Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells

Wu, Deng‐Chyang; Wang, Sophie S.W.; Liu, Chung‐Jung; Wuputra, Kenly; Kato, Kohsuke; Lee, Yen‐Liang; Lin, Ying‐Chu; Tsai, Ming‐Ho; Ku, Chia‐Chen; Lin, Wen‐Hsin; Wang, Shin‐Wei; Kishikawa, Shotaro; Noguchi, Michiya; Wu, Chu‐Chieh; Chen, Yi‐Ting; Chai, Chee‐Yin; Lin, Chen‐Lung Steve; Kuo, Kung‐Kai; Yang, Ya-Sung; Miyoshi, Hiroyuki; Nakamura, Yukio; Saito, Shoji; Nagata, Kyosuke; Lin, Chang-Sheng; Yokoyama, Kazunari K.

doi:10.1002/stem.2674

Cited by 38 publications

(25 citation statements)

References 46 publications

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“…As shown in Figure 3B, the expression of 5 lncRNAs (HOTAIR, HOTTIP, HOXA11-AS, HOXB-AS4, and HOXC-AS3) generated in HOX family genes were negatively correlated with their methylation levels. The functions of these 17 lncRNAs are listed in Supplementary Table S4; only 6 of the lncRNAs have been reported to function GC (Zhang et al, 2014;Liu et al, 2015;Sun et al, 2016;Wu et al, 2017;Liu et al, 2018;Zhang et al, 2018;Song et al, 2019).…”

Section: Integrated Analysis Of Differential Methylation and Long Nonmentioning

confidence: 99%

Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

Song

Guan

2020

Front. Genet.

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Abnormal DNA methylation, an epigenetic modification, has increasingly been linked to the pathogenesis of many human cancers. However, there has been little focus on the DNA methylation patterns of genes encoding long noncoding RNAs (lncRNAs) in gastric cancer (GC). This study comprehensively determined DNA methylation and lncRNA expression profiles in GC through genome-wide analysis. Differentially methylated loci and lncRNAs were identified by integrating multi-omics data. In total, 548 differentially methylated CpG sites in lncRNA promoters and 2,399 differentially expressed lncRNAs were screened that were capable of distinguishing GC from normal tissues. Among them, 22 differentially methylation sites in 17 lncRNAs were inversely related to expression levels. Further analysis of DNA methylation status and gene expression level in GC revealed that three CpG sites (cg01550148, cg22497867, and cg20001829) and two lncRNAs (RP11-366F6.2 and RP5-881L22.5) were significantly associated with GC patient overall survival. Molecular function analysis showed that these abnormally methylated lncRNAs were mainly involved in transcriptional activator activity. Our study identified several lncRNAs regulated by aberrant DNA methylation that have clinical utility as novel prognostic biomarkers in GC. These findings help improve the understanding of methylated patterns of lncRNAs and further our knowledge of the role of epigenetics in cancer development.

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Section: Integrated Analysis Of Differential Methylation and Long Nonmentioning

confidence: 99%

Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

Song

Guan

2020

Front. Genet.

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“…In recent years, the role of HOXA13 in cancer has been extensively investigated. It has been revealed that HOXA13 expression levels are associated with the occurrence of tumors of the digestive tract, gliomas, prostate cancer, cervical cancer, bladder cancer and ovarian cancer ( 17 – 24 ). There are currently only two studies on the role of HOXA13 in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

The expression of HOXA13 in lung adenocarcinoma and its clinical significance: A study based on The Cancer Genome Atlas, Oncomine and reverse transcription‑quantitative polymerase chain reaction

