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EIF4E binding protein 1 expression is associated with clinical survival outcomes in colorectal cancer.

ABSTRACT: eIF4E binding protein 1 (4E-BP1), is critical for cap-dependent and cap-independent translation. This study is the first to demonstrate that 4E-BP1 expression correlates with colorectal cancer (CRC) progression. Compared to its expression in normal colon epithelial cells, 4E-BP1 was upregulated in CRC cell lines and was detected in patient tumor tissues. Furthermore, high 4E-BP1 expression was statistically associated with poor prognosis. Hypoxia has been considered as an obstacle for cancer therapeutics. Our previous data showed that YXM110, a cryptopleurine derivative, exhibited anticancer activity via 4E-BP1 depletion. Here, we investigated whether YXM110 could inhibit protein synthesis under hypoxia. 4E-BP1 expression was notably decreased by YXM110 under hypoxic conditions, implying that cap-independent translation could be suppressed by YXM110. Moreover, YXM110 repressed hypoxia-inducible factor 1? (HIF-1?) expression, which resulted in decreased downstream vascular endothelial growth factor (VEGF) expression. These observations highlight 4E-BP1 as a useful biomarker and therapeutic target, indicating that YXM110 could be a potent CRC therapeutic drug.

SUBMITTER: Chao MW

PROVIDER: S-EPMC4695172 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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eIF4E binding protein 1 expression is associated with clinical survival outcomes in colorectal cancer.

Chao Min-Wu MW Wang Li-Ting LT Lai Chin-Yu CY Yang Xiao-Ming XM Cheng Ya-Wen YW Lee Kuo-Hsiung KH Pan Shiow-Lin SL Teng Che-Ming CM

Oncotarget 20150901 27

eIF4E binding protein 1 (4E-BP1), is critical for cap-dependent and cap-independent translation. This study is the first to demonstrate that 4E-BP1 expression correlates with colorectal cancer (CRC) progression. Compared to its expression in normal colon epithelial cells, 4E-BP1 was upregulated in CRC cell lines and was detected in patient tumor tissues. Furthermore, high 4E-BP1 expression was statistically associated with poor prognosis. Hypoxia has been considered as an obstacle for cancer the ...[more]

PMID: 26204490

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Project description:Tri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics.Extracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman's rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts.Increased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p=0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts.Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.

Project description:BackgroundSelenium-binding protein 1 (SELENBP1), a member of the selenium-containing protein family, plays an important role in malignant tumorigenesis and progression. However, it is currently lacking research about relationship between SELENBP1 and immunotherapy in colorectal cancer (CRC).MethodsWe first analyzed the expression levels of SELENBP1 based on the Cancer Genome Atlas (TCGA), Oncomine andUALCAN. Chisq.test, Fisher.test, Wilcoxon-Mann-Whitney test and logistic regression were used to analyze the relationship of clinical characteristics with SELENBP1 expression. Then Gene ontology/ Kyoto encyclopedia of genes and genomes (GO/KEGG), Gene set enrichment analysis (GSEA) enrichment analysis to clarify bio-processes and signaling pathways. The cBioPortal was used to perform analysis of mutation sites, types, etc. of SELENBP1. In addition, the correlation of SELENBP1 gene with tumor immune infiltration and prognosis was analyzed using ssGSEA, ESTIMATE, tumor immune dysfunction and rejection (TIDE) algorithm and Kaplan-Meier (KM) Plotter database. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to validate the expression of SELENBP1 in CRC samples and matched normal tissues. Immunohistochemistry (IHC) was further performed to detect the expression of SELENBP1 in CRC samples and matched normal tissues.ResultsWe found that SELENBP1 expression was lower in CRC compared to normal colorectal tissue and was associated with poor prognosis. The aggressiveness of CRC increased with decreased SELENBP1 expression. Enrichment analysis showed that the SELENBP1 gene was significantly enriched in several pathways, such as programmed death 1 (PD-1) signaling, signaling by interleukins, TCR signaling, collagen degradation, costimulation by the CD28 family. Decreased expression of SELENBP1 was associated with DNA methylation and mutation. Immune infiltration analysis identified that SELENBP1 expression was closely related to various immune cells and immune chemokines/receptors. With increasing SELENBP1 expression, immune and stromal components in the tumor microenvironment were significantly decreased. SELENBP1 expression in CRC patients affects patient prognosis by influencing tumor immune infiltration. Beside this, SELENBP1 expression is closely related to the sensitivity of chemotherapy and immunotherapy.ConclusionsSurvival analysis as well as enrichment and immunoassay results suggest that SELENBP1 can be considered as a promising prognostic biomarker for CRC. SELENBP1 expression is closely associated with immune infiltration and immunotherapy. Collectively, our study provided useful information on the oncogenic role of SELENBP1, contributing to further exploring the underlying mechanisms.

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EIF4E binding protein 1 expression is associated with clinical survival outcomes in colorectal cancer.

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eIF4E binding protein 1 expression is associated with clinical survival outcomes in colorectal cancer.

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