Small nucleolar RNAs and SNHGs in the intestinal mucosal barrier: Emerging insights and current roles

Graphical abstract

Highlights

• •Small nucleolar RNAs (snoRNAs) and SNHGs are mainly involved in the biological behavior of the tumor via multiple pathways.
• •These molecular mechanisms affect the integrity of the intestinal mucosal barrier.
• •Impairment of intestinal mucosal disease is associated with a variety of diseases.
• •SnoRNAs and SNHGs may be involved in multiple diseases by affecting the intestinal barrier.

Abstract

Background

Previous studies have focused on the involvement of small nucleolar RNAs (snoRNAs) and SNHGs in tumor cell proliferation, apoptosis, invasion, and metastasis via multiple pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), Wnt/β catenin, and mitogen-activated protein kinase (MAPK). These molecular mechanisms affect the integrity of the intestinal mucosal barrier.

Aim of review

Current evidence regarding snoRNAs and SNHGs in the context of the mucosal barrier and modulation of homeostasis is fragmented. In this review, we collate the established information on snoRNAs and SNHGs as well as discuss the major pathways affecting the mucosal barrier.

Key scientific concepts of review

Intestinal mucosal immunity, microflora, and the physical barrier are altered in non-neoplastic diseases such as inflammatory bowel diseases. Dysregulated snoRNAs and SNHGs may impact the intestinal mucosal barrier to promote the pathogenesis and progression of multiple diseases. SnoRNAs or SNHGs has been shown to be associated with poor disease behaviors, indicating that they may be exploited as prognostic biomarkers. Additionally, clarifying the complicated interactions between snoRNAs or SNHGs and the mucosal barrier may provide novel insights for the therapeutic treatment targeting strengthen the intestinal mucosal barrier.

Introduction

Under physiological conditions, the intestinal mucosal barrier allows the selective passage of nutrients while protecting against penetration by pathogens [1]. This barrier contributes to the maintenance of intestinal homeostasis, and its dysfunction has been closely linked to diverse conditions, including type 2 diabetes, cardiovascular disease, autoimmune disease, inflammatory bowel disease, and various cancers [2].

Small nucleolar RNAs (snoRNAs) are a set of single-stranded non-coding RNAs ranging in length from 60 to 300 nucleotides. SnoRNAs are classified into two classes: C/D box snoRNAs and H/ACA box snoRNAs, which are respectively responsible for 2′-O-ribose methylation and pseudouridylation of ribosomal RNAs (rRNAs) [3]. However, an increasing body of evidence has recently implicated snoRNAs in the novel post-transcriptional regulation, such as rRNA acetylation, alternative splicing of mRNA, control of mRNA abundance, and translational efficiency [4], [5]. Additionally, snoRNAs can produce shorter, stable RNA species, which are believed to function as principal or alternative bioactive isoforms [4]. Some researchers have also indicated that snoRNAs also implicated in stress response and metabolic homeostasis [3]. Michel et al. have shown that three snoRNAs (SNORD32A, 33, and 35A) were remarkablely increased in palmitate and hydrogen peroxide administration elicited oxidative stress [6]. By contrast, snoRNA ACA11 reduces ribosomal protein genes and some snoRNAs to inhibit oxidative stress [7]. Brandis et al. have confirmed that the lack of snoRNA U60 decreases plasma membrane-to-endoplasmic reticulum cholesterol transferring and promotes de novo synthesis of cholesterol [8]. In addition, several studies have revealed that snoRNA U17 and four snoRNAs (snoRNAs U32A, U33, U34A, and U35A) modulate cellular metabolic homeostasis, Both of which regulates cellular cholesterol trafficking and systematic glucose metabolism, respectively [9], [10].

