INTRODUCTION
Colorectal cancer (CRC) is a major global health concern, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide [
1]. CRC arises through a multistep process, starting with the formation of polyps in the colon or rectum, which can progress to adenomas and eventually develop into invasive carcinoma [
2]. Polyps are abnormal tissue growths that can develop in various parts of the body, including the colon and rectum [
3]. Colorectal polyps are common and can be benign (non-cancerous) or malignant (cancerous) [
4]. CRC is a type of cancer that starts in the colon or rectum and is the most commonly diagnosed cancer type in Spain [
5]. The primary risk factor for CRC is age, with 90% of all diagnosed patients aged over 50 years [
6]. The prognosis of CRC mainly depends on the tumor stage, with the 5-year survival rate decreasing from 91% in the early stage to around 10% in the advanced stage [
7]. The prevalence of colorectal polyps and cancer is significant. In a study conducted in China, 2,064 colorectal polyp cases were identified among 6,783 eligible participants between March 2018 and December 2019. Certain dietary factors, such as meat consumption, have been linked to an increased prevalence of colorectal polyps. For instance, higher poultry consumption was significantly related to a higher polyp prevalence [
8]. Microsatellite instability (MSI) is a key biomarker in CRC, with crucial diagnostic, prognostic, and predictive implications [
9,
10]. Testing for mismatch repair deficiency (MMR-D)/MSI is recommended during screening for Lynch syndrome, an autosomal-dominant hereditary disease characterized by germline mutations in the MMR genes and associated with an increased risk for several types of cancer [
11]. MSI-high status is associated with a better prognosis in early-stage CRC and a lack of benefit from adjuvant treatment with 5-fluorouracil in stage II disease. More recently, MSI has emerged as a predictor of sensitivity to immunotherapy-based treatments, opening a new therapeutic scenario for patients with these tumors [
12].
In this study, we employed a systems biology approach to investigate the similarities between polyp and CRC at the molecular level. Specifically, we focused on the analysis of differentially expressed genes (DEGs) using protein-protein interaction (PPI) networks, transcription factor (TF) analysis, and gene ontology (GO) analysis. By integrating these different analytical approaches, we aimed to identify common DEGs that are dysregulated in both polyp and CRC. These shared DEGs may represent key molecular players and pathways that contribute to the progression of polyps to CRC. To the best of our knowledge, this study represents one of the first comprehensive analyses of the shared molecular features between polyp and CRC using a systems biology approach. By elucidating the molecular similarities between these 2 conditions, our findings have the potential to contribute to the development of precision medicine strategies that target shared pathways and improve patient outcomes.
DISCUSSION
CRC and colorectal polyps share a close relationship, with polyps being considered precursors to CRC. Understanding the molecular mechanisms underlying their development and progression is crucial for improving diagnostic and therapeutic strategies [
19]. In doing so, we have identified unique factors that have not received significant attention in existing literature. The detailed exploration of common DEGs, PPIs, and TFs was conducted to emphasize these novel aspects.
In this study, we employed a systems biology approach to investigate the similarities between polyp and CRC at the molecular level. Our analysis of gene expression profiles, PPIs, TFs, and GO revealed valuable insights into the shared molecular features and potential mechanisms underlying these 2 conditions. The identification of common DEGs between polyp and CRC provides important insights into the shared molecular pathways and potential drivers of disease progression. We found a substantial number of common DEGs between the 2 conditions, suggesting shared molecular alterations and dysregulated pathways. These common DEGs may serve as potential biomarkers for early detection, diagnosis, and prognosis of both polyps and CRC. Furthermore, they may represent key molecular players that contribute to the transition from benign polyps to malignant CRC. Interestingly, among the 520 genes commonly dysregulated in both colorectal polyps and CRC, only 8 genes exhibited opposite expression patterns. These genes, namely LY75, SMARCA1, EXOSC7, CYP2A7P1, PAWR, PSIP1, TRACK1, and SPINK4, showed differential expression between the 2 conditions. This observation highlights the complexity and heterogeneity of the molecular alterations occurring during the transition from polyps to CRC. While the majority of the common genes exhibited consistent dysregulation, these 8 genes stood out as unique in their opposing expression patterns. The differential expression of these genes suggests potential divergent roles and molecular mechanisms in the progression of polyps to CRC. While the roles of these specific genes in CRC or colorectal polyps have not been well-established in the available literature, some of them have been studied in other types of cancer and BP.
