scholarly journals Involvement of Dual Strands of miR-143 (miR-143-5p and miR-143-3p) and Their Target Oncogenes in the Molecular Pathogenesis of Lung Adenocarcinoma

2019 ◽  
Vol 20 (18) ◽  
pp. 4482 ◽  
Author(s):  
Hiroki Sanada ◽  
Naohiko Seki ◽  
Keiko Mizuno ◽  
Shunsuke Misono ◽  
Akifumi Uchida ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Target Genes ◽  
Ectopic Expression ◽  
Molecular Pathogenesis ◽  
Molecular Networks ◽  
Migration And Invasion ◽  
Aberrant Expression ◽  
Clinical Specimens ◽  
Genome Wide ◽  
Tumor Suppressive Mirnas

Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 duplex was observed in LUAD clinical specimens. Ectopic expression of these miRNAs suppressed malignant phenotypes in cancer cells, suggesting that these miRNAs have tumor-suppressive activities in LUAD cells. Here, we evaluated miR-143-5p molecular networks in LUAD using genome-wide gene expression and miRNA database analyses. Twenty-two genes were identified as potential miR-143-5p-controlled genes in LUAD cells. Interestingly, the expression of 11 genes (MCM4, RAD51, FAM111B, CLGN, KRT80, GPC1, MTL5, NETO2, FANCA, MTFR1, and TTLL12) was a prognostic factor for the patients with LUAD. Furthermore, knockdown assays using siRNAs showed that downregulation of MCM4 suppressed cell growth, migration, and invasion in LUAD cells. Aberrant expression of MCM4 was confirmed in the clinical specimens of LUAD. Thus, we showed that miR-143-5p and its target genes were involved in the molecular pathogenesis of LUAD. Identification of tumor-suppressive miRNAs and their target oncogenes may be an effective strategy for elucidation of the molecular oncogenic networks of this disease.

scholarly journals Molecular Pathogenesis of Gene Regulation by the miR-150 Duplex: miR-150-3p Regulates TNS4 in Lung Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 601 ◽  
Author(s):  
Shunsuke Misono ◽  
Naohiko Seki ◽  
Keiko Mizuno ◽  
Yasutaka Yamada ◽  
Akifumi Uchida ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Ectopic Expression ◽  
Disease Free Survival ◽  
Molecular Networks ◽  
In Vitro Assays ◽  
Aberrant Expression ◽  
Clinical Specimens ◽  
Passenger Strand ◽  
Genome Wide

Based on our miRNA expression signatures, we focused on miR-150-5p (the guide strand) and miR-150-3p (the passenger strand) to investigate their functional significance in lung adenocarcinoma (LUAD). Downregulation of miR-150 duplex was confirmed in LUAD clinical specimens. In vitro assays revealed that ectopic expression of miR-150-5p and miR-150-3p inhibited cancer cell malignancy. We performed genome-wide gene expression analyses and in silico database searches to identify their oncogenic targets in LUAD cells. A total of 41 and 26 genes were identified as miR-150-5p and miR-150-3p targets, respectively, and they were closely involved in LUAD pathogenesis. Among the targets, we investigated the oncogenic roles of tensin 4 (TNS4) because high expression of TNS4 was strongly related to poorer prognosis of LUAD patients (disease-free survival: p = 0.0213 and overall survival: p = 0.0003). Expression of TNS4 was directly regulated by miR-150-3p in LUAD cells. Aberrant expression of TNS4 was detected in LUAD clinical specimens and its aberrant expression increased the aggressiveness of LUAD cells. Furthermore, we identified genes downstream from TNS4 that were associated with critical regulators of genomic stability. Our approach (discovery of anti-tumor miRNAs and their target RNAs for LUAD) will contribute to the elucidation of molecular networks involved in the malignant transformation of LUAD.

scholarly journals Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 599
Author(s):  
Reona Okada ◽  
Yusuke Goto ◽  
Yasutaka Yamada ◽  
Mayuko Kato ◽  
Shunichi Asai ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Molecular Pathogenesis ◽  
Molecular Networks ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Passenger Strand

We previously found that both the guide and passenger strands of the miR-139 duplex (miR-139-5p and miR-139-3p, respectively) were downregulated in cancer tissues. Analysis of TCGA datasets revealed that low expression of miR-139-5p (p < 0.0001) and miR-139-3p (p < 0.0001) was closely associated with 5-year survival rates of patients with renal cell carcinoma (RCC). Ectopic expression assays showed that miR-139-5p and miR-139-3p acted as tumor-suppressive miRNAs in RCC cells. Here, 19 and 22 genes were identified as putative targets of miR-139-5p and miR-139-3p in RCC cells, respectively. Among these genes, high expression of PLXDC1, TET3, PXN, ARHGEF19, ELK1, DCBLD1, IKBKB, and CSF1 significantly predicted shorter survival in RCC patients according to TCGA analyses (p < 0.05). Importantly, the expression levels of four of these genes, PXN, ARHGEF19, ELK1, and IKBKB, were independent prognostic factors for patient survival (p < 0.05). We focused on PXN (paxillin) and investigated its potential oncogenic role in RCC cells. PXN knockdown significantly inhibited cancer cell migration and invasion, possibly by regulating epithelial–mesenchymal transition. Involvement of the miR-139-3p passenger strand in RCC molecular pathogenesis is a new concept. Analyses of tumor-suppressive-miRNA-mediated molecular networks provide important insights into the molecular pathogenesis of RCC.

scholarly journals AP4 is a mediator of epithelial–mesenchymal transition and metastasis in colorectal cancer

2013 ◽  
Vol 210 (7) ◽  
pp. 1331-1350 ◽  
Author(s):  
Rene Jackstadt ◽  
Simone Röh ◽  
Jens Neumann ◽  
Peter Jung ◽  
Reinhard Hoffmann ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Helix Loop Helix ◽  
Genome Wide ◽  
A Genome ◽  
Tumor Types

The basic helix-loop-helix transcription factor AP4/TFAP4/AP-4 is encoded by a c-MYC target gene and displays up-regulation concomitantly with c-MYC in colorectal cancer (CRC) and numerous other tumor types. Here a genome-wide characterization of AP4 DNA binding and mRNA expression was performed using a combination of microarray, genome-wide chromatin immunoprecipitation, next-generation sequencing, and bioinformatic analyses. Thereby, hundreds of induced and repressed AP4 target genes were identified. Besides many genes involved in the control of proliferation, the AP4 target genes included markers of stemness (LGR5 and CD44) and epithelial–mesenchymal transition (EMT) such as SNAIL, E-cadherin/CDH1, OCLN, VIM, FN1, and the Claudins 1, 4, and 7. Accordingly, activation of AP4 induced EMT and enhanced migration and invasion of CRC cells. Conversely, down-regulation of AP4 resulted in mesenchymal–epithelial transition and inhibited migration and invasion. In addition, AP4 induction was required for EMT, migration, and invasion caused by ectopic expression of c-MYC. Inhibition of AP4 in CRC cells resulted in decreased lung metastasis in mice. Elevated AP4 expression in primary CRC significantly correlated with liver metastasis and poor patient survival. These findings imply AP4 as a new regulator of EMT that contributes to metastatic processes in CRC and presumably other carcinomas.

scholarly journals FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p)

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2083
Author(s):  
Keiko Mizuno ◽  
Kengo Tanigawa ◽  
Nijiro Nohata ◽  
Shunsuke Misono ◽  
Reona Okada ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Ectopic Expression ◽  
Disease Free Survival ◽  
In Silico Analysis ◽  
The Cancer Genome Atlas ◽  
Aberrant Expression ◽  
Therapeutic Molecules ◽  
Cancer Tissues

Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a (miR-99a-5p and miR-99a-3p) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre-miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.

scholarly journals DOT1L-Mediated H3K79 Methylation in Chromatin Is Dispensable for Wnt Pathway-Specific and Other Intestinal Epithelial Functions

2013 ◽  
Vol 33 (9) ◽  
pp. 1735-1745 ◽  
Author(s):  
Li-Lun Ho ◽  
Amit Sinha ◽  
Michael Verzi ◽  
Kathrin M. Bernt ◽  
Scott A. Armstrong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelium ◽  
Target Genes ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Aberrant Expression ◽  
Genome Wide ◽  
Transcript Profiles ◽  
H3k79 Methylation

Methylation of H3K79 is associated with chromatin at expressed genes, though it is unclear if this histone modification is required for transcription of all genes. Recent studies suggest that Wnt-responsive genes depend particularly on H3K79 methylation, which is catalyzed by the methyltransferase DOT1L. Human leukemias carrying MLL gene rearrangements show DOT1L-mediated H3K79 methylation and aberrant expression of leukemogenic genes. DOT1L inhibitors reverse these effects, but their clinical use is potentially limited by toxicity in Wnt-dependent tissues such as intestinal epithelium. Genome-wide positioning of the H3K79me2 mark in Lgr5 + mouse intestinal stem cells and mature intestinal villus epithelium correlated with expression levels of all transcripts and not with Wnt-responsive genes per se . Selective Dot1l disruption in Lgr5 + stem cells or in whole intestinal epithelium eliminated H3K79me2 from the respective compartments, allowing genetic evaluation of DOT1L requirements. The absence of methylated H3K79 did not impair health, intestinal homeostasis, or expression of Wnt target genes in crypt epithelium for up to 4 months, despite increased crypt cell apoptosis. Global transcript profiles in Dot1l -null cells were barely altered. Thus, H3K79 methylation is not essential for transcription of Wnt-responsive or other intestinal genes, and intestinal toxicity is not imperative when DOT1L is rendered inactive in vivo .

scholarly journals E2a-Pbx1 induces aberrant expression of tissue-specific and developmentally regulated genes when expressed in NIH 3T3 fibroblasts.

1997 ◽  
Vol 17 (3) ◽  
pp. 1503-1512 ◽  
Author(s):  
X Fu ◽  
M P Kamps
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Ectopic Expression ◽  
Cellular Transformation ◽  
Transactivation Domain ◽  
Developmentally Regulated ◽  
Aberrant Expression ◽  
Tissue Specific ◽  
3T3 Fibroblasts ◽  
Nih 3T3

The E2a-Pbx1 oncoprotein contains the transactivation domain of E2a joined to the DNA-binding homeodomain (HD) of Pbx1. In mice, E2a-Pbx1 transforms T lymphoblasts and fibroblasts and blocks myeloblast differentiation. Pbx1 and E2a-Pbx1 bind DNA as heterodimers with other HD proteins whose expression is tissue specific. While the transactivation domain of E2a is required for all forms of transformation, DNA binding by the Pbx1 HD is essential for blocking myeloblast differentiation but dispensable for fibroblast or T-lymphoblast transformation. These properties suggest (i) that E2a-Pbx1 causes cellular transformation by activating gene transcription, (ii) that transcription of E2a-Pbx1 target genes is normally regulated by ubiquitous Pbx proteins and tissue-specific partners, and (iii) that DNA-binding mutants of E2a-Pbx1 activate a subset of all gene targets. To test these predictions, genes induced in NIH 3T3 fibroblasts by E2a-Pbx1 were identified and examined for tissue- and stage-specific expression and their differential abilities to be upregulated by E2a-Pbx1 in NIH 3T3 fibroblasts and myeloblasts and by a DNA-binding mutant of E2a-Pbx1 in NIH 3T3 cells. Of 12 RNAs induced by E2a-Pbx1, 4 encoded known proteins (a J-C region of the immunoglobulin kappa light chain, natriuretic peptide receptor C, mitochondrial fumarase, and the 3',5'-cyclic nucleotide phosphodiesterase, PDE1A) and 5 encoded new proteins related to angiogenin, ion channels, villin, epidermal growth factor repeat proteins, and the human 2.19 gene product. Expression of many of these genes was tissue specific or developmentally regulated, and most were not expressed in fibroblasts, indicating that E2a-Pbx1 can induce ectopic expression of genes associated with lineage-specific differentiation.

scholarly journals NUSAP1 Promotes Gastric Cancer Tumorigenesis and Progression by Stabilizing the YAP1 Protein

2021 ◽  
Vol 10 ◽  
Author(s):  
Hui Guo ◽  
Jianping Zou ◽  
Ling Zhou ◽  
Min Zhong ◽  
Yan He ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Target Genes ◽  
Hippo Pathway ◽  
Therapeutic Targets ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Aberrant Expression ◽  
Downstream Target ◽  
Tumorigenesis And Progression

The Yes-associated protein (YAP1) is a main effector of the canonical Hippo pathway, which contributes greatly to tumor initiation, progression, and metastasis in multiple cancers, including gastric cancer (GC). Due to limited knowledge of YAP1 upregulation in cancer, it is a great challenge of therapeutic targets toward the Hippo–YAP1 pathway. Here, we identify nucleolar spindle-associated protein 1 (NUSAP1) as a novel binding partner of YAP1. The upregulation of NUSAP1 is associated with unfavorable clinical outcomes in GC patients, and NUSAP1 depletion impairs its oncogenic properties in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 functions as a positive regulator of YAP1 protein stability, thereby inducing the transcription of Hippo pathway downstream target genes, such as CTGF and CYR61. More interestingly, we find that the cancer-promoting effects of NUSAP1 on GC cell growth, migration, and invasion are mainly mediated by YAP1. Furthermore, aberrant expression of NUSAP1 and YAP1 is highly correlated in GC cell lines and tissues. We herein clarify the role of the oncogenic NUSAP1–YAP1 axis in GC tumorigenesis and progression and, therefore, provide novel therapeutic targets for GC treatment.

scholarly journals BAP1 Downregulates NRF2 Target Genes and Exerts Anti-Tumorigenic Effects by Deubiquitinating KEAP1 in Lung Adenocarcinoma

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 114
Author(s):  
Jong-Su Kang ◽  
Le Ba Nam ◽  
Ok-Kyung Yoo ◽  
Kyeong Lee ◽  
Young-Ah Suh ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Target Genes ◽  
Human Lung ◽  
Lung Tumor ◽  
A549 Cells ◽  
Adaptor Protein ◽  
Migration And Invasion ◽  
Related Factor ◽  
Lentiviral Transduction ◽  
Induced Apoptosis

KELCH-ECH-associated protein 1 (KEAP1) is an adaptor protein of Cullin 3 (CUL3) E3 ubiquitin ligase that targets a redox sensitive transcription factor, NF-E2-related factor 2 (NRF2). BRCA1-associated protein 1 (BAP1) is a tumor suppressor and deubiquitinase whose mutations increase the risk of several types of familial cancers. In the present study, we have identified that BAP1 deubiquitinates KEAP1 by binding to the BTB domain. Lentiviral transduction of BAP1 decreased the expression of NRF2 target genes, suppressed the migration and invasion, and sensitized cisplatin-induced apoptosis in human lung adenocarcinoma (LUAD) A549 cells. Examination of the lung tissues in KrasG12D/+ mice demonstrated that the level of Bap1 and Keap1 mRNAs progressively decreases during lung tumor progression, and it is correlated with NRF2 activation and the inhibition of oxidative stress. Supporting this observation, lentiviral transduction of BAP1 decreased the growth of A549 xenografts in athymic nude mice. Transcriptome analysis of human lung tissues showed that the levels of Bap1 mRNA are significantly higher in normal samples than LUAD samples. Moreover, the expression of Bap1 mRNA is associated with a better survival of LUAD patients. Together, our study demonstrates that KEAP1 deubiquitination by BAP1 is novel tumor suppressive mechanism of LUAD.

scholarly journals The noncoding RNA LINC00152 conveys contradicting effects in different glioblastoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stefanie Binder ◽  
Ivonne Zipfel ◽  
Claudia Müller ◽  
Karolin Wiedemann ◽  
Carolin Schimmelpfennig ◽  
...  
Keyword(s):  
Genetic Heterogeneity ◽  
Noncoding Rna ◽  
Target Genes ◽  
Migration And Invasion ◽  
Glioblastoma Cells ◽  
Transcription Analysis ◽  
Rna Targets ◽  
Genome Wide ◽  
Unknown Risk ◽  
A Genome

AbstractGlioblastoma multiforme (GBM) is an extremely aggressive brain tumor, characterized by its high genetic heterogeneity. In search of novel putative therapeutic RNA targets we investigated the role of the oncogenic long noncoding RNA LINC00152 (CYTOR, and STAiR18) in A172 glioblastoma cells. Here, we are the first to describe, that LINC00152 unexpectedly acts in a tumor suppressive manner in this cell line. SiRNA-based knockdown of LINC00152 enhanced malignant tumor behaviors including proliferation, cell cycle entry, migration, and invasion, contradicting previous studies using U87-MG and LN229 glioblastoma cells. Furthermore, LINC00152 knockdown had no influence on survival of A172 glioblastoma cells. In a genome wide transcription analysis of A172 and U87-MG glioblastoma cells, we identified 70 LINC00152 target genes involved in locomotion, cell migration, and motility in A172 cells, whereas in U87-MG cells only 40 target genes were detected. The LINC00152-regulated genes found in A172 differed from those identified in U87-MG glioblastoma cells, none of them being regulated in both cell lines. These findings underline the strong genetic heterogeneity of glioblastoma and point to a potential, yet unknown risk addressing LINC00152 lncRNA as a prospective therapeutic target in GBM.

scholarly journals MIR-301b-3p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting DLC1

2021 ◽  
Vol 20 ◽  
pp. 153303382199003
Author(s):  
Haitao Liu ◽  
Xingjie Ma ◽  
Niu Niu ◽  
Junjie Zhao ◽  
Chao Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Biological Properties ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation ◽  
Dlc1 Expression

Background: miR-301b-3p is reported in various human cancers for its abnormal expression, while the role and molecular mechanisms in lung adenocarcinoma (LUAD) remain unclear, and this is the focus of the present study. Materials and Methods: TCGA database was consulted to know gene expression in LUAD tissue. CCK-8, colony formation assay and Transwell assay were applied to identify the role of target genes in regulating LUAD cell biological properties. Bioinformatics analysis plus dual-luciferase assay were performed to validate the potential connection between genes. Results: miR-301b-3p and DLC1 were the target genes of this study and respectively differentially up-regulated and down-regulated in LUAD. Functional experiments indicated that miR-301b-3p contributed to cancer cell proliferation, migration and invasion, while this effect was reversed with overexpressed DLC1 which was identified as a direct target of and regulated by miR-301b-3p. Conclusions: Collectively, miR-301b-3p was identified to actively function on LUAD malignant progression by suppressing DLC1 expression. This discovery provides a novel therapeutic strategy for LUAD patients, which helps improve the survival of patients.

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