Prognostic and Predicted Significance of FENDRR in Colon and Rectum Adenocarcinoma

BackgroundThe role of fetal-lethal non-coding developmental regulatory RNA (FENDRR) has been explored in various cancers; however, its relationship with colon adenocarcinoma/rectum adenocarcinoma (COAD/READ) remains unclear. The objectives of this study were to identify and assess any associations between FENDRR and COAD/READ using The Cancer Genome Atlas (TCGA) database and the Genetic Data Commons (GDC) Data Portal.MethodsThe records of patients with COAD/READ were collected from the GDC Data Portal. After comparing the expression level of FENDRR in COAD/READ and healthy tissues, we evaluated the association of FENDRR with clinicopathological characters and the survival rate, the impact of FENDRR on prognosis, the biological function of FENDRR, and the relative abundance of tumor-infiltrating immune cells in patients with COAD/READ. Moreover, we aimed to construct a protein-protein interaction (PPI) network for selecting genes and a ceRNA network for presenting mRNA-miRNA-lncRNA interactions.ResultsIn patients with COAD/READ, FENDRR expression could differentiate tumor tissues from the adjacent healthy tissues since it was significantly lower in the former than in the latter. High FENDRR expression was correlated with poorer survival and higher tumor stage, current tumor stage, and metastasis stage, and also exhibited high scores for apoptosis, autophagy, and senescence. Immune cell infiltration analysis showed that the high expression group had significantly lower immune and stromal scores. Low FENDRR expression was correlated with poor overall survival (OS), and thus, it could serve as an independent risk factor. The prognostic models constructed in the study performed well for the prediction of OS and disease-specific survival (DFS) using FENDRR expression. Gene set enrichment analysis revealed that vascular smooth muscle contraction, melanogenesis, basal cell carcinoma, and Hedgehog signaling pathways were significantly enriched in patients with high FENDRR expression. Eight hub genes, namely, PKM, ALDOA, PFKP, ALDOC, PYGL, CTNNB1, PSMA5, and WNT5A, were selected from the PPI network, and a ceRNA network was constructed based on the differentially expressed mRNAs, miRNAs, and lncRNAs to illustrate their regulatory relationships.ConclusionFENDRR may serve as a potential biomarker for the diagnosis and prognosis of COAD/READ.

miR-376a Provokes Rectum Adenocarcinoma Via CTC1 Depletion-Induced Telomere Dysfunction

CTC1 is a component of the mammalian CST (CTC1–STN1–TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3′-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression via CTC1 downregulating induced telomere dysfunction.

A Ten-N6-Methyladenosine (m6A)-Modified Gene Signature Based on a Risk Score System Predicts Patient Prognosis in Rectum Adenocarcinoma

ObjectivesThe study aims to analyze the expression of N6-methyladenosine (m6A)-modified genes in rectum adenocarcinoma (READ) and identify reliable prognostic biomarkers to predict the prognosis of READ.Materials and MethodsRNA sequence data of READ and corresponding clinical survival data were obtained from The Cancer Genome Atlas (TCGA) database. N6-methyladenosine (m6A)-modified genes in READ were downloaded from the “m6Avar” database. Differentially expressed m6A-modified genes in READ stratified by different clinicopathological characteristics were identified using the “limma” package in R. Protein-protein interaction (PPI) network and co-expression analysis of differentially expressed genes (DEGs) were performed using “STRING” and Cytoscape, respectively. Principal component analysis (PCA) was done using R. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were used to functionally annotate the differentially expressed genes in different subgroups. Univariate Cox regression analyses were conducted to identify the powerful independent prognostic factors in READ associated with overall survival (OS). A robust likelihood-based survival model was built using the “rbsurv” package to screen for survival-associated signature genes. The Support Vector Machine (SVM) was used to predict the prognosis of READ through the risk score of survival-associated signature genes. Correlation analysis were carried out using GraphPad prism 8.ResultsWe screened 974 differentially expressed m6A-modified genes among four types of READ samples. Two READ subgroups (group 1 and group 2) were identified by K means clustering according to the expression of DEGs. The two subgroups were significantly different in overall survival and pathological stages. Next, 118 differentially expressed genes between the two subgroups were screened and the expression of 112 genes was found to be related to the prognosis of READ. Next, a panel of 10 survival-associated signature genes including adamtsl1, csmd2, fam13c, fam184a, klhl4, olfml2b, pdzd4, sec14l5, setbp1, tmem132b was constructed. The signature performed very well for prognosis prediction, time-dependent receiver-operating characteristic (ROC) analysis displaying an area under the curve (AUC) of 0.863, 0.8721, and 0.8752 for 3-year survival rate, prognostic status, and pathological stage prediction, respectively. Correlation analysis showed that the expression levels of the 10 m6A-modified genes were positively correlated with that of m6A demethylase FTO and ALKBH5.ConclusionThis study identified potential m6A-modified genes that may be involved in the pathophysiology of READ and constructed a novel gene expression panel for READ risk stratification and prognosis prediction.

Gene signature and prognostic merit of M6a regulators in colorectal cancer

Although new diagnostic techniques and treatments are increasingly updated, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to evaluate gene signature and prognostic ability of N6-methyladenosine in CRC. We used the gene expression, copy number variation, simple nucleotide variation and clinical messages from The Cancer Genome Atlas database. We first identified mutation and copy number variations of N6-methyladenosine regulatory genes in both colon adenocarcinoma and rectum adenocarcinoma. Fourteen of all 17 N6-methyladenosine regulatory genes were related with higher mRNA expression, whereas deletion leads to reduced expression. Using univariate Cox regression analysis, RBM15, YTHDC2, and METTL14 genes in the rectum adenocarcinoma samples were conspicuously associated with the prognosis of patients. Based on the least absolute shrinkage and selection operator regression models, we built a 2-gene (YTHDC2 and IGF2BP3) signature of N6-methyladenosine regulators with prognostic ability. The 1-, 3-, and 5-year AUCs of this signature were all greater than 0.6, and the P-value for risk prediction for patients was also less than 0.0001. Moreover, high IGF2BP3 gene expression was significantly associated with IFN-γ in colon adenocarcinoma , and related to the azurophil granule membrane pathway in rectum adenocarcinoma. High YTHDC2 expression in colon adenocarcinoma is closely related to cell energy metabolism. In the rectum adenocarcinoma, high YTHDC2 gene expression is related to the cell centrosome pathway. In conclusion, for the first time, we identified genetic changes of N6-methyladenosine modulators and built a prognostic gene signature in CRC. Impact statement Although new diagnostic techniques and treatments are increasingly updated for CRC, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine (m6A) as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to identify gene signature and prognostic ability of m6A modulators in CRC. For the first time, we identified genetic changes of m6A modulators and built prognostic gene signature in CRC, which may provide effective targets for the diagnosis and management of CRC.