A dramatic number of studies have suggested that snoRNAs take part in numerous diseases including viral infection, Prader-Willi Syndrome (PWS) [11], asthma [12], multiple cancers and so on. Researchers have indicated that snoRNAs can function as mediators of host antiviral response and be utilized by viruses to regulate their life cycle [13], [14]. Kocher et al. have ascertained that the depletion of SNORD116 locus results in PWS phenotypes via lowering the stability of NHLH2 mRNA [11]. Overexpressed SNORA42 reinforces proliferation ability in non-small-cell lung cancer (NSCLC) cell cultures and is inversely associated with clinical patient survival [15]. A study regarding pancreatic ductal adenocarcinoma (PDAC) has revealed that increased SNORA23 maybe regulate ribosome biogenesis to enhance SYNE2 expression, promoting cell survival and invasion [16]. Xu et al. have demonstrated that SNORD47 exerts a tumor-repressive function in glioblastoma and is positively related to overall survival (OS) in clinical [17].

In mammals, most snoRNAs are encoded in the introns of protein-coding or non-protein-coding genes, namely small nucleolar RNA host genes [18]. Primary RNA transcripts of host genes are cleaved into distinct exons and introns. The former is rearranged and acts in the cytoplasm, the latter is processed into snoRNAs. SNHGs, a subset of non-coding snoRNA host genes, have been involved in neonatal pneumonia [19], diabetic retinopathy (DR) [20], acute cerebral infarction [21], endometriosis [22], and various cancers including thyroid cancer, pancreatic cancer (PC) and ovarian cancer [23]. Yu et al. have suggested that SNHG4 upregulates the expression of oxidation resistance 1 (Oxr1) via sponging miR-200b to suppress cell apoptosis in DR [20]. A study has proposed that SNHG4 contributes to ectopic growth of endometrial tissue through modulating c-Met via targeting miR-148a-3p [22]. In thyroid cancer, SNHG2, namely growth arrest specific transcript 5 (GAS5), functions as a sponge for miR-222-3p to regulate phosphatase and tensin homolog (PTEN) expression, activating PTEN/AKT pathway and inhibiting cell proliferation [24]. Cheng et al. have revealed that highly expressed SNHG7 promotes proliferation, invasion and migration of PC cell via regulating inhibitor of DNA binding 4 (ID4) expression by sponging miR-342-3p. Meanwhile, patients with the high level of SNHG7 have reduced OS and poor prognosis [25].

Until now, studies have mainly focused on the participation of snoRNAs and SNHGs in the occurrence of tumors via various pathways and molecular mechanisms. Some of mechanisms affect intestinal barrier function, the disruption of which has been confirmed to promote the development of intestinal bowel disease (IBD) by multiple studies. Consequently, it is hypothesized that snoRNAs or SNHGs impact the intestinal mucosal barrier via analogous or specialized mechanisms. However, to date, there are no comprehensive summaries available on the roles of snoRNAs or SNHGs in the integrity of the mucosal barrier. Herein, we conclude the potential pathways mediated by snoRNAs and SNHGs that modulate the intestinal barrier and thereby affect gut homeostasis (Table 1).

Table 1.

SnoRNAs and SNHGs modulate the intestinal mucosal barrier by multiple pathways or molecules.

SnoRNAs or SNHGs	Pathways or Molecules	Reference
SNHG1	PI3K/AKT	[89]
	Wnt/β catenin	[129]
SNHG2	Wnt/β catenin	[130]
	mTOR	[90]a
SNHG3	Wnt/β catenin	[131]
SNHG6	PI3K/AKT	[92], [93]
	Wnt/β catenin	[92], [132]
SNHG7	PI3K/AKT	[94]
	MAPK	[128]
SNHG11	Wnt/β catenin	[133]
	HIF-1α	[141]
SNHG12	PI3K/AKT	[95]
SNHG14	PI3K/AKT	[96]
SNHG15	Wnt/β catenin	[134]b
SNHG16	PI3K/AKT	[97]
	Wnt/β catenin	[135]c
SNORD50A/B	PI3K/AKT	[91], [98], [99], [100], [101]
	MAPK	[98], [99], [100], [101]
SNORD126	PI3K/AKT	[102]

^aGAS5 and mTOR mutually inhibit each other in terms of expression level.

