Introduction
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that predominantly affects the colon. Originating from multiple sources, its complexities lie in factors such as genetic predispositions, anomalies in the epithelial barrier, misaligned immune responses, and environmental elements [
1].
UC’s incidence is steadily increasing worldwide [
2]. The figures are concerning, with incidences ranging from 9 to 20 cases per 100,000 person-years, and prevalence oscillating between 156 to 291 cases per 100,000 people [
1]. The symptoms of UC can be severe and have a significant impact on the quality of life of affected individuals [
3,
4]. Moreover, studies link UC to subsequent psychological challenges, further adding to the burden of the disease [
5‐
7].
One alarming consequence of UC is its potential progression to colorectal cancer (CRC) [
8]. For those living with UC over three decades, the odds of developing colon cancer can rise up to 20% [
9,
10]. UC-induced CRC patients often tend to be of a younger demographic and exhibit a propensity for multiple malignant lesions, and histologically exhibit mucinous or signet ring cell carcinomas [
11].
Both UC and UC-related cancer are believed to be intrinsically linked to sustained inflammation in the colon [
12]. Although the definitive etiology of inflammatory bowel disease (IBD) is yet to be pinpointed, it’s speculated to be a nexus of genetic, environmental, microbial, and immune factors [
13]. Existing medical interventions for IBD primarily aim at curtailing the mucosal inflammation to alleviate associated symptoms. Nevertheless, for a segment of patients, the treatment journey extends to encompassing cancer therapies like chemotherapy, radiation, or surgical procedures [
14,
15].
Our present research is anchored in unearthing the underlying intricacies of UC pathogenesis. By leveraging UC mouse models, we probed its DEGs. Comprehensive functional assessments were undertaken, encompassing enrichment analysis, protein-protein interactions, the Competing Endogenous RNA (ceRNA) network, and relevant pathway enrichments. These endeavors cast light on the multifaceted molecular mechanisms integral to UC.
Discussion
UC is an increasingly prevalent chronic inflammatory disease of the colon globally. Its etiology is multifaceted, resulting from a sophisticated interplay between genetic predisposition, environmental influencers, altered immune responses, and abnormal epithelial barrier function [
13]. The understanding of the genetic underpinnings of inflammatory bowel disease (IBD) has been significantly enhanced over the past few decades [
32], thanks to technological advances in DNA analysis and sequencing, as well as the use of large-scale multinational databases [
33].
The DSS-induced colitis model stands validated as an effective tool for assessing potential therapeutic compounds pertinent to human conditions [
34]. This model’s histopathological markers are close to those observed in human IBDs [
35], particularly UC. Importantly, the induced inflammatory environment encompasses features of both Crohn’s disease (CD) and UC [
36].
In contrasting the UC and control groups, our DEG analysis identified pronounced disparities in gene expression. Specifically, within the UC group, 379 genes manifested heightened activity, while 230 genes displayed diminished activity compared to the control group. Notably, Tppp3 registered higher levels in the control group, whereas Saa3, Cemip, Pappa, and Nr1d1 were accentuated within the UC group. Both Saa3 and Nr1d1 established links to inflammatory events and IBD. To substantiate these DEG findings, we also implemented quantitative real-time PCR assessments.
Our pathway enrichment investigation pinpointed several crucial pathways involved in inflammation and tissue restructuring. These include inflammation and tissue remodeling, including cytokine-mediated signaling, extracellular matrix organization, and encapsulating structure organization. These pathways displayed marked activation within the UC group.
Protein-protein interaction analysis has underscored the significance of hub genes, notably Stat3, Il1b, Mmp3, and Lgals3, in the progression of ulcerative colitis. Among these, Stat3 stands out due to its association with immune response regulation, inflammation, and cell survival, highlighting its potential as a therapeutic focal point.
Furthermore, a network exploration of lncRNA-miRNA-mRNA ceRNA interactions has spotlighted several lncRNAs and miRNAs intricately connected with pivotal DEGs, such as C1qtnf3, Col8a1, Saa3, Pappa, Pla2g3, and Prss22. It’s worth emphasizing that Sema7a, a hub mRNA, plays a part in anti-colitis effects by stimulating macrophage IL-10 production.
Summarily, our observations provide a clearer picture of the molecular intricacies of ulcerative colitis and spotlight promising therapeutic avenues for addressing this specific inflammatory bowel disease. The delineated DEGs and pathways could potentially pave the way for innovative research and the development of breakthrough treatment protocols to better patient prognosis.
While our study offers valuable perspectives into the molecular dynamics governing UC, it is not without limitations. The employed mouse sample size is relatively constrained, which might temper the conclusiveness of our findings. Furthermore, given the intricate nature of gene functionalities, any predictions rooted solely in bioinformatics warrant corroboration through cellular and animal trials. However, the study’s contributions to elucidating genetic factors in UC hold promise for shaping future therapeutic interventions for this challenging condition.
Conclusion
The current research illuminates the potential roles of DEGs and associated pathways in the onset and progression of UC when evaluating UC mouse models against controls. Delving into the ceRNA network-mediated genes, we unveiled probable molecular pathways underpinning UC’s pathogenesis.
Our findings offer new insights into the complex molecular processes that contribute to the onset and progression of UC. Leveraging advanced bioinformatics methodologies, we pinpointed pivotal DEGs and pathways likely instrumental in the trajectory of this chronic inflammatory ailment.
We anticipate that these findings will serve as a stepping stone for deeper exploration into UC’s underpinnings, and the formulation of innovative therapeutic approaches tailored for this debilitating disorder. By elucidating the molecular foundation of UC, our endeavor holds the potential to significantly enhance the living standards of countless individuals globally afflicted by this condition.
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