • Google Scholar

• 63

  Nik Mohamed KamalN. N. S.AwangR. A. R.MohamadS.ShahidanW. N. S. (2020). Plasma- and saliva exosome profile reveals a distinct MicroRNA signature in chronic periodontitis. Front. Physiol.11, 587381. 10.3389/fphys.2020.587381

  • CrossRef
  • Google Scholar

• 64

  O’BrienJ.HayderH.ZayedY.PengC. (2018). Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. (Lausanne)9, 402. 10.3389/fendo.2018.00402

  • CrossRef
  • Google Scholar

• 65

  OanaS. M.ClaudiaB.LeliaR. A.SimonaM.ClaudiaC.DanielaD. E. (2022). Differential expression of tissular miRNA-155 in pediatric gastritis. J. Clin. Med.11, 3351. 10.3390/jcm11123351

  • CrossRef
  • Google Scholar

• 66

  OhtsukaM.IwamotoK.NaitoA.ImasatoM.HyugaS.NakaharaY.et al (2021). Circulating MicroRNAs in gastrointestinal cancer. Cancers (Basel)13, 3348. 10.3390/cancers13133348

  • CrossRef
  • Google Scholar

• 67

  ParkN. J.ZhouH.ElashoffD.HensonB. S.KastratovicD. A.AbemayorE.et al (2009). Salivary microRNA: Discovery, characterization, and clinical utility for oral cancer detection. Clin. Cancer Res.15, 5473–5477. 10.1158/1078-0432.CCR-09-0736

  • CrossRef
  • Google Scholar

• 68

  PatelR. S.JakymiwA.YaoB.PauleyB. A.CarcamoW. C.KatzJ.et al (2011). High resolution of microRNA signatures in human whole saliva. Arch. Oral Biol.56, 1506–1513. 10.1016/j.archoralbio.2011.05.015

  • CrossRef
  • Google Scholar

• 69

  PatelV.MaS.YadlapatiR. (2022). Salivary biomarkers and esophageal disorders. Dis. Esophagus35, doac018. 10.1093/dote/doac018

  • CrossRef
  • Google Scholar

• 70

  PengQ.ZhangX.MinM.ZouL.ShenP.ZhuY. (2017). The clinical role of microRNA-21 as a promising biomarker in the diagnosis and prognosis of colorectal cancer: A systematic review and meta-analysis. Oncotarget8, 44893–44909. 10.18632/oncotarget.16488

  • CrossRef
  • Google Scholar

• 71

  QuiricoL.OrsoF. (2020). The power of microRNAs as diagnostic and prognostic biomarkers in liquid biopsies. Cancer Drug Resist3, 117–139. 10.20517/cdr.2019.103

  • CrossRef
  • Google Scholar

• 72

  Rapado-GonzálezÓ.MajemB.Álvarez-CastroA.Díaz-PeñaR.AbaloA.Suárez-CabreraL.et al (2019). A novel saliva-based miRNA signature for colorectal cancer diagnosis. J. Clin. Med.8, 2029. 10.3390/jcm8122029

  • CrossRef
  • Google Scholar

• 73

  Sanz-RubioD.Martin-BurrielI.GilA.CuberoP.FornerM.KhalyfaA.et al (2018). Stability of circulating exosomal miRNAs in healthy subjects. Sci. Rep.8, 10306. 10.1038/s41598-018-28748-5

  • CrossRef
  • Google Scholar

• 74

  SăsăranM. O.MelițL. E.DobruE. D. (2021). MicroRNA modulation of host immune response and inflammation triggered by Helicobacter pylori. Int. J. Mol. Sci.22, 1406. 10.3390/ijms22031406

  • CrossRef
  • Google Scholar

• 75

  SazanovA. A.KiselyovaE. V.ZakharenkoA. A.RomanovM. N.ZarayskyM. I. (2017). Plasma and saliva miR-21 expression in colorectal cancer patients. J. Appl. Genet.58, 231–237. 10.1007/s13353-016-0379-9

  • CrossRef
  • Google Scholar

• 76

  SchaeferJ. S.AttumiT.OpekunA. R.AbrahamB.HouJ.ShelbyH.et al (2015). MicroRNA signatures differentiate Crohn’s disease from ulcerative colitis. BMC Immunol.16, 5. 10.1186/s12865-015-0069-0

  • CrossRef
  • Google Scholar

• 77

  ScholtzB.HorváthJ.TarI.KissC.MártonI. J. (2022). Salivary miR-31-5p, miR-345-3p, and miR-424-3p are reliable biomarkers in patients with oral squamous cell carcinoma. Pathogens11, 229. 10.3390/pathogens11020229

  • CrossRef
  • Google Scholar

• 78

  Sembler-MøllerM. L.BelstrømD.LochtH.PedersenA. M. L. (2020). Distinct microRNA expression profiles in saliva and salivary gland tissue differentiate patients with primary Sjögren’s syndrome from non-Sjögren’s sicca patients. J. Oral Pathol. Med.49, 1044–1052. 10.1111/jop.13099