In bladder cancer, LY75 has been implicated in the regulation of cell function. It has been shown that nitidine chloride, a potential therapeutic agent, can inhibit bladder cancer cell proliferation, migration, and invasion by downregulating the expression of LY75, as well as induce apoptosis and arrest cell cycles [
20].
SMARCA1 gene is part of the SWI/SNF chromatin remodeling complex, which plays a role in regulating gene expression. Mutations in SMARCA1 have been investigated in relation to Smith-Fineman-Myers syndrome, a rare genetic disorder [
21].
EXOSC7 is known to be a component of the exosome complex, which is involved in the degradation of various types of RNA molecules [
22].
CYP2A7P1 gene is a pseudogene of the cytochrome P450 family, which is involved in the metabolism of various endogenous and exogenous compounds [
23]. PAWR known as Par-4, this gene has been associated with major depressive disorder. Genetic variations in
PAWR have been found to be related to susceptibility to major depressive disorder, but not to the response to antidepressant treatment [
24]. PSIP1 encodes a protein that is involved in transcriptional regulation and chromatin remodeling, suggesting potential roles in gene expression regulation [
25]. It is important to note that further research is needed to elucidate the specific functions and potential involvement of these genes in CRC and colorectal polyps. The opposite expression of these 8 genes emphasizes the need for comprehensive analyses and further investigations to unravel the complexities of colorectal tumorigenesis. Unraveling the specific roles and interactions of these genes within the context of polyp and CRC development may shed light on the underlying mechanisms and provide valuable insights for future research and therapeutic interventions in CRC.
GO analysis revealed distinct BP associated with the upregulated and downregulated DEGs in polyp and CRC. In CRC, the upregulated genes were enriched in cell adhesion and signal transduction, while the downregulated genes were associated with apoptotic processes and cell division. Similarly, in polyps, the upregulated genes were involved in cell adhesion and cell differentiation, while the downregulated genes were associated with signal transduction and cell division. These findings suggest that dysregulation of these BP may contribute to the pathogenesis of both conditions.
PPI network analysis allowed us to explore the molecular interactions and identify subnetworks associated with specific BP in CRC and polyps. We observed distinct subnetworks related to rRNA processing and positive regulation of cell proliferation in CRC, and mRNA splicing and cell division in polyps. These subnetworks likely play important roles in the molecular mechanisms underlying the progression of polyps to CRC. The identification of hub genes within the PPI networks provides potential targets for further investigation and therapeutic intervention. The analysis of PPI networks revealed several hub genes that play crucial roles in colorectal polyps and CRC. These hub genes, including
PIK3R1, FYN, FGFR1, BUB1B, CDC20, CDK1, and
CALM1, emerged as highly connected nodes within the networks, suggesting their significance in the molecular processes underlying these conditions. PIK3R1 gene encodes the regulatory subunit of phosphoinositide-3-kinase (PI3K), which is involved in cell growth, proliferation, and survival. Aberrant PIK3R1 expression has been observed in various cancers, including breast cancer and nasopharyngeal carcinoma, where it has been shown to regulate cell proliferation, migration, and invasion [
26,
27]. FYN is a non-receptor tyrosine kinase involved in various cellular processes, including cell growth, differentiation, and adhesion. In diabetic kidney disease, Fyn has been shown to regulate autophagy through the Fyn-STAT3-VPS34 signaling pathway [
28]. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase involved in cell growth, differentiation, and angiogenesis. Aberrant FGFR1 signaling has been reported in many human cancers, including breast cancer, where it is associated with poor prognosis, shorter overall survival, and resistance to endocrine therapies [
