Identification of genes related to ribosomal proteins in colorectal cancer: exploring their potential as biomarkers, prognostic indicators, and therapeutic targets.

BACKGROUND: Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer in both females and males, underscoring the need for the identification of effective biomarkers. METHODS AND RESULTS: We assessed the expression levels of ribosomal proteins (RPs) at both mRNA and protein levels. Subsequently, leveraging the STRING database, we constructed a protein-protein interaction network and identified hub genes. The co-expression network of differentially expressed genes associated with CRC and their target hub RPs was constructed using the weighted gene co-expression network analysis algorithm. Gene ontology and molecular signatures database were conducted to gain insights into the biological roles of genes associated with the identified module. To confirm the results, the expression level of the candidate genes in the CRC samples compared to the adjacent healthy was evaluated by the RT-qPCR method. Our findings indicated that the genes related to RPs were predominantly enriched in biological processes associated with Myc Targets, Oxidative Phosphorylation, and cell proliferation. Also, results demonstrated that elevated levels of GRWD1, MCM5, IMP4, and RABEPK that related to RPs were associated with poor prognostic outcomes for CRC patients. Notably, IMP4 and RABEPK exhibited higher diagnostic value. Moreover, the expression of IMP4 and RABEPK showed a significant association with drug resistance using cancer cell line encyclopedia and genomics of drug sensitivity in cancer databases. Also, the results showed that the expression level of IMP4 and RABEPK in cancerous samples was significantly higher compared to the adjacent healthy ones. CONCLUSION: The general results of this study have shown that many genes related to RPs are increased in cancer and could be associated with the death rate of patients. We also highlighted the therapeutic and prognostic potentials of RPs genes in CRC.

Exploring the role of interleukin 11 in cancer progression, patient survival, and therapeutic insights.

BACKGROUND: The Interleukin (IL)-11 gene, which is one of the members of the cytokine family, has an oncogenic role in some cancers. The main goal of this study is to analyze IL-11 expression level in 14 prevalent cancers and highlights its role in patients' survival, drug resistance, and sensitivities. Also, an association of this gene with metastasis and inflammation pathways has been investigated. METHODS AND RESULTS: Using the cancer genome atlas (TCGA) data, the level of IL-11 expression and its role in prognosis and survival rate were evaluated in 13 common cancers. Then, confirming the obtained in-silico outcomes, the relative expression level of this gene in colorectal cancer (CRC) samples and their adjusted tissues were assayed by the RT-qPCR method. Furthermore, to examine the association between IL-11 expression and drug resistance and sensitivity, PharmacoGX data was applied. The co-expression network was used to recognize the pathways in which IL-11 was involved. The results from the TCGA dataset indicated that the expression level of IL-11 increased significantly in 13 prevalence cancers compared to the control groups. Interestingly, this enhanced expression level is associated with a high rate of mortality in patients with bladder, stomach, colorectal, and endometrial cancers. Also, the co-expression network analysis showed a strong correlation between IL-11 and the genes of metastasis pathway and the genes related to the inflammation process. Finally, regarding drug sensitivity, IL-11 expression level can be introduced as a remarkable biomarker for cancer detection due to area under curve (AUC). CONCLUSION: Altered expression of the IL-11 gene is observed in 13 common cancers and is associated with prognosis and mortality rate in patients. Moreover, this gene can be considered a prognostic biomarker in different types of cancer, such as CRC.

TBX15 and SDHB expression changes in colorectal cancer serve as potential prognostic biomarkers.

Alterations in the expression of certain genes could be associated with both patient mortality rates and drug resistance. This study aimed to identify genes in colorectal cancer (CRC) that potentially serve as hub genes influencing patient survival rates. RNA-Seq data were downloaded from the cancer genome atlas database, and differential expression analysis was performed between tumors and healthy controls. Through the utilization of univariate and multivariate Cox regression analyses, in combination with the MCODE clustering module, the genes whose expression changes were related to survival rate and the hub genes related to them were identified. The mortality risk model was computed using the hub genes. CRC samples and the RT-qPCR method were utilized to confirm the outcomes. PharmacoGx data were employed to link the expression of potential genes to medication resistance and sensitivity. The results revealed the discovery of seven hub genes, which emerged as independent prognostic markers. These included HOXC6, HOXC13, HOXC8, and TBX15, which were associated with poor prognosis and overexpression, as well as SDHB, COX5A, and UQCRC1, linked to favorable prognosis and downregulation. Applying the risk model developed with the mentioned genes revealed a markedly higher incidence of deceased patients in the high-risk group compared to the low-risk group. RT-qPCR results indicated a decrease in SDHB expression and an elevation in TBX15 levels in cancer samples relative to adjacent healthy tissue. Also, PharmacoGx data indicated that the expression level of SDHB was correlated with drug sensitivity to Crizotinib and Dovitinib. Our findings highlight the potential association between alterations in the expression of genes such as HOXC6, HOXC13, HOXC8, TBX15, SDHB, COX5A, and UQCRC1 and increased mortality rates in CRC patients. As revealed by the PPI network, these genes exhibited the most connections with other genes linked to survival.