^bMyc increases the expression of SNHG15.

^cWnt/β catenin pathway upregualtes SNHG16 expression.

Components and metabolites of the intestinal mucosal barrier

The intestinal mucosal barrier refers to the isolation zone that segregates the potentially hostile intestinal contents from the internal milieu by preventing toxic substances and pathogens entering into the human body and maintaining homeostasis. Various components including mucins, antimicrobial peptides (AMPs), glycocalyx, tight junctions, the immune barrier, commensal bacteria, and their metabolites are involved in the proper functioning of this barrier [26], [27].

Mucus consists of substantial mucin glycoproteins produced by intestinal goblet cells and functions as a lubricant, provides physical impedance, and interacts with AMPs to kill bacteria [28]. AMPs, including defensins, cathelicidin, lysozyme, and lactoferrin, are produced by Paneth cells (PCs) situated at the bottom of crypts in the small intestine, as well as by enterocytes and immune cells [26]. The defensin family proteins, are categorized into α-defensins (HD5 and HD6), which are also known as cryptdins in mice, and β-defensins (constitutive HBD1 and inducible HBD2 and HBD3). It is now generally accepted that α-defensins require proteolytic cleavage to gain antimicrobial activity [29]. Intriguingly, while PC-derived trypsin is responsible for HD5 and HD6 activation, the conversion of pro-cryptdin into mature cryptdin requires matrix metalloproteinase-7 (MMP-7) [30], [31], [32]. Mechanistically, defensins combine with the negatively charged microbial cell membrane, penetrate the cell membrane and destroy its integrity [33]. Further, recent evidence suggests HBD3 can inhibit bacterial cell wall biosynthesis by interacting with lipid II, a component of the peptidoglycan wall [34].

Tight junctions (TJs) are comprised of occludin, claudin, tricellulin, and junctional adhesion molecules [35], the phosphorylation of which increases paracellular permeability. In addition, elevation of claudin l induces Notch signaling activation in an MMP-9 and p-ERK signaling pathways dependent manner, which in turn inhibits differentiation of goblet cells [36]. Phosphorylation of the myosin light chain (MLC) mediated by myosin light chain kinase (MLCK) causes contraction of the actomyosin ring [37]. Studies have demonstrated that the interplay between the TJ complex and the actomyosin ring maintains TJ integrity, thereby suggesting an essential role for MLCK in regulating TJ and altering the permeability of paracellular pathways [37]. Moreover, several studies have indicated that the proinflammatory cytokines IL-1β, TNF-α, IFN-γ, and IL-13 can augment mucosal permeability mostly through the induction of MLCK, which destabilizes TJs [38], [39], [40], [41], [42], [43].

Commensal bacteria competitively inhibit the adhesion of enteropathogens [44], involved in the development and modulation of the intestinal immune system [44], [45], [46], [47], [48], [49], [50], [51] and repress intestinal inflammation by inhibiting degradation of NF-κB inhibitor-α (IKB-α) [52]. The glycocalyx facilitates the colonization of symbiotic intestinal flora [35] and its rapid turnover rate is conducive to the removal of attached pathogens [53], [54]. Short-chain fatty acids (SCFAs) comprise primarily butyrate, generated mostly by Firmicutes, as well as propionate and acetate, mainly produced by Bacteroidetes in the gut. [55], [56]. Multiple studies have attributed an indispensable role to SCFAs in protecting mucosal barrier function through distinct mechanisms. Butyrate is conducive to the maintenance of a hypoxic environment, as well as expression and stabilization of hypoxia-inducible factor (HIF) [57], [58]. Wang et al. reported elevated level of actin-binding protein synaptopodin as a consequence of histone deacetylase (HDAC) suppression by butyrate and a subsequent decrease in epithelial permeability and maintenance of intestinal homeostasis [59]. Butyrate also upregulates the expression of TJ proteins, induces trefoil factors, and induces AMP production [60], [61], [62]. Several studies indicate that it stimulates the production of peroxisome proliferator-activated receptor gamma (PPAR-γ), which contributes to HBD-1 expression and maintains a local hypoxic environment [63], [64]. Interestingly, inhibiting the PPAR-γ signaling pathway stimulates SCFA exhaustion [2]. Research has confirmed that SCFAs are crucial for upregulation of mucus secretion from goblet cells, amelioration of local inflammation, prevention of pathogen infiltration, and maintenance of the integrity of the intestinal barrier [2], [65].

