Upregulation of miR-196a and<i>HOTAIR</i>Drive Malignant Character in Gastrointestinal Stromal Tumors

Niinuma, Takeshi; Suzuki, Hiromu; Nojima, Masanori; Nosho, Katsuhiko; Yamamoto, Hiroyuki; Takamaru, Hiroyuki; Yamamoto, Eiko; Maruyama, Reo; Nobuoka, Takayuki; Miyazaki, Yasuaki; Nishida, Toshirou; Bamba, Takeo; Kanda, Tatsuo; Ajioka, Yoichi; Taguchi, Takahiro; Okahara, Satoshi; Takahashi, Hiroaki; Nishida, Yasunori; Hosokawa, Masao; Hasegawa, Tadashi; Tokino, Takashi; Hirata, Koichi; Imai, Kohzoh; Toyota, Minoru; Shinomura, Yasuhisa

doi:10.1158/0008-5472.can-11-1803

Cited by 332 publications

(296 citation statements)

References 39 publications

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“…HOTAIR, which is transcribed from the HOX genes, is upregulated in breast cancer (17), hepatocellular carcinoma (22), colorectal cancer (23), pancreatic cancer (31), laryngeal squamous cell carcinoma (32) and gastrointestinal stromal tumors (33). Furthermore, a higher HOTAIR expression has been shown to negatively regulate metastasis-related suppressor genes and promote tumor malignancy (17).…”

Section: Discussionmentioning

confidence: 99%

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

Bao

et al. 2013

International Journal of Molecular Medicine

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Abstract. Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer. Homeobox (HOX) transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA (lncRNA), is associated with a variety of human cancers, such as breast, liver and lung cancer. However, whether HOTAIR can function as a molecular marker in endometrial carcinoma (EC) remains unknown. In the present study, the expression of HOTAIR in 66 EC tissues from patients with EC and 30 normal tissues from healthy age-matched control subjects was determined using quantitative reverse transcription PCR. Furthermore, using in situ hybridization, we measured HOTAIR expression in 129 formalin-fixed paraffin-embedded (FFPE) tissue sections, which included 96 tissues that matched the frozen cases, 21 other EC tissues and 12 atypical hyperplasia tissues. Correlations between HOTAIR expression and the clinicopathological characteristics of patients were analyzed. Our results revealed that HOTAIR expression in the EC tissues was significantly upregulated compared with normal tissues (p<0.001). In addition, we observed a significant association between HOTAIR expression and the EC grade (p<0.05) and lymph node metastasis (p<0.05). