Translation regulation in skin cancer from a tRNA point of view

Grafanaki, Katerina; Anastasakis, Dimitrios G.; Kyriakopoulos, George; Skeparnias, Ilias; Georgiou, Sophia; Stathopoulos, Constantinos

doi:10.2217/epi-2018-0176

Cited by 20 publications

(11 citation statements)

References 283 publications

(297 reference statements)

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“…4b). As PERK is a protein kinase and GADD34 a protein phosphatase, which both act on EIF2α 33 , we hypothesized that KDELR3-low cells are primed to activate the PERK-EIF2α arm of the UPR. We knocked down KDELR3 (KD) in both 1205Lu and WM-46 human cell lines (shRNA knockdown, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

et al. 2020

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Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.

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“…As we included tumor and paired normal liver samples from 159 HCC patients for investigation at protein level here, the sample size is much larger than the previous study that included 46 HCC patients (Dietrich et al, 2019), and the results are reliable. In addition, considering the variety of regulatory factors implicated in the process of translation (Grafanaki et al, 2019;Moutinho et al, 2019;Kim et al, 2020), it is understandable to see the inconsistence between the mRNA and protein levels of specific genes. As no significant correlation of NRAS with MKI67 was shown at protein level in HCC, further studies were needed to investigate the specific functions of NRAS in HCC.…”

Section: Discussionmentioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang¹,

Zhang²,

Gao³

et al. 2020

Front. Genet.

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Karyopherin α2 (KPNA2) was reported to be overexpressed and have unfavorable prognostic effects in many malignancies including hepatocellular carcinoma (HCC). Although its contributions to inflammatory response were reported in many studies, its specific associations with immune infiltrations and immune pathways during cancer progression were unclear. Here, we aimed to identify new markers for HCC diagnosis and prognosis through KPNA2-associated immune analyses. RNA-seq expression data of HCC datasets were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. The gene expressions were counts per million normalized. The infiltrations of 24 kinds of immune cells in the samples were evaluated with ImmuCellAI (Immune Cell Abundance Identifier). The Spearman correlations of the immune infiltrations with KPNA2 expression were investigated, and the specific positive correlation of B-cell infiltration with KPNA2 expression in HCC tumors was identified. Fifteen genes in KEGG (Kyoto Encyclopedia of Genes and Genomes) B-cell receptor signaling pathway presented significant correlations with KPNA2 expression in HCC. Among them, GRB2 and NRAS were indicated to be independent unfavorable prognostic factors for HCC overall survival. Clinical Proteomic Tumor Analysis Consortium HCC dataset was investigated to validate the results at protein level. The upregulation and unfavorable prognostic effects of KPNA2 and GRB2 were confirmed, whereas, unlike its mRNA form, NRAS protein was presented to be downregulated and have favorable prognostic effects. Through receiver operating characteristic curve analysis, the diagnostic potential of the three proteins was shown. The RNA-binding proteins (RBPs) of KPNA2, NRAS, and GRB2, downloaded via The Encyclopedia of RNA Interactomes, were investigated for their clinical significance in HCC at protein level. An eight-RBP signature with independent prognostic value and dysregulations in HCC was identified. All the RBPs were significantly correlated with MKI67 expression and at least one of KPNA2, GRB2, and NRAS at protein level in HCC, indicating Zhang et al. KPNA2-Associated Immune Analyses in HCC Frontiers in Genetics | www.frontiersin.org 2 October 2020 | Volume 11 | Article 593273 their roles in HCC progression and the regulation of the three proteins. We concluded that KPNA2, GRB2, NRAS, and their RBPs might have coordinating roles in HCC immunoregulation and progression. They might be new markers for HCC diagnosis and prognosis predication and new targets for HCC immunotherapy.

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“…AKT phosphorylation is induced by mTORC2, a nodal stress sensor. In addition, AKT represents a key mediator and a cross-talk checkpoint between the two signaling pathways, which activates mTORC1 [ 72 ]. Our results suggest that both MAPK and PI3K/AKT pathways contribute to the aberrant downstream signaling, with the latter being more prominent.…”

Section: Discussionmentioning

confidence: 99%

Contribution of miRNAs, tRNAs and tRFs to Aberrant Signaling and Translation Deregulation in Lung Cancer

Skeparnias

Anastasakis

Grafanaki

et al. 2020

Cancers

Self Cite

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Transcriptomics profiles of miRNAs, tRNAs or tRFs are used as biomarkers, after separate examination of several cancer cell lines, blood samples or biopsies. However, the possible contribution of all three profiles on oncogenic signaling and translation as a net regulatory effect, is under investigation. The present analysis of miRNAs and tRFs from lung cancer biopsies indicated putative targets, which belong to gene networks involved in cell proliferation, transcription and translation regulation. In addition, we observed differential expression of specific tRNAs along with several tRNA-related genes with possible involvement in carcinogenesis. Transfection of lung adenocarcinoma cells with two identified tRFs and subsequent NGS analysis indicated gene targets that mediate signaling and translation regulation. Broader analysis of all major signaling and translation factors in several biopsy specimens revealed a crosstalk between the PI3K/AKT and MAPK pathways and downstream activation of eIF4E and eEF2. Subsequent polysome profile analysis and 48S pre-initiation reconstitution experiments showed increased global translation rates and indicated that aberrant expression patterns of translation initiation factors could contribute to elevated protein synthesis. Overall, our results outline the modulatory effects that possibly correlate the expression of important regulatory non-coding RNAs with aberrant signaling and translation deregulation in lung cancer.

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“…The results of the GO and KEGG pathway analyses revealed that the differentially expressed RBPs were significantly enriched in the defense response to virus as well as RNA-and protein translation-related processes that have been linked to the pathogenesis of various human diseases (Scotti and Swanson, 2016;Anastasiadou et al, 2018;Grafanaki et al, 2019). RBPs form the RNP complex that regulates RNA stability and hence, gene expression; dysfunction of the RNP complex can lead to cancer development and progression (Carotenuto et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of an RNA-Binding Protein-Based Prognostic Model for Ovarian Serous Cystadenocarcinoma

Zeng

et al. 2020

Front. Genet.

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Ribonucleic acid-binding proteins (RBPs) are reportedly involved in tumor progression and recurrence; however, the functions and mechanisms of action of RBPs in ovarian serous cystadenocarcinoma (OSC) are not known. To address these issues, gene expression profiles of OSC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression database were compared in order to identify RBPs that are differentially expressed in OSC. We also analyzed the biological functions of these RBPs and their relationship to clinical outcome. There were 190 RBPs that were differentially expressed between OSC and normal tissues, including 93 that were upregulated and 97 that were downregulated. Five of the RBPs were used to construct a prediction model that was evaluated by univariate and multivariate Cox regression analyses. TCGA data were randomly divided into training and test cohorts, and further categorized into high-and low-risk groups according to risk score in the model. The overall survival (OS) of the high-risk group was shorter than that of the low-risk group (training cohort P = 0.0007596; test cohort P = 0.002219). The area under the receiver operating characteristic curve of the training and test cohorts was 0.701 and 0.638, respectively, demonstrating that the model had good predictive power. A nomogram was established to quantitatively describe the relationship between the five prognostic RBPs and OS in OSC, which can be useful for developing individualized management strategies for patients.

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“…4b). As PERK is a protein kinase and GADD34 a protein phosphatase that both act on EIF2α 33 , we hypothesized that KDELR3 -low cells are primed to activate the PERK-EIF2α arm of the UPR. We knocked down KDELR3 (KD) in both 1205Lu and WM-46 human cell lines (shRNA knockdown; Supplementary Fig.…”

Section: Kdelr3 and The Er Stress Response In Metastatic Melanomamentioning

confidence: 99%

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Marie

Sassano

Michalowski

et al. 2019

Preprint

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Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene, KDELR3, whose loss impaired experimental metastasis. In contrast, KDELR1 deficiency enhanced metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover novel targetable pathways for melanoma therapy.Melanoma is an aggressive cancer that frequently progresses to metastatic proficiency. Treatment of metastatic melanoma remains a challenge, highlighting an urgent need to uncover new targets that could be used in the clinic to broaden therapeutic options. In the early 19 th century, Virchow first described cancer cells as being "embryonic-like" 1 . Developmental systems have since proven useful to study melanoma, and melanoma cell plasticity appears to be a key feature of melanoma progression. Melanocyte lineage pathways are a recurring theme in melanoma etiology, reinforcing the importance of uncovering new melanocyte developmental pathways and biology 2-13 . Here we use a genetically engineered mouse (GEM), designed to facilitate the isolation and analysis of developing melanocytes (melanoblasts), to attempt to uncover new targets relevant to melanoma metastasis.Melanocytes are neural crest-derived cells whose development necessitates extensive migration/invasion to populate the skin and other sites 14 . This process requires melanoblasts to adopt a migratory phenotype, to interact with and survive in foreign microenvironments and to colonize distant sites − functions that are analogous to metastatic competence 15 . To complete these processes, the cell may encounter numerous cellular stressors, such as shear stress, nutrient deprivation, hypoxia, lipid stress and oxidative stress 16 . The cellular impact of these stressors converges at the Endoplasmic Reticulum (ER), the organelle tied closely to protein synthesis and responsible for correct protein folding, protein quality control and post-translational modifications.Stress stimuli can result in aberrant ER function, a build-up of unfolded/misfolded proteins (ER stress), and an overwhelmed system. The ER can therefore be viewed as an exquisitely sensitive stress sensor. Upon ER stress insult, the ER launches an immediate counter measure known as of the Unfolded Protein Response (UPR) 17 . T...

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Translation regulation in skin cancer from a tRNA point of view

Cited by 20 publications

References 283 publications

Melanoblast transcriptome analysis reveals pathways promoting melanoma metastasis

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Contribution of miRNAs, tRNAs and tRFs to Aberrant Signaling and Translation Deregulation in Lung Cancer

Development and Validation of an RNA-Binding Protein-Based Prognostic Model for Ovarian Serous Cystadenocarcinoma

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

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