29]. BUB1B gene encodes a protein involved in the regulation of cell division and the maintenance of chromosomal stability. Dysregulation of BUB1B has been observed in various cancers, including breast cancer, where it has been shown to be associated with poor prognosis [
30]. Cell division cycle 20 (CDC20) functions as a critical cell cycle regulator and has been implicated in cancer development and drug resistance. Elevated CDC20 expression has been detected in various cancers, including breast cancer, kidney cancer, and lung cancer, and has been associated with poor prognosis and increased tumor grade [
27]. Cyclin-dependent kinase 1 (
CDK1) is a key regulator of cell cycle progression and has been implicated in various cancers. It has been shown to be involved in the regulation of cell proliferation, migration, and invasion in some cancer types [
31]. Calmodulin 1 (CALM1) is a calcium-binding protein involved in the regulation of various cellular processes, including cell proliferation, migration, and invasion. It has been implicated in the regulation of cell growth and survival in some cancer types [
32].
TF analysis revealed the regulatory relationships between TFs and the DEGs in CRC and polyps. We identified specific TFs that may act as major regulators in each condition, as well as common DE-TFs. Notably, certain TFs exhibited differential expression between CRC and polyps. Among these hub genes,
ZNF217, GATA6, and
KLF5 were found to be downregulated, while
STAT3 and
NR3C1 were upregulated. Zinc-finger protein 217 (ZNF217) is thought to be involved in malignant processes in various cancers, such as breast, gastric, colorectal, and prostate cancer. In ovarian cancer, ZNF217 has been shown to play a central role in malignant processes, with silencing of ZNF217 resulting in the effective inhibition of ovarian cancer cell growth and invasiveness [
33]. GATA6 is a TF involved in the regulation of cell differentiation and tissue development. In gastric cancer, GATA6 has been shown to cooperate with other TFs, such as KLF5, to promote cancer development [
34,
35]. In CRC, GATA6 and Krüppel-like factor 5 (KLF5) have been implicated in the regulation of cancer stem cell characteristics and chemoresistance [
36,
37]. Signal transducer and activator of transcription 3 (STAT3) is a TF involved in various cellular processes, including cell growth, differentiation, and survival. In endometrial cancer, silencing of STAT3 has been shown to inhibit cell proliferation, migration, and invasion, as well as induce cell cycle arrest and apoptosis [
38]. Nuclear receptor subfamily 3 group C member 1 (NR3C1) is a nuclear receptor involved in the regulation of various cellular processes, including cell proliferation, differentiation, and apoptosis. In colon cancer, NR3C1 expression has been found to be correlated with miR-200 expression, and this functional relationship might contribute to colon cancer cell survival [
39]. In breast cancer, NR3C1 has been implicated in the regulation of cell growth and survival [
40]. These TFs may contribute to the dysregulation of gene expression and play crucial roles in the progression of CRC.
Our study represents one of the first comprehensive analyses of the shared molecular features between polyp and CRC using a systems biology approach. By elucidating the molecular similarities between these 2 conditions, our findings contribute to the understanding of the molecular basis of polyp formation and CRC development. The identification of common DEGs, the exploration of PPIs, and the analysis of TFs provide valuable insights into the underlying molecular mechanisms and potential therapeutic targets for further investigation.
In conclusion, our study highlights the importance of systems biology approaches in uncovering the shared molecular features and potential mechanisms underlying polyp and CRC. The identification of common DEGs, the exploration of PPIs, and the analysis of TFs provide a comprehensive view of the molecular landscape of these conditions. These findings pave the way for future research focused on developing personalized therapeutic strategies and improving patient outcomes in both polyp and CRC.