Deng

Zhang

et al. 2018

Oncol Lett

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Previous studies have investigated the association between HOXA13 and non-small cell lung cancer. However, the role of HOXA13 expression in the occurrence and progression of lung adenocarcinoma (LUAD) has not yet been investigated. In the present study, HOXA13-related data mining of The Cancer Genome Atlas (TCGA), polymerase chain reaction (PCR) data from our cases and the case information in Oncomine was conducted for validation. The expression data of HOXA13 in lung cancer cell lines were also collected from the Cancer Cell Line Encyclopedia (CCLE) database for further verification. A comprehensive meta-analysis of the expression of HOXA13 was also performed, integrating the data of TCGA, in-house PCR and Oncomine. Genes that were co-expressed with HOXA13 were subsequently identified through cBioPortal and Multi Experiment Matrix (MEM), and the potential role and mechanism of HOXA13 in LUAD was investigated. The expression value of HOXA13 in the LUAD group, which comprised 237 cases, was 3.74±2.694, significantly higher than its expression value in the non-cancerous group (0.92±0.608, P<0.001). The pooled SMD for HOXA13 was 0.346 (95% CI, 0.052–0.640; P=0.068; I2=51.3%; P=0.021), The meta-analysis of diagnostic tests revealed that the area under the summary receiver operating characteristic curve (SROC) was 0.78 (95% CI, 0.75–0.82). The results demonstrated that HOXA13 is highly expressed in LUAD. In addition to the studies on HOXA13 expression in tissues, the expression data of HOXA13 in lung cancer cell lines were also collected from the CCLE database for further verification of these conclusions. Genes that were co-expressed with HOXA13 were identified for pathway analysis. The most enriched Gene Ontology terms in the genes co-expressed with HOXA13 were positive regulation of transcription from RNA polymerase II promoter, signal transduction and positive regulation of GTPase activity in biological process; cytoplasm, integral component of membrane and plasma membrane in cellular component; and significantly involved in protein binding, transcription factor activity, sequence-specific DNA binding and sequence-specific DNA binding in molecular function. Kyoto Encyclopedia of Genes and Genomes analysis revealed that these target genes were clearly involved in Pathways in cancer, Proteoglycans in cancer and cAMP signaling pathway. The hub genes obtained from the four protein-protein interaction networks were associated with HOXA13. The results of the bioinformatics research in the present study revealed that HOXA13 may influence the expression of these hub genes in such a way as to promote the occurrence and development of LUAD. In conclusion, the expression of HOXA13 in patients with LUAD and its potential clinical value were analyzed comprehensively in the present study using data from a variety of sources. Through bioinformatics analysis, evidence that HOXA13 may promote the occurrence and development of LUAD was obtained.

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“…HOTTIP, located on 7p15.2, plays a pivotal role in a number of human cancers, including gastric cancer, hepatocellular carcinoma, and colorectal cancer [14][15][16]. High HOTTIP expression has been detected in human HCC specimens and associated with the clinical progression and disease outcome of HCC patients [15].…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA HOTTIP Promotes Mouse Hepatic Stellate Cell Activation via Downregulating miR-148a

Li¹,

Wang²,

Zeng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: HOTTIP is a critical modulator in human diseases including liver cancer, but its role and molecular biological mechanisms in liver fibrosis are still unclear. Methods: The expression profile of HOTTIP during the progression of liver fibrosis was detected in human liver samples and in CCl₄-treated mice using qRT-PCR. The expressing sh-HOTTIP adenoviral vector was used to reduce HOTTIP levels in vivo. Dual-Luciferase Reporter Assay was performed to validate the interaction between miR-148a and HOTTIP, TGFBR1, or TGFBR2. Results: HOTTIP expressions in fibrotic liver samples and cirrhotic liver samples were significantly upregulated compared with healthy liver controls, and cirrhotic samples exhibited the highest levels of HOTTIP. Moreover, HOTTIP expressions were substantially induced in the liver tissues and hepatic stellate cells (HSC) of CCl₄-treated mice. Ad-shHOTTIP delivery could alleviate CCl₄- induced liver fibrosis in mice. Down-regulation of HOTTIP inhibited the viability and activation of HSCs in vitro, and HOTTIP negatively regulated miR-148a expression in HSCs. miR-148a had a negative effect on HSC activation by targeting TGFBR1 and TGFBR2. Conclusion: HOTTIP is involved in the progression of liver fibrosis by promoting HSC activation. The high level of HOTTIP downregulates miR-148a, thus to increase the level of TGFBR1 and TGFBR2 and contribute to liver fibrosis.

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Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells

Cited by 38 publications

References 46 publications

Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

Genome-Wide Identification and Characterization of DNA Methylation and Long Non-Coding RNA Expression in Gastric Cancer

The expression of HOXA13 in lung adenocarcinoma and its clinical significance: A study based on The Cancer Genome Atlas, Oncomine and reverse transcription‑quantitative polymerase chain reaction

Long Noncoding RNA HOTTIP Promotes Mouse Hepatic Stellate Cell Activation via Downregulating miR-148a

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