Certain molecules may enhance or weaken the mucosal barrier function by affecting paracellular permeability or defensins. TNF-α and HIF-1α regulate paracellular permeability by modulating the composition and activity of TJ proteins. TNF-α has been demonstrated to enhance SYNPO protein degradation, promote removal of claudin 1 from TJs, increase claudin 2 expression, promote occludin degradation, and augment both MLCK expression and its enzymatic function, thereby increasing paracellular permeability [66], [67], [68], [69]. Studies have also revealed that TNF-α changes both TJ structure and the expression of its constituent proteins through NF-κB signaling [70], [71], [72], [73]. In addition, it can upregulate apoptosis of intestinal epithelial cells and cell shedding [74].

Under physiological conditions, the intestinal microbiota primarily comprises anaerobes, which dramatically decrease oxygen levels, resulting in hypoxia [75]. Interestingly, high metabolism due to inflammation and tumors further drives hypoxia in the intestine [76], [77], [78], [79]. Additionally, hypoxia markedly elevates the HIF and NF-κB pathways [80]. Consistent with these findings, several studies have demonstrated that intestine at the cellular level primarily relies on HIFs’ regulation to adapt to hypoxia [81]. The activation of HIF-1α, directly controling the transcription of several mucins [82], [83], contributes to β-defensin-1 expression [84]. In addition, HIF-1α regulates claudin 1 level, as HIF-1α knockdown in intestinal and esophageal epithelial cells results in down-regulated expression of claudin 1, and study has confirmed the interaction of HIF-1α with the CLDN1 promoter [85], [86]. Moreover, TNF-α and HIF-1α as well as MMP-2 and MMP-9 have been demonstrated to associate positively with mucosal permeability [87]. Other MMPs are also critical regulatory factors in mucosal barrier protection via their effect on α-defensins. Pro-cryptidin is known to be converted into mature cryptidin by MMP-7 [27], and mature α-defensins deficiency due to MMP-7 lack correlates with decreased Bacteroidetes and concomitant increased Firmicutes [88].