The expression changes of transcription factors including ANKZF1, LEF1, CASZ1, and ATOH1 as a predictor of survival rate in colorectal cancer: a large-scale analysis.

INTRODUCTION: Transcription factors (TFs) are essential for many biological processes and regulate the expression of several genes. This study's objective was to analyze the abnormalities in TF expression, their impact on patient prognosis, and related pathways in colorectal cancer (CRC). METHOD: The expression alterations of all TFs were investigated using the cancer genome atlas and GSE39582 data. Clinical data were also used to study the association between TFs expression and patient prognosis through the Cox regression test, and a predictive model of CRC patient survival was constructed based on TFs expression. Co-expression network was used to discover TF-related pathways. To validate the findings, the RT-qPCR method was applied to CRC samples and adjacent normal tissue. RESULTS: The findings revealed that ANKZF1, SALL4, SNAI1, TIGD1, LEF1, FOXS1, SIX4, and ETV5 expression levels increased in both cohorts and were linked to the poor prognosis. NR3C2, KLF4, CASZ1, FOXD2, ATOH1, SALL1, and RORC expression, on the other hand, exhibited a significant decrease, and their increase was related to the good prognosis of patients. The patient mortality risk model based on expression of mentioned TFs revealed that, independent of clinical characteristics, the expression of ANKZF1, LEF1, CASZ1, and ATOH1 could accurately predict patient survival rates. According to the co-expression network, increased transcription factors were linked to metastatic pathways, while decreasing TFs were involved to apoptotic pathways. RT-qPCR findings showed that FOXS1 expression was markedly overexpressed in CRC samples. However, in CRC samples, the expression of CASZ1 decreased. CONCLUSION: In CRC, TFs expression of ANKZF1, LEF1, CASZ1 and ATOH1 are deregulated, which are associated with prognosis in patients. According to our findings, changes in the expression of the mentioned TFs have the potential to be considered diagnostic and prognostic biomarkers for CRC patients.

Identification of genes with high heterogeneity of expression as a predictor of different prognosis and therapeutic responses in colorectal cancer: a challenge and a strategy.

BACKGROUND: Molecular heterogeneity is one of the most important concerns in colorectal cancer (CRC), which results in a wide range of therapy responses and patient prognosis. We aimed to identify the genes with high heterogeneity of expression (HHE) and their relation with prognosis and drug resistance. METHODS: Two cohort studies, the cancer genome atlas (TCGA) and the GSE39582, were used to discover oncogenes genes with HHE. The relationship between identified genes with clinical and genomic characteristics was evaluated based on TCGA data. Also, the GDSC and CCLE data were used for drug resistance and sensitivity. Sixty CRC samples were used to validate the obtained data by RT-qPCR. RESULTS: Findings revealed that 132 genes with HHE were found to be up-regulated in both cohorts and were enriched in pathways such as hypoxia, angiogenesis, and metastasis. Forty-nine of selected genes related to clinical and genomic variables, including stage, common mutations, the tumor site, and microsatellite state that were ignored. The expression level of CXCL1, SFTA2, SELE, and SACS as genes with HHE were predicted survival patients, and RT-qPCR results demonstrated that levels of SELE and SACS had HHE in CRC samples. The expression of many identified genes like BGN, MMP7, COL11A1, FAP, KLK10, and TNFRSE11B was associated with resistance to chemotherapy drugs. CONCLUSIONS: Some genes expression, including SELE, SACS, BGN, KLK10, COL11A1, and TNFRSE11B have an oncogenic function with HHE, and their expression can be used as indicators for differing treatment responses and survival rates in CRC.

Elevated CDK5R1 expression associated with poor prognosis, proliferation, and drug resistance in colorectal and breast malignancies: CDK5R1 as an oncogene in cancers.

