Identification of<i>IL11RA</i>and<i>MELK</i>amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines

Calcagno, Danielle Queiroz; Takeno, Sylvia Santomi; Gigek, Carolina Oliveira; Leal, Mariana Ferreira; Wisnieski, Fernanda; Chen, Elizabeth; Araújo, Taíssa Maíra Thomaz; Lima, Eleonidas Moura; Melaragno, Maria Isabel; Demachki, Sâmia; Assumpção, Paulo Pimentel de; Burbano, Rommel Rodrı́guez; Smith, Marı́lia de Arruda Cardoso

doi:10.3748/wjg.v22.i43.9506

Cited by 16 publications

(14 citation statements)

References 51 publications

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“…Furthermore, a marked increase of MELK expression was detected in tumors associated with shorter survival length of the patients, thus underlining a role of MELK also in iCCA biological aggressiveness and the patient's prognosis. In agreement with our data, high levels of MELK have been previously shown to directly correlate with an unfavorable outcome in various cancer entities [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Therefore, overall the present findings strongly support an important pathogenetic and prognostic role of MELK in human iCCA.…”

Section: Discussionsupporting

confidence: 92%

“…MELK may also play a key role in tumor resistance to therapies and DNA repair, as MELK inhibition significantly increases the sensitivity to radiotherapy and chemotherapy in various models [16,17]. Thus, it is not surprising that high levels of MELK are detected in many solid tumors and in leukemia, where increased MELK expression correlates with poor prognosis and aggressiveness [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Genomic and pharmacological inhibition of MELK has been shown to hamper tumor growth, both in vitro and in various preclinical tumor models, further suggesting that this kinase could be a potential therapeutic target in cancer [22,28,29,32].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma

et al. 2019

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Background and Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a pernicious tumor characterized by a dismal outcome and scarce therapeutic options. To substantially improve the prognosis of iCCA patients, a better understanding of the molecular mechanisms responsible for development and progression of this disease is imperative. In the present study, we aimed at elucidating the role of the maternal embryonic leucine zipper kinase (MELK) protooncogene in iCCA. Materials and Methods: We analyzed the expression of MELK and two putative targets, Forkhead Box M1 (FOXM1) and Enhancer of Zeste Homolog 2 (EZH2), in a collection of human iCCA by real-time RT-PCR and immunohistochemistry (IHC). The effects on iCCA growth of both the multi-kinase inhibitor OTSSP167 and specific small-interfering RNA (siRNA) against MELK were investigated in iCCA cell lines. Results: Expression of MELK was significantly higher in tumors than in corresponding non-neoplastic liver counterparts, with highest levels of MELK being associated with patients’ shorter survival length. In vitro, OTSSP167 suppressed the growth of iCCA cell lines in a dose-dependent manner by reducing proliferation and inducing apoptosis. These effects were amplified when OTSSP167 administration was coupled to the DNA-damaging agent doxorubicin. Similar results, but less remarkable, were obtained when MELK was silenced by specific siRNA in the same cells. At the molecular level, siRNA against MELK triggered downregulation of MELK and its targets. Finally, we found that MELK is a downstream target of the E2F1 transcription factor. Conclusion: Our results indicate that MELK is ubiquitously overexpressed in iCCA, where it may represent a prognostic indicator and a therapeutic target. In particular, the combination of OTSSP167 (or other, more specific MELK inhibitors) with DNA-damaging agents might be a potentially effective therapy for human iCCA.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma

et al. 2019

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“…Genes such as SYT13 [71] and BCYRN1 [72] were responsible for invasion and migration of many cancer cells such as gastric cancer and lung cancer, but these genes may be associated with invasion and migration of GBM cells. Overexpression of genes such as IL11RA [73], BST2 [74] and GAS6 [75] were important for pathogenesis of many cancer types such as gastric cancer, breast cancer, and ovarian cancer, but high expression of these genes may be responsible for advancement of GBM. FERMT2 was responsible for proliferation of esophageal squamous cancer cells [76], but this gene may be linked with proliferation of GBM.…”

Section: Discussionmentioning

confidence: 99%

Identification of Crucial Candidate Genes and Pathways in Glioblastoma Multiform by Bioinformatics Analysis