  • CrossRef
  • Google Scholar

• 79

  SettiG.PezziM. E.VianiM. V.PertinhezT. A.CassiD.MagnoniC.et al (2020). Salivary MicroRNA for diagnosis of cancer and systemic diseases: A systematic review. Int. J. Mol. Sci.21, 907. 10.3390/ijms21030907

  • CrossRef
  • Google Scholar

• 80

  ShinV. Y.ChuK.-M. (2014). MiRNA as potential biomarkers and therapeutic targets for gastric cancer. World J. Gastroenterol.20, 10432–10439. 10.3748/wjg.v20.i30.10432

  • CrossRef
  • Google Scholar

• 81

  SreedharanL.MayneG. C.WatsonD. I.BrightT.LordR. V.AnsarA.et al (2017). MicroRNA profile in neosquamous esophageal mucosa following ablation of Barrett’s esophagus. World J. Gastroenterol.23, 5508–5518. 10.3748/wjg.v23.i30.5508

  • CrossRef
  • Google Scholar

• 82

  St JohnM. A. R.LiY.ZhouX.DennyP.HoC.-M.MontemagnoC.et al (2004). Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch. Otolaryngol. Head. Neck Surg.130, 929–935. 10.1001/archotol.130.8.929

  • CrossRef
  • Google Scholar

• 83

  SugiyamaT.TaniguchiK.MatsuhashiN.TajirikaT.FutamuraM.TakaiT.et al (2016). MiR-133b inhibits growth of human gastric cancer cells by silencing pyruvate kinase muscle-splicer polypyrimidine tract-binding protein 1. Cancer Sci.107, 1767–1775. 10.1111/cas.13091

  • CrossRef
  • Google Scholar

• 84

  ThéryC.ZitvogelL.AmigorenaS. (2002). Exosomes: Composition, biogenesis and function. Nat. Rev. Immunol.2, 569–579. 10.1038/nri855

  • CrossRef
  • Google Scholar

• 85

  ThéryC.OstrowskiM.SeguraE. (2009). Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol.9, 581–593. 10.1038/nri2567

  • CrossRef
  • Google Scholar

• 86

  TüfekciK. U.OnerM. G.MeuwissenR. L. J.GençS. (2014). The role of microRNAs in human diseases. Methods Mol. Biol.1107, 33–50. 10.1007/978-1-62703-748-8_3

  • CrossRef
  • Google Scholar

• 87

  UrbizuA.ArnaldoL.BeyerK. (2023). Obtaining miRNA from saliva-comparison of sampling and purification methods. Int. J. Mol. Sci.24, 2386. 10.3390/ijms24032386

  • CrossRef
  • Google Scholar

• 88

  VasapolliR.VeneritoM.SchirrmeisterW.ThonC.WeigtJ.WexT.et al (2021). Inflammatory microRNAs in gastric mucosa are modulated by Helicobacter pylori infection and proton-pump inhibitors but not by aspirin or NSAIDs. PLoS One16, e0249282. 10.1371/journal.pone.0249282

  • CrossRef
  • Google Scholar

• 89

  VasudevanS. (2012). Posttranscriptional upregulation by microRNAs. Wiley Interdiscip. Rev. RNA3, 311–330. 10.1002/wrna.121

  • CrossRef
  • Google Scholar

• 90

  VidalA. F.CruzA. M. P.MagalhãesL.PereiraA. L.AnaissiA. K. M.AlvesN. C. F.et al (2016). hsa-miR-29c and hsa-miR-135b differential expression as potential biomarker of gastric carcinogenesis. World J. Gastroenterol.22, 2060–2070. 10.3748/wjg.v22.i6.2060

  • CrossRef
  • Google Scholar

• 91

  WanJ.WuW.CheY.KangN.ZhangR. (2016). Insights into the potential use of microRNAs as a novel class of biomarkers in esophageal cancer. Dis. Esophagus29, 412–420. 10.1111/dote.12338

  • CrossRef
  • Google Scholar

• 92

  WangJ.SenS. (2011). MicroRNA functional network in pancreatic cancer: From biology to biomarkers of disease. J. Biosci.36, 481–491. 10.1007/s12038-011-9083-4

  • CrossRef
  • Google Scholar

• 93

  WangY.WangQ.ZhangN.MaH.GuY.TangH.et al (2014). Identification of microRNAs as novel biomarkers for detecting esophageal squamous cell carcinoma in asians: A meta-analysis. Tumour Biol.35, 11595–11604. 10.1007/s13277-014-2350-x

  • CrossRef
  • Google Scholar

• 94

  WangJ.ChenJ.SenS. (2016). MicroRNA as biomarkers and diagnostics. J. Cell. Physiology231, 25–30. 10.1002/jcp.25056

  • CrossRef
  • Google Scholar

• 95

  WangJ.-Y.WangC.-L.WangX.-M.LiuF.-J. (2017). Comprehensive analysis of microRNA/mRNA signature in colon adenocarcinoma. Eur. Rev. Med. Pharmacol. Sci.21, 2114–2129.

