New Pancreatic Cancer Biomarkers eIF1, eIF2D, eIF3C and eIF6 Play a Major Role in Translational Control in Ductal Adenocarcinoma

Golob-Schwarzl, Nicole; Puchas, Philip; Gogg-Kamerer, Margit; Weichert, Wilko; Göppert, Benjamin; Haybaeck, Johannes

doi:10.21873/anticanres.14292

Cited by 24 publications

(26 citation statements)

References 28 publications

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“…Differentially expressed genes of LINC01133 marked Cluster 0 were also input into IPA and the top Ingenuity Canonical Pathways and Upstream Regulators were also presented. Top pathways, including Oxidative Phosphorylation, EIF2 Signaling and Mitochondrial Dysfunction, were closely associated with stem and immunoevasive properties ( 33 ), tumor biology ( 42 ) and cancer metabolic phenotypes ( 43 ) of pancreatic cancer. Taken together, these ingenuity canonical pathways and upstream regulator analysis consistently confirmed our observation in scRNA-seq data and further identified the MEG + metastatic cancer cell cluster as the leader of cancer cell EMT and metastasis.…”

Section: Resultsmentioning

confidence: 99%

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence worldwide. Late detection and particularly aggressive characteristics are the major challenges that lead to therapeutic failure of this disease. A well described gene program and core regulators are yet to be discovered to drive the metastasis of the PDAC cells. As the development of single cell omics technologies including single cell RNA-sequencing (scRNA-seq), detailed characterization of the cellular composition of solid tumors and their microenvironments are well elaborated. In the current study, we accessed a recently published scRNA-seq dataset on primary and metastatic PDAC tissues and subset the tumor cells. By comparative analysis, we profiled the differentially expressed gene programs of primary and metastatic PDAC and found several long intergenic non-coding RNAs (LincRNAs) in top genes. The PDAC cancer cells showed some heterogeneity and were divided into four major subclusters based on gene profiles, one of which was mostly contributed by metastatic PDAC. Interestingly, this subcluster was remarkably marked by one of the above LincRNAs, MEG3, and exhibited significantly increased Epithelial–Mesenchymal-Transition (EMT) signatures. Ingenuity Pathway Analysis (IPA) on the signature genes of this subcluster gave multiple cancer metastasis associated and EMT signaling pathways, suggesting a critical role of this cluster in leading tumor cell metastasis. Taken together, this study displayed a PDAC cancer subcluster and its marker gene, biologically targeting of which might significantly attenuate the metastasis of tumor and might be a potential strategy for the therapeutic treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

et al. 2021

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“…For example, when disordered or overexpressed, eIF4E can trigger neoplastic transformation and result in tumorigenesis via regulating the conventional translation rate of speci c proteins, and patients with eIF4E-high expression tend to have a relatively dismal prognosis [8,9]. In contrast, obvious deletion of eIF1 is revealed in pancreatic cancer samples compared with non-neoplastic pancreatic tissue [10]. From this perspective, interpreting the function of eIFs in protein synthesis can be conducive to discovering the molecular mechanisms involved in cancer progression.…”

Section: Introductionmentioning

confidence: 99%

eIF6 Promotes the Malignant Progression of Human Hepatocellular Carcinoma via the mTOR Signaling Pathway