SnoRNAs or SNHGs affect the intestinal mucosal barrier via the PI3K/AKT pathway

A study on colorectal cancer (CRC) suggests that SNHG1 functions as a competing endogenous RNA (ceRNA) that sponges miR-137, thereby upregulating RICTOR expression [89]. RICTOR, a subunit of mammalian rapamycin target protein complex 2 (mTORC2), is primarily responsible for regulating AGC kinase activation (including AKTSer473) [89]. Therefore, it is reasonable to infer that SNHG1 likely affects barrier function through the regulation of the mTORC2 pathway. Zhang et al. have revealed that GAS5 forms a negative regulation feedback loop with the miR-34a/mTOR/SIRT1 axis in CRC, in which GAS5 and mTOR mutually inhibit each other in terms of expression level [90]. These findings have suggested that GAS5 might modulate the mucosal barrier via the PI3K/Akt/mTOR pathway. Studies have demonstrated that the PI3K/Akt/mTOR pathway is upregulated in CRC [91]. However, there are different views regarding the expression of SNHG6 in CRC [92], [93]. Therefore, the interplay between SNHG6 and the PI3K/Akt/mTOR pathway remains to be determined. A recent study on CRC verified that SNHG7 acts as a ceRNA that sponges miR-34a, consequently regulating GALNT7, which holds potential positive regulatory relevance in the PI3K/Akt/mTOR pathway [94]. These findings suggest that SNHG6 and SNHG7 may regulate the mucosal barrier through the PI3K/AkT/mTOR pathway. A recent study showed that SNHG12 activates the PI3K/AKT signaling pathway [95] in CRC cells, indicating that SNHG12 may perform a regulatory part in the intestinal mucosal barrier. However, the underlying mechanism warrants further investigation [95]. Study on CRC has suggested that SNHG14 sponges miR-944 to increase K-ras mediated by the PI3K/AKT pathway, which might exert a regulatory role in the intestinal mucosal barrier [96]. SNHG16 positively regulates AKT expression by sponging miR-302a-3p in colon cancer cells, which illustrates that SNHG16 may modulate the PI3K/AKT signaling pathway and thereby affecting the mucosal barrier [97]. Many studies have confirmed that SNORD50A/B is commonly deleted in multiple human cancers, including colon cancer [98]. Lack of SNORD50A and SNORD50B increases the K-Ras binding of active GTP and FTase, producing increased levels of activated K-Ras and hyperactivated PI3K and MAPK pathways [91], [99], [100], [101], which in turn affects the mucosal barrier. The increased expression of SNORD126 upregulates the fibroblast growth factor receptor 2 (FGFR2), leading to the activation of the PI3k-AKT pathway [102]. The latter is strongly linked to the intestinal mucosal barrier.

Ligand binding leads to the immediate activation of cytoplasmic PI3K, resulting in the conversion of phosphatidylinositol 3,4-bisphosphate (PIP2) to phosphatidylinositol 3,4,5 -triphosphate (PIP3). PIP3 combines with and activates AKT, which is then mobilized to the cytoplasm or nucleus in order to regulate downstream signaling molecules, such as mammalian target of rapamycin (mTOR), cyclin D1, and nuclear transcription factor (NF-κB).

In mammals, mTOR functions as the catalytic domain of two multi-protein complexes, mTORC1 and mTORC2. On one hand, AKT phosphorylation activates mTOR and downstream pathways [103], [104]. Activated mTORC2 has a positive feedback effect on AKT activation [103], [104]. This may activate mTORC1, which subsequently activates PPAR-γ [105] and drives HIF-1α synthesis in multiple ways [106]. On the other hand, phosphorylated AKT also activates IκB kinase (IKK), promoting the degradation of the NF-κB inhibitor IκB, thereby activating NF-κB and its downstream pathways [107], [108], [109]. The NF-κB signaling pathway in turn upregulates TNF-α secretion, activates transcriptional upregulation of HIF-1α mRNA, and regulates MMP-2 and MMP-9 expression [80], [110], [111]. In addition, NF-κB may enhance the intestinal barrier by preventing intestinal epithelial cell apoptosis (Fig. 1) [80].

Fig. 1.

SnoRNAs or SNHGs affect the intestinal mucosal barrier via the PI3K/AKT pathway.