  • Google Scholar

• 96

  WongD. T. W. (2012). Salivaomics. J. Am. Dent. Assoc.143, 19S–24S. 10.14219/jada.archive.2012.0339

  • CrossRef
  • Google Scholar

• 97

  WuF.GuoN. J.TianH.MarohnM.GearhartS.BaylessT. M.et al (2011). Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn’s disease. Inflamm. Bowel Dis.17, 241–250. 10.1002/ibd.21450

  • CrossRef
  • Google Scholar

• 98

  WuW.HouW.WuZ.WangY.YiY.LinW. (2013). miRNA-144 in the saliva is a genetic marker for early diagnosis of esophageal cancer. Nan Fang. Yi Ke Da Xue Xue Bao33, 1783–1786.

  • Google Scholar

• 99

  XiaoH.ZhangY.KimY.KimS.KimJ. J.KimK. M.et al (2016). Differential proteomic analysis of human saliva using tandem mass tags quantification for gastric cancer detection. Sci. Rep.6, 22165. 10.1038/srep22165

  • CrossRef
  • Google Scholar

• 100

  XieZ.-J.ChenG.ZhangX.-C.LiD.-F.HuangJ.LiZ.-J. (2012). Saliva supernatant miR-21: A novel potential biomarker for esophageal cancer detection. Asian Pac J. Cancer Prev.13, 6145–6149. 10.7314/apjcp.2012.13.12.6145

  • CrossRef
  • Google Scholar

• 101

  XieZ.ChenG.ZhangX.LiD.HuangJ.YangC.et al (2013). Salivary microRNAs as promising biomarkers for detection of esophageal cancer. PLoS One8, e57502. 10.1371/journal.pone.0057502

  • CrossRef
  • Google Scholar

• 102

  XieZ.YinX.GongB.NieW.WuB.ZhangX.et al (2015). Salivary microRNAs show potential as a noninvasive biomarker for detecting resectable pancreatic cancer. Cancer Prev. Res. (Phila)8, 165–173. 10.1158/1940-6207.CAPR-14-0192

  • CrossRef
  • Google Scholar

• 103

  XuF.JiangM. (2020). Evaluation of predictive role of carcinoembryonic antigen and salivary mRNA biomarkers in gastric cancer detection. Medicine99, e20419. 10.1097/MD.0000000000020419

  • CrossRef
  • Google Scholar

• 104

  YeM.YeP.ZhangW.RaoJ.XieZ. (2014). Diagnostic values of salivary versus and plasma microRNA-21 for early esophageal cancer. Nan Fang. Yi Ke Da Xue Xue Bao34, 885–889.

  • Google Scholar

• 105

  YoshizawaJ. M.WongD. T. W. (2013). Salivary microRNAs and oral cancer detection. Methods Mol. Biol.936, 313–324. 10.1007/978-1-62703-083-0_24

  • CrossRef
  • Google Scholar

• 106

  YoshizawaJ. M.SchaferC. A.SchaferJ. J.FarrellJ. J.PasterB. J.WongD. T. W. (2013). Salivary biomarkers: Toward future clinical and diagnostic utilities. Clin. Microbiol. Rev.26, 781–791. 10.1128/CMR.00021-13

  • CrossRef
  • Google Scholar

• 107

  ZabagliaL. M.SallasM. L.SantosM. P. D.OrciniW. A.PeruquettiR. L.ConstantinoD. H.et al (2018). Expression of miRNA-146a, miRNA-155, IL-2, and TNF-α in inflammatory response to Helicobacter pylori infection associated with cancer progression. Ann. Hum. Genet.82, 135–142. 10.1111/ahg.12234

  • CrossRef
  • Google Scholar

• 108

  ZhangL.FarrellJ. J.ZhouH.ElashoffD.AkinD.ParkN.-H.et al (2010). Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer. Gastroenterology138, 949–957.e1-7. 10.1053/j.gastro.2009.11.010

  • CrossRef
  • Google Scholar

• 109

  ZhangZ.DongY.HuaJ.XueH.HuJ.JiangT.et al (2019). A five-miRNA signature predicts survival in gastric cancer using bioinformatics analysis. Gene699, 125–134. 10.1016/j.gene.2019.02.058

  • CrossRef
  • Google Scholar

• 110

  ZhengB.LiangL.WangC.HuangS.CaoX.ZhaR.et al (2011). MicroRNA-148a suppresses tumor cell invasion and metastasis by downregulating ROCK1 in gastric cancer. Clin. Cancer Res.17, 7574–7583. 10.1158/1078-0432.CCR-11-1714

  • CrossRef
  • Google Scholar

• 111

  ZhouS.XuJ. (2019). Downregulation of microRNA-204 increases the expression of matrix metallopeptidase 9 in pediatric patients with pulpitis and Helicobacter pylori infection in the stomach. Exp. Ther. Med.18, 253–259. 10.3892/etm.2019.7528

  • CrossRef
  • Google Scholar