BACKGROUND: Studies have shown that the CDK5R1 gene could have a part in some types of cancer. This study sought to examine the relationship between CDK5R1 expression and prognosis and medication resistance in 13 commonly occurring cancers. METHOD: The cancer genome atlas data and clinical data were utilized to assess the role of CDK5R1 in malignancies. The expression data of 13 cancers were also integrated and used for the co-expression network. The relationship between CDK5R1 expression and drug resistance and sensitivity was evaluated using pharmacogenomics data. The colorectal cancer (CRC) and breast cancer (BC) were used to confirm the results through the RT-qPCR method. RESULTS: With the exception of gastric cancer, all common malignancies showed an increase in CDK5R1 expression. Also, outcomes of sensitivity and specificity showed that CDK5R1 level could be a really good potential biomarker. Additionally, CDK5R1 expression was higher in CRC and BC samples compared to adjacent normal, according to RT-qPCR data. In six types of tumors and combined data, a poor prognosis was associated with increased CDK5R1 expression. The CDK5R1-associated genes were connected to the primary oncogenic pathways in cancer cells, according to the co-expression network. Also, CDK5R1 level was significantly linked to the resistance and sensitivity of several chemotherapy drugs and caused the highest resistance to cyclophosphamide. CONCLUSION: CDK5R1 expression is upregulated in 12 prevalent cancers and can play an oncogenic role. Also, this gene's expression could be used as a biomarker to predict patient survival and medication resistance.

Identification of a novel interplaying loop of PPARγ and respective lncRNAs are involved in colorectal cancer progress.

Long noncoding RNAs (lncRNAs) as regulatory molecules play important roles in early treatment and diagnosis of cancers. Considering the role of PPARγ in colorectal cancer (CRC) as a tumor suppressor, the GEO database was used to identify candidate genes that affect the activation of PPARγ protein in CRC cell lines. Then were selected 5 genes containing PPARγ response element (PPRE) in up to 4000 bp upstream and were affected by PPARγ protein activation in HT-29 colon cancer cell line using UCSC database. Expression meta-analysis was applied to map the expression network between candidate genes and all known lncRNAs through expression correlation and lncRNAs that correlated with a greater number of candidate genes (R > 0.5, P.value < 0.001). Moreover, were selected 3 lncRNAs as lncRNAs affected by PPARγ protein activation. Next, the expression levels of candidate genes and lncRNAs were evaluated using RT-qPCR in HT-29 cell line. Results showed a significant increase (FDR <0.05) in the expression level of 5 candidate genes and lncRNAs LINC01133, MBNL1-AS, LOC100288911 after treatment with pioglitazone as PPARγ ligand compared to the untreated group in HT-29 cells. Although additional tests are needed to confirm bioinformatics predictions, it can be concluded that increased expression of PPARγ may increase genes and lncRNAs expression. In summary, this study could be suggested identifying lncRNAs affected by PPARγ activation could be a new strategy in understanding the function and activity of PPARγ in colon cancer.

Title: Involvement of unsaturated fatty acid biosynthesis in CRC progression based on in vitro and in silico studies.

Obesity is one of the risk factors concerns of colorectal cancer (CRC), the most common type of gastrointestinal cancer, due to the changing lifestyle and especially diet. There are various molecular pathways associated with obesity and the risk of CRC incidence, such as insulin resistance or elevated plasma free fatty acids, which alter the signaling pathways of intestinal epithelial cells. The aim of this study was to better understand the significance of unsaturated fatty acid biosynthesis on pathogenesis of colon cancer in obese. Based on GSE20931 dataset, obese individuals affected by CRC had higher increased gene expression than non-obese individuals. The analysis showed that in obese individuals, the 16 signaling pathway genes were activated and increased (FDR <0.05) significantly. The biosynthetic pathway of unsaturated fatty acids showed a cross-talk with the arachidonic acid metabolism pathway and the PPAR signaling pathway is influenced and regulated via these pathways. The biosynthetic pathway of unsaturated fatty acids consisting of 22 genes, were analyzed using GEO data and revealed that 4 genes (HSD17B12, TECR, FADS2, ELOVL5) from this pathway were significantly increased (FDR <0.05). These data were validated based on TCGA data (Adj.p.value <0.001). The expression level of candidate genes in HT-29 cells decreased significantly (P.value <0.01), and PPARγ expression increased under linoleic acid treatment (200 µM) compared to control cells. Moreover, in presence of linoleic acid treatment, migration, colony formation, and proliferation decreased (P.value <0.01) in presence of treatment. In summary, the Biosynthesis pathway of unsaturated fatty acids is an interesting and critical pathway in CRC.

Introduction of mutant TP53 related genes in metabolic pathways and evaluation their correlation with immune cells, drug resistance and sensitivity.