IBD patients hold abnormal gut microflora, characterized by reduced Firmicutes and Bacteroidetes 16S rRNA and increased in Proteobacteria and Actinobacteria 16S rRNA, as seen by gene sequencing [112]. In summary, IBD patients exhibit a significant reduction in SCFA-producing bacteria. Several lines of evidence indicate that IBD mainly involves epithelial cell shedding and TJ changes [113], [114], [115]. The latter is associated with elevated MLCK expression and enzymatic activity [116], altered TJ protein expression, and subcellular distribution [117]. For instance, expression of occludin, claudin-1, claudin-4, and claudin-7 is downregulated, while pore-forming claudin-2 is upregulated, in ulcerative colitis (UC) [118], [119]. Likewise, similar changes in TJ proteins were discovered in Crohn's disease (CD), including the downregulation of occludin, claudin-3, claudin-5, and claudin-8 and the upregulation of the pore-forming claudin 2 [120], [121]. These barrier defects have been ascribed to the activation of inflammatory cytokines including TNF-α, INF-γ, IL-1β, and IL-13, which show high levels of expression in the chronically inflamed intestine [117]. Modifications in defensin expression patterns have also been observed in IBD. Similarly, patients with UC exhibit elevated levels of HBD-2 and HBD-3, and diminished expression of HBD-1 [122]. CD is characterized by downregulation of HD-5, HD-6, and HBD-1 [122], [123], [124]. SYNPO, located at TJs of the enterocytes, has been demonstrated to reduce epithelial permeability [59]. Studies recently have manifested that in addition to directly reducing butyrate and SYNPO levels, mucosal inflammation indirectly reduces these levels by targeting butyrate-producing bacteria, consequently resulting in intestinal barrier dysfunction [59]. Furthermore, elevated expression of HIF-1α and NF-κB have also been observed in IBD patients [125], [126].

SNHG7 and SNORD50A/B affect intestinal mucosal barrier via MAPK pathway

Receptor dimerization post receipt of a specific signal results in activation of its own tyrosine kinase. The phosphorylated tyrosine on the receptor binds to the SH2 domain of growth factor receptor binding protein 2 (Grb2) on the cell membrane, whereas the SH3 domain of Grb2 combines with the guanylic acid exchange factor (SOS), which in turn activates rat sarcoma virus (Ras). In general, K-ras of the Ras superfamily of GTPases binds to FTase, thereby upregulating the expression of active, prenylated K-Ras[101]. While activated K-ras induces PI3K activation [91], it also interacts with the amino terminal of serine/threonine protein kinase-1 (Raf-1) and activates it. Raf-1 phosphorylates two regulatory serines on mitogen-activated protein kinase (MEK)1/2, thus activating MEKs. MEKs are bispecific kinases that can phosphorylate serine/threonine and tyrosine residues and selectively activate extracellular regulated protein kinases (ERK)1/2 (i.e., p44 MAPK and p42 MAPK). Phosphorylation of activated ERK regulates the transcription of downstream target genes. Additionally, p-ERK also induces the phosphorylation of claudin-1 to strengthen the mucosal barrier [127]. Researchers have proved that SNHG7 activates K-ras/ERK/cyclinD1 via interaction with miR-193b in CRC [128]. However, SNORD50A and SNORD50B can increase the abundance of active K-ras. These findings indicate that SNHG7 and SNORD50A/B might regulate intestinal barrier via MAPK signaling pathway (Fig. 2).

Fig. 2.

SNHG7 and SNORD50A/B affect intestinal mucosal barrier via MAPK pathway.

The relationships among SNHGs, Wnt/β-catenin pathway and intestinal mucosal barrier

In CRC cells, SNHG1 induces the Wnt/β-catenin pathway activation [129], which is closely associated with the mucosal barrier. Song et al. have demonstrated that GAS5 suppresses the Wnt/β-catenin signaling pathway in CRC [130]. SNHG3 serves as a ceRNA that sponges miR-182-5p, consequently increasing the levels of c-Myc and its target genes [131]. These findings suggest that GAS5 and SNHG3 might regulate the intestinal mucosal barrier through the Wnt/β-catenin pathway. Research on CRC has resulted in the establishment of opposing views on the expression of SNHG6, and therefore the interplay of SNHG6 and the Wnt/β-catenin pathway requires further investigation [92], [132]. However, the regulatory relevance of SNHG6 in the protection of the intestinal barrier via the Wnt/β-catenin pathway has been unequivocally established. Huang et al. have revealed that SNHG11 interacts with insulin-like growth factor 2 (IGF2) mRNA-binding protein 1 (IGF2BP1), contributing to the interplay between IGF2BP1 and c-Myc mRNA in CRC, which stabilizes c-Myc expression and upregulates its downstream genes. More importantly, SNHG11 forms a positive feedback regulatory loop with c-Myc, which is increased c-Myc caused by SNHG11 in turn upregulates SNHG11 [133]. Consequently, it is plausible to deduce that SNHG11 likely affects barrier function through the regulation of the Wnt/β-catenin pathway. In CRC cells, researchers have shown that MYC, a downstream target gene of the Wnt/β-catenin pathway, transcriptionally increases the expression of SNHG15 [134]. Similarly, a study regarding CRC has revealed that SNHG16 expression is increased modulated by the Wnt pathway [135]. However, the complex relationships among SNHG15 or SNHG16, Wnt/β-catenin pathway and intestinal barrier remains to be verified.

