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Colorectal cancer (CRC) is a major leading cause of cancer mortality worldwide in which dysregulated protein synthesis plays an etiologic role. The eukaryotic elongation factor 1 A1 (eEF1A1) exerts significant effects on protein synthesis by contributing to peptide chain extension. Whereas its role in CRC remains to be investigated. In this study, we found that the mRNA and protein levels of eEF1A1 were significantly upregulated in CRC cell lines and tissues. Elevated expression of eEF1A1 was correlated with shorter overall survival in 94 CRC patients. The inhibition of proliferation and cell cycle block were observed in CRC cells after eEF1A1 downregulation. Mechanistically, weighted gene correlation network analysis and further Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that mitogen‐activated protein kinases (MAPKs) signaling pathways were significantly enriched in high‐eEF1A1 expression group, and the levels of phosphorylated p38/JNK/ERK MAPK were dramatically decreased after eEF1A1 downregulation. Overexpression of eEF1A1 in CRC correlated with a poor prognosis. Collectively, this study determined the oncogenic role of eEF1A1 in CRC proliferation and tumorigenesis. eEF1A1 might be a promising therapeutic target and prognostic biomarker in CRC. [ABSTRACT FROM AUTHOR]

• First report on the link between alternative splicing and colorectal cancer. • 15-AS prognostic model identified as an independent CRC prognostic factor. • 15-AS prognostic model correlates with immune cell infiltration and therapy sensitivity. • Potential regulatory role of BCAS1 in ANO7 splicing event in CRC discovered. • Single-cell sequencing shows BCAS1 and ANO7 distribution in cancer stem cells. This study aims to comprehensively analyze alternative splicing (AS) features in colorectal cancer (CRC) using integrative multi-omics and to elucidate their relationship with the CRC immune microenvironment. Transcriptomic data, clinical information, and Percent Spliced In (PSI) values of AS events for CRC patients were obtained from The Cancer Genome Atlas (TCGA) and TCGA SpliceSeq databases. Differentially expressed AS events were identified. Univariate Cox analysis was used to pinpoint prognosis-related AS events. A prognostic risk model was developed and validated using multivariate Cox analysis, patient survival analysis, and the area under the receiver operating characteristic (ROC) curve (AUC). Gene Set Enrichment Analysis (GSEA), immune infiltration, immunotherapy, chemotherapy sensitivity analyses, and regulatory relationships between AS events and splicing factors (SFs) were conducted. Single-cell sequencing was used to study the distribution of key factors. siRNA and overexpression vectors were utilized to silence/overexpress BCAS1 in CRC cells and evaluate their effects on cell growth, migration, and invasion. Furthermore, the interaction between BCAS1 and ANO7 pre-mRNA was investigated using RIP-PCR. 82 prognosis-related AS events were identified in CRC patients. A 15-AS prognostic model was constructed, which correlated with immune cell infiltration and showed differences in immunotherapy and chemotherapy sensitivity. BCAS1 was identified as a potential regulator of the ANO7|58341|AT splicing event in CRC. Single-cell sequencing analysis revealed the distribution of BCAS1 and ANO7 in cancer stem cells. In vitro experiments demonstrated that overexpression of BCAS1 and silencing of ANO7 inhibit the proliferation, migration, and invasion of CRC cells. Moreover, BCAS1 suppresses the progression of CRC by modulating ANO7 alternative splicing. This study provides new insights into the role of alternative splicing in colorectal cancer, particularly the potential regulatory action of BCAS1 on the ANO7|58341|AT splicing event. It also identifies the impact of alternative splicing on the tumor microenvironment and potential implications for immunotherapy, highlighting its relevance for the in-depth study and treatment of CRC. [ABSTRACT FROM AUTHOR]

Metastasis is a well-known poor prognostic factor and primary cause of mortality in patients with colorectal cancer (CRC). Recently, with the progress of high through-put sequencing, aberrantly expressed non-coding RNAs (ncRNAs) were found to participate in the initiation and development of cancer. However, the mechanisms of ncRNA-mediated regulation of metastasis in CRC remain largely unknown. In this study, we systematically analyzed the expression network of microRNAs (miRNAs) and genes in CRC metastasis using bioinformatics, and discovered that the miR-581/SMAD7 axis could be a potential factor that drives CRC metastasis. A dual luciferase report assay and protein analysis confirmed the binding relationship between miR-581 and SMAD7. Further functional assays revealed that miR-581 inhibition could suppress cell proliferation and induce apoptosis in SW480 cells. Up-regulation or down-regulation of miR-581 could both affect cell invasion capacity and modulate epithelial to mesenchymal transition (EMT) via a SMAD7/TGFβ signaling pathway. In conclusion, our findings elucidated that miR-581/SMAD7 could be essential for CRC metastasis, and may serve as a potential therapeutic target for CRC patients. [ABSTRACT FROM AUTHOR]

Growing evidence has indicated that prognostic biomarkers have a pivotal role in tumor and immunity biological processes. TP53 mutation can cause a range of changes in immune response, progression, and prognosis of colorectal cancer (CRC). Thus, we aim to build an immunoscore prognostic model that may enhance the prognosis of CRC from an immunological perspective. We estimated the proportion of immune cells in the GSE39582 public dataset using the CIBERSORT (Cell type identification by estimating relative subset of known RNA transcripts) algorithm. Prognostic genes that were used to establish the immunoscore model were generated by the LASSO (Least absolute shrinkage and selection operator) Cox regression model. We established and validated the immunoscore model in GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) cohorts, respectively; significant differences of overall survival analysis were found between the low and high immunoscore groups or TP53 subgroups. In the multivariable Cox analysis, we observed that the immunoscore was an independent prognostic factor both in the GEO cohort (HR (Hazard ratio) 1.76, 95% CI (confidence intervals): 1.26–2.46) and the TCGA cohort (HR 1.95, 95% CI: 1.20–3.18). Furthermore, we established a nomogram for clinical application, and the results suggest that the nomogram is a better predictive model for prognosis than immunoscore or TNM staging. [ABSTRACT FROM AUTHOR]

MiRNA regulation is a crucial way of epigenetic changes. Mir-32 has been reported in several studies as an oncogene, however, its role and target in colorectal cancer (CRC) remains unclear. In this study, we aimed to explore the role of miR-32 in CRC using bioinformatic analysis and functional assays. We collected 28 pairs of CRC tumor tissues and adjacent normal tissues and confirmed miR-32 was significantly upregulated in CRC. Expression and clinical data from The Cancer Genome Atlas (TCGA) identified miR-32 expression is associated with CRC lymphatic invasion, metastasis, and correlates with patients’ poor survival. Functional studies demonstrated that overexpression of miR-32 in LoVo cells promoted cell proliferation and migration, whereas inhibition of miR-32 in HCT 116 cells showed the opposite results. Using bioinformatics, we identified Bone morphogenetic protein 5 (BMP5) is a direct target of miR-32, and loss of tumor suppressor BMP5 may partially due to the miR-32 dysregulation. The inverse correlation between miR-32 and BMP5 was observed in CRC, especially in advanced tumor patients. Moreover, cotransfection of miR-32 mimics and BMP5 recombinant vector in LoVo cells demonstrated that BMP5 could reverse the oncomir effect of miR-32. Taken together, our results suggested a significant role of miR-32/BMP5 axis in CRC tumorigenesis. [ABSTRACT FROM AUTHOR]