Sun

Wang

Zheng³

et al. 2020

Preprint

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Background Eukaryotic translation initiation factor 6 (eIF6) has a crucial function in the maturation of 60S ribosomal subunits, and it controls the initiation of protein translation. Although emerging studies indicate that eIF6 is aberrantly expressed in various types of cancers, the functions and underlying molecular mechanisms of eIF6 in the pathological progression of hepatocellular carcinoma (HCC) remain unclear. This study aimed to evaluate the potential diagnostic and prognostic value of eIF6 in patients with HCC. Methods HCC samples enrolled from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and our cohort were used to explore the role and mechanism of eIF6 in HCC. The diagnostic power of eIF6 was verified by receiver operating characteristic curve (ROC) analysis and its prognostic value was assessed by Kaplan-Meier analysis, and then related biological functions of eIF6 were determined in vitro and in vivo cancer models. In addition, potential molecular mechanism of eIF6 in HCC was unveiled by the gene set enrichment analysis and western blot assay. Results We demonstrated that eIF6 expression was markedly increased in HCC, and elevated eIF6 expression correlated with pathological progression of HCC. Besides, eIF6 served as not only a new diagnostic biomarker but also an independent risk factor for OS in HCC patients. Functional studies indicated that the deletion of eIF6 displayed tumor-suppressor activity in HCC cells. Furthermore, we found that eIF6 could activate the mTOR-related signaling pathway and regulate the expression level of its target genes, such as CCND1, CDK4, CDK6, MYC, CASP3 and CTNNBL1, and these activities promoted proliferation and invasion of HCC cells. Conclusions The findings of this study provided a novel basis for understanding the potential role of eIF6 in promoting tumor growth and invasion, and exploited a promising strategy for improving diagnosis and prognosis of HCC.

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“…A threshold set at three standard deviations above the background was chosen to compare the performance of the three Dz. [24] With this threshold, BiRDz, DTh-2i and DTh-3i would be activated with 42, 630 and 1100 pM miR-17, respectively. The data indicates that the proposed approach can modulate the RNA cleaving activities of the Dz constructs within more than one order of magnitude of miR concentration.…”

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confidence: 99%

“…Next, we tailored the RNA-binding arms of the BiRDz, DTh-2i and DTh-3i to bind mRNA fragment of eukaryotic translation initiation factor 3 subunit C EIF3C gene (RNA-60) [24] and mRNA coding for DAD1 (RNA-46), the defender against apoptotic cell death protein. [24] Both genes are known to be essential for cell survival. [24,25] The structure of DTh-3i-60 with RNA-binding Arm 1 and 2 tailored to cleave RNA-60 is shown in Figure 2A (see Figure S4 for more details).…”

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confidence: 99%

“…[24] Both genes are known to be essential for cell survival. [24,25] The structure of DTh-3i-60 with RNA-binding Arm 1 and 2 tailored to cleave RNA-60 is shown in Figure 2A (see Figure S4 for more details). For DTh-3i-46, the RNA-46 cleavage product was visible in gel starting from 200 nM miR-17, while for BiRDz-60 and DTh-2i-60, the notable cleavage product band was observed at a lower miRNA concentration (Figure 2B).…”

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confidence: 99%

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RNA‐Cleaving DNA Thresholder Controlled by Concentrations of miRNA Cancer Marker

et al. 2021

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Oligonucleotide gene therapy (OGT) agents suppress specific mRNAs in cells and thus reduce the expression of targeted genes. The ability to unambiguously distinguish cancer from healthy cells can solve the low selectivity problem of OGT agents. Cancer RNA markers are expressed in both healthy and cancer cells with a higher expression level in cancer cells. We have designed a DNA‐based construct, named DNA thresholder (DTh) that cleaves targeted RNA only at high concentrations of cancer marker RNA and demonstrates low cleavage activity at low marker concentrations. The RNA‐cleaving activity can be adjusted within one order of magnitude of the cancer marker RNA concentration by simply redesigning DTh. Importantly, DTh recognizes cancer marker RNA, while cleaving targeted RNA; this offers a possibility to suppress vital genes exclusively in cancer cells, thus triggering their death. DTh is a prototype of computation‐inspired molecular device for controlling gene expression and cancer treatment.

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New Pancreatic Cancer Biomarkers eIF1, eIF2D, eIF3C and eIF6 Play a Major Role in Translational Control in Ductal Adenocarcinoma

Cited by 24 publications

References 28 publications

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

eIF6 Promotes the Malignant Progression of Human Hepatocellular Carcinoma via the mTOR Signaling Pathway

RNA‐Cleaving DNA Thresholder Controlled by Concentrations of miRNA Cancer Marker

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