The secretion ligand protein Wnt binds to the membrane surface receptor protein frizzled (FZD), with the assistance of low-density lipoprotein receptor-related protein 5/6 (LRP-5/6). The interaction of these three proteins activates the intracellular protein DVL, which stabilizes free cytoplasmic β-catenin by suppressing the activity of the β-catenin degradation complex formed by glycogen synthase kinase 3 (GSK3β) and other proteins. Subsequently, stably accumulated β-catenin enters the nucleus and binds to the lymphoid enhancer factor (LEF)/T-cell transcription factor (TCF) to initiate the transcription of downstream target genes, such as c-myc, MMP-7, and MMP-9 [136], [137]. The Wnt target gene MMP-7 is further linked to the maturation of pro-cryptdin [27], while MMP-9 increases intestinal mucosal permeability [87]. The Wnt signaling pathway affects AMP production and controls PC differentiation [138]. It has been demonstrated that trypsin produced by PCs activates HD-5 [32]. In addition, Wnt-regulated genes interact with TCF to regulate the expression of defensins, such as α-defensin expression regulation by TCF-4 (Fig. 3) [139], [140]. Studies have shown modifications in the expression patterns of defensins in IBD patients, such as the downregulation of HD-5 and HD-6 in CD patients [123].

Fig. 3.

The relationships among SNHGs, Wnt/β-catenin pathway and intestinal mucosal barrier.

In light of the above findings, it may be reasonable to hypothesize that the Wnt/β-catenin pathway regulates defensins via SNHGs.

SNHG11 affects intestinal mucosal barrier by interacting with HIF-1α

SNHG11 in CRC was demonstrated to function only in an oxygen-deficient environment, indicating that it may interplay with HIF-1α or proteins modulating HIF-1α stability. Further studies have verified that SNHG11 interacts with and stabilizes HIF-1α. The protein combines with the pVHL recognition site of the HIF-1α N segment, consequently hindering the interplay between pVHL and HIF-1α and interrupting the ubiquitination and degradation of HIF-1α, ultimately leading to its accumulation. Additionally, SNHG11 enhances HIF-1α transcriptional activity and upregulates its target gene expression [141]. Furthermore, patients with IBD exhibit hypoxia in the intestinal epithelium as well as HIF activation owing to high levels of tissue metabolism and vasculitis [80]. Thus, it is possible to infer that SNHG11 may affect the intestinal mucosal barrier by interacting with HIF-1α.