Alshabi

Vastrad²,

Shaikh

et al. 2019

Biomolecules

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The present study aimed to investigate the molecular mechanisms underlying glioblastoma multiform (GBM) and its biomarkers. The differentially expressed genes (DEGs) were diagnosed using the limma software package. The ToppGene (ToppFun) was used to perform pathway and Gene Ontology (GO) enrichment analysis of the DEGs. Protein-protein interaction (PPI) networks, extracted modules, miRNA-target genes regulatory network and TF-target genes regulatory network were used to obtain insight into the actions of DEGs. Survival analysis for DEGs was carried out. A total of 590 DEGs, including 243 up regulated and 347 down regulated genes, were diagnosed between scrambled shRNA expression and Lin7A knock down. The up-regulated genes were enriched in ribosome, mitochondrial translation termination, translation, and peptide biosynthetic process. The down-regulated genes were enriched in focal adhesion, VEGFR3 signaling in lymphatic endothelium, extracellular matrix organization, and extracellular matrix. The current study screened the genes in the PPI network, extracted modules, miRNA-target genes regulatory network, and TF-target genes regulatory network with higher degrees as hub genes, which included NPM1, CUL4A, YIPF1, SHC1, AKT1, VLDLR, RPL14, P3H2, DTNA, FAM126B, RPL34, and MYL5. Survival analysis indicated that the high expression of RPL36A and MRPL35 were predicting longer survival of GBM, while high expression of AP1S1 and AKAP12 were predicting shorter survival of GBM. High expression of RPL36A and AP1S1 were associated with pathogenesis of GBM, while low expression of ALPL was associated with pathogenesis of GBM. In conclusion, the current study diagnosed DEGs between scrambled shRNA expression and Lin7A knock down samples, which could improve our understanding of the molecular mechanisms in the progression of GBM, and these crucial as well as new diagnostic markers might be used as therapeutic targets for GBM.

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“…Additionally, amplification was detected at 9p13.3, where the IL11RA gene is located. Some primary gastric adenocarcinoma samples (19.1%) were found to have an increased copy number of IL11RA [ 48 ]. Semaphorin 6D (SEMA6D) has been previously implicated in immune responses, heart development, and neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

Integrated analyses of multi-omics reveal global patterns of methylation and hydroxymethylation and screen the tumor suppressive roles of HADHB in colorectal cancer

Zhu

Zhang

et al. 2018

Clin Epigenet

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BackgroundDNA methylation is an important epigenetic modification, associated with gene expression. 5-Methylcytosine and 5-hydroxymethylcytosine are two epigenetic hallmarks that maintain the equilibrium of epigenetic reprogramming. Disequilibrium in genomic methylation leads to carcinogenesis. The purpose of this study was to elucidate the epigenetic mechanisms of DNA methylation and hydroxymethylation in the carcinogenesis of colorectal cancer.MethodsGenome-wide patterns of DNA methylation and hydroxymethylation in six paired colorectal tumor tissues and corresponding normal tissues were determined using immunoprecipitation and sequencing. Transcriptional expression was determined by RNA sequencing (RNA-Seq). Groupwise differential methylation regions (DMR), differential hydroxymethylation regions (DhMR), and differentially expressed gene (DEG) regions were identified. Epigenetic biomarkers were screened by integrating DMR, DhMR, and DEGs and confirmed using functional analysis.ResultsWe identified a genome-wide distinct hydroxymethylation pattern that could be used as an epigenetic biomarker for clearly differentiating colorectal tumor tissues from normal tissues. We identified 59,249 DMRs, 187,172 DhMRs, and 948 DEGs by comparing between tumors and normal tissues. After cross-matching genes containing DMRs or DhMRs with DEGs, we screened seven genes that were aberrantly regulated by DNA methylation in tumors. Furthermore, hypermethylation of the HADHB gene was persistently found to be correlated with downregulation of its transcription in colorectal cancer (CRC). These findings were confirmed in other patients of colorectal cancer. Tumor functional analysis indicated that HADHB reduced cancer cell migration and invasiveness. These findings suggested its possible role as a tumor suppressor gene (TSG).ConclusionThis study reveals the global patterns of methylation and hydroxymethylation in CRC. Several CRC-associated genes were screened with multi-omic analysis. Aberrant methylation and hydroxymethylation were found to be in the carcinogenesis of CRC.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0458-3) contains supplementary material, which is available to authorized users.

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Identification ofIL11RAandMELKamplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines

Cited by 16 publications

References 51 publications

Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma

Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma

Identification of Crucial Candidate Genes and Pathways in Glioblastoma Multiform by Bioinformatics Analysis

Integrated analyses of multi-omics reveal global patterns of methylation and hydroxymethylation and screen the tumor suppressive roles of HADHB in colorectal cancer

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