BACKGROUND: Although the relationship between TP53 mutation, TP53 metabolism pathways, and tumorigenesis has been investigated, pan-cancer analysis of TP53 mutations and related metabolism pathways is not completely available in common types of human cancers. Thus, this study was going to represent TP53 mutant-related metabolism genes and pathways in a pan-cancer study and investigate the relationship between selected genes and drug resistance. METHODS: The DNA-seq data, RNA-seq data, and clinical information of 12 types of cancer were downloaded from the cancer genome atlas (TCGA) database. GSE70479 data were obtained from GEO database for validation of our TCGA data. To evaluate the survival rate of patients, GEPIA2 was applied. The CCLE and GDSC database were used to investigate drug resistance and sensitivity. RESULTS: Our findings indicated that TTN, MUC16, and TP53 were present in 12 types of cancer with high level of mutation frequency which abundance of TP53 mutations was higher. Mutant TP53-related (mTP53) pathways and genes including PKM, SLC16A3, HK2, PFKP, PHGDH, and CTSC were obtained from enrichment analysis and interestingly, top pathways were associated with metabolism including glycolysis and mTORC1 pathway. Our results showed the expression of some candidate genes correlated with immune markers, prognosis, and drug resistance. CONCLUSIONS: Top mutant genes for 12 cancers were highlighted while TP53 was selected as top mutant gene, and metabolic genes associated with the TP53 mutation were identified that some of which are important in poor prognosis. In doing so, mutations in TP53 could run some metabolic pathways and drug resistance and sensitivity.

Steroid receptor RNA activator gene footprint in the progression and drug resistance of colorectal cancer through oxidative phosphorylation pathway.

BACKGROUND: The steroid receptor RNA activator 1 (SRA1) gene is involved in the progression of various cancers via different molecular mechanisms mediated by long non-coding RNA SRA (lncRNA SRA). This study aimed to evaluate the lncRNA SRA effect on the tumor progression of colorectal cancer (CRC). METHODS: SRA1 expression was assessed in the cancer genome atlas datasets, CRC cell lines, and tumor specimens. Meta-analysis and gene co-expression network analysis were performed to identify pathways related to SRA1. RNA interference and cell treatment were utilized to examine the role of SRA1 expression in HT-29 and Caco-2 cell lines. Also, the effect of SRA1 expression was investigated on drug resistance, clinical parameters, and mutations in CRC samples. RESULTS: The SRA1 transcripts, especially lncRNA SRA, were dysregulated in CRC tissue samples compared with normal tissue samples. Furthermore, SRA1 depletion decreased colony formation and proliferation while induced apoptosis in HT-29 and Caco-2 cells. In silico analyses indicated that SRA1 level was correlated with expression levels of oxidative phosphorylation (OXPHOS) genes. LncRNA SRA expression increased in response to the increased oxidative capacity, and when lncRNA SRA was knocked down, the expression level of OXPHOS pathway genes, including NDUFB5 and ATP5F1B, was changed. Also, KRAS-mutant samples had the highest SRA1 expression level. CONCLUSIONS: LncRNA SRA could function as an oncogene through the OXPHOS pathway in CRC, and serve as a potential biomarker for identifying CRC subtype with KRAS mutations. The findings suggest that lncRNA SRA might be a therapeutic target to inhibit cell proliferation in CRC.

The role of cell surface proteins gene expression in diagnosis, prognosis, and drug resistance of colorectal cancer: In silico analysis and validation.

Cell surface proteins (CSPs) are an important type of protein in different essential cell functions. This study aimed to distinguish overexpressed CSPs in colorectal cancer to investigate their biomarker, prognosis, and drug resistance potential. Raw data of three datasets including 1187 samples was downloaded then normalization and differential expression were performed. By the combination of the cancer genome atlas (TCGA) clinical data, survival analysis was carried out. Information of all CSPs was collected from cell surface protein atlas. The role of each candidate gene expression was investigated in drug resistance by CCEL and GDSC data from PharmacoGX. CRC samples including 30 tumor samples and adjacent normal were used to confirm data by RT-qPCR. Outcomes showed that 66 CSPs overexpressed in three datasets, and 146 CSPs expression associated with poor prognosis features in TCGA data that TIMP1 and QSOX2 can associate with poor patient survival independently. High-risk patients illustrated more fatality than low-risk patients based on the risk score calculated by the expression level of these genes. Receiver operating characteristic curve analysis showed that 39 CSPs as perfect biomarkers for diagnosis in CRC. Furthermore, QSOX2 and TIMP1 expression levels increased in tumor samples compared to adjacent normal samples. The Drug resistance analysis demonstrated ADAM12 and COL1A2 up-regulation among 66 overexpressed CSPs caused resistance to Venetoclax and Cyclophosphamide with a high estimate, respectively. Many CSPs are deregulated in CRC, and can be valuable candidates as biomarkers for diagnosis, prognosis, and drug resistance.