Correlation of MTDH/AEG-1 and HOTAIR Expression with Metastasis and Response to Treatment in Sarcoma Patients

Milhem, Mohammed M.; Knutson, Tina; Yang, Shujie; Zhu, Danlin; Wang, Xinjun; Leslie, Kimberly K.; Meng, Xiangjun

doi:10.4172/1948-5956.s5-004

Cited by 32 publications

(36 citation statements)

References 20 publications

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“…Additionally, breast cancer patients with high HOTAIR expression had a poorer prognosis for overall survival and for metastasis-free survival than did those with low HOTAIR expression (6)(7)(8). Similar phenomena have been observed in other cancer types, such as hepatocellular carcinoma (9-11), colorectal cancer (12), sarcoma (13), gastrointestinal stromal tumors (14), pancreatic cancer (15), laryngeal squamous cell carcinoma (16), nasopharyngeal carcinoma (17), lung cancer (18,19), ESCC (20)(21)(22), gastric cancer (23,24) and melanoma (25). All these evidences indicate that lncRNA HOTAIR can act as an oncogene and increased HOTAIR expression might result in malignant transformation of normal cells.…”

Section: Discussionsupporting

confidence: 68%

The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNAHOTAIRvia a novel intronic enhancer

Zhang¹,

Zhou

et al. 2014

CARCIN

149

169

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Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), which could induce genome-wide retargeting of polycomb-repressive complex 2, trimethylates histone H3 lysine-27 (H3K27me3) and deregulation of multiple downstream genes, is involved in development and progression of esophageal squamous cell carcinoma (ESCC). We hypothesized that the functional single nucleotide polymorphisms (SNP) in HOTAIR may affect HOTAIR expression and/or its function and, thus, ESCC risk. Therefore, we examined the association between three haplotypetagging SNPs (htSNP) across the whole HOTAIR locus and ESCC risk as well as the functional relevance of an ESCC susceptibility SNP rs920778. Genotypes were determined in three independent case-control sets consisted of 2098 ESCC patients and 2150 controls. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was investigated in vitro and in vivo. We found that the HOTAIR rs920778 TT carriers had a 1.37-fold, 1.78-fold and 2.08-fold increased ESCC risk in Jinan, Shijiazhuang and Huaian populations, respectively, compared with the CC carriers (P = 0.003, 7.7 × 10 -4 and 5.9 × 10 -4). During inspecting functional relevance of the rs920778 SNP, we identified a novel intronic HOTAIR enhancer locating between +1719bp and +2353bp from the transcriptional start site through reporter assays. Moreover, there is an allelic regulation of rs920778 on HOTAIR expression via this enhancer in both ESCC cell lines and normal esophageal tissue specimens, with higher HOTAIR expression among T allele carriers. These results demonstrate that functional genetic variants influencing lncRNA regulation may explain a fraction of ESCC genetic basis.

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Section: Discussionsupporting

confidence: 68%

The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNAHOTAIRvia a novel intronic enhancer

Zhang¹,

Zhou

et al. 2014

CARCIN

149

169

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“…7,[19][20][21][22] However, the role of lncRNA-HOTAIR in the chemoresistance of SCLC remains unknown. In this study, we initially identified lncRNA-HOTAIR as a regulator in chemoresistance of SCLC by qRT-PCR in H69/H69AR and H446/H446AR cells.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells

Fang

Gao

Tong

et al. 2016

Laboratory Investigation

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Homeobox (HOX) transcript antisense RNA (HOTAIR), a long intergenic noncoding RNA (lincRNA), has been reported to play an oncogenic role in various cancers including small cell lung cancer (SCLC). However, it is not known whether HOTAIR can modulate chemoresistance in SCLC. The aim of this study is to investigate the roles of HOTAIR in chemoresistance of SCLC and its possible molecular mechanism. Knockdown of HOTAIR was carried out in SCLC multidrug-resistant cell lines (H69AR and H446AR) and the parental cell lines (H69 and H446) to assess its influence on chemoresistance. The results showed that downregulation of HOTAIR increased cell sensitivity to anticancer drugs through increasing cell apoptosis and cell cycle arrest, and suppressed tumor growth in vivo. Moreover, HOXA1 methylation increased in the resistant cells using bisulfite sequencing PCR. Depletion of HOTAIR reduced HOXA1 methylation by decreasing DNMT1 and DNMT3b expression. The interaction between HOTAIR and HOXA1 was validated by RNA immunoprecipitation. Taken together, our study suggested that HOTAIR mediates chemoresistance of SCLC by regulating HOXA1 methylation and could be utilized as a potential target for new adjuvant therapies against chemoresistance.

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“…A growing body of literature implicates MTDH as a specific mediator of lung metastasis in breast adenocarcinoma, 34 a provocative finding in light of the frequent lung metastasis among the CIC-DUX sarcomas (and, for that matter, among Ewing sarcomas). Expression of MTDH has been recently noted as a poor prognostic factor in Ewing sarcoma and other sarcomas, 35,36 and proposed as a targetable cell surface marker. 37 In contrast, we found that expression of p21 was significantly greater in CIC-DUX sarcomas.…”

Section: Discussionmentioning

confidence: 99%

CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression

et al. 2015

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Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases. Given our prior observation of trisomy 8 in these tumors, we assayed for amplification and expression of MYC (cMyc) and representative downstream targets. Trisomy 8 was detected in 5/7 testable cases, with further amplification of MYC locus in 6/7 testable cases and immunohistochemical expression of MYC in 10/10. The canonical MYC transcriptional target, p21, but not MTDH, was differentially expressed compared with Ewing sarcomas. Given prior observation of induction of ETS-family transcription factors by the fusion oncoprotein, we assayed and identified highly prevalent positivity for ERG (9/10) and FLI1 (8/8). These findings are cautionary regarding use of these immunostains in prospective case workup, whereas the prevalent MYC amplification may represent a therapeutically targetable oncogenic pathway in CIC-DUX sarcomas.

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Correlation of MTDH/AEG-1 and HOTAIR Expression with Metastasis and Response to Treatment in Sarcoma Patients

Cited by 32 publications

References 20 publications

The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNAHOTAIRvia a novel intronic enhancer

The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNAHOTAIRvia a novel intronic enhancer

Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells

CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression

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