Conclusion

The intestinal mucosal barrier is a dynamic system evolutionarily selected to maintain homeostasis by relying on a variety of mechanisms. Several studies have shown that snoRNAs and SNHGs can activate cellular pathways that participate in the occurrence of diseases. The interaction between snoRNAs or SNHGs and the intestinal barrier is likely to be mediated by cellular signaling pathways, including the PI3K/AKT, Wnt/β-catenin, and MAPK pathways. Here, we summarized the latent effects of snoRNAs and SNHGs on the intestinal mucosal barrier. However, the precise mechanisms that underlie these effects are yet to be elucidated. SNHG6 has been postulated to regulate the intestinal barrier via the PI3K/AKT and Wnt/βcatenin pathways. However, there is no consensus on the expression levels of SNHG6. Wang et al. reported upregulation of SNHG6 in CRC cells; however, a subsequent study reported that SNHG6 is downregulated in CRC [92]. Both studies quantified SNHG6 by quantitative real-time PCR (qRT-PCR), and the discrepancy in their observations may be accounted for by the detection of different isoforms, differences in cancer cell percentage, or differences in preoperative chemotherapy [135]. While patients in the study by Meng et al. did not receive preoperative chemotherapy, similar information was not provided for patients in the study by Wang et al. Further, data on the other parameters that may have resulted in the contradictory outcomes were not provided in either study, and hence, cannot be addressed. Consequently, the positive or negative correlation between SNHG6 and the intestinal barrier remains to be determined.

Several studies on snoRNAs and SNHGs have demonstrated that both can potentially serve as diagnostic markers [142]. Some of these parameters can be detected during the early stages of the disease with higher sensitivity than other indicators [143]. Furthermore, multiple studies indicate that dysregulation of snoRNAs or SNHGs is closely related to poor overall survival, poor recurrence-free survival, and unfavorable clinicopathological outcomes, including progression to the advanced TNM and clinical stages, lymph node metastasis, and distant metastasis [143], [144], [145], [146], [147]. Therefore, snoRNAs or SNHGs may be exploited as prognostic biomarkers. Additionally, elucidating the complex array of interactions between snoRNAs or SNHGs and the mucosal barrier will pave the way for viable therapeutic approaches designed to strengthen intestinal barrier function.

Notably, there is complex interplay between snoRNAs and their host genes. It was thought that most snoRNAs’ expression relied on the transcription and splicing of their host genes in the past [148], [149]. However, studies recently suggest that the expression of snoRNAs is decouple from their host genes, and there is even an orphan snoRNA that can modulate the splicing of its host genes according to the amount of protein encoded by the host gene [150]. Importantly, intronic snoRNAs are functionally related to their host genes by taking part in associated cellular signaling pathways [151]. In addition, studies have demonstrated that snoRNAs and proteins encoded by snoRNA host genes are involved in ribosome biogenesis [152], [153], [154]. Are there some snoRNAs and their corresponding SNHGs that both have roles in the context of the intestinal mucosal barrier? And whether there is a mutual regulatory relationship between snoRNA and its SNHG in the regulation of intestinal homeostasis? We think these questions merit further investigation in the future.

Compliance with Ethics Requirements

This article does not contain any studies with human or animal subjects.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Jun Shen is the Chief Physician of Department of Gastroenterology, Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China. Dr. Jun is also the Associated Professor of Shanghai Institute of Digestive Disease and leading research teams in the field of IBD. Jun Shen, MD & PhD, is a renowned gastroenterologist who specializes in the treatment and assessment of inflammatory bowel diseases (Crohn’s disease and ulcerative colitis). He is also in charge of the Shanghai Inflammatory Bowel Disease Research Center as the Executive Director. Dr. Jun focuses on clinical and translational researches related to therapy in inflammatory bowel diseases, with particular interest in the area of evaluation and prediction of medical outcomes for IBD, and joint studies related to the microbiome and recurrence of IBD. Dr. Jun published over 80 peer-reviewed papers in the area of IBD in the well-know journal as Autophagy, Lancet Gastroenterology and Hepatology, Mucosal Immunology, Journal of Crohn’s and Colitis, Inflammatory Bowel Diseases, etc. He is also the executive director of Chinese Young Association for Crohn’s and Colitis and IBD Association, Chinese Medical Assembly.

Tian Yang is a master student at Shanghai Jiaotong University, focusing on inflammatory bowel disease and intestinal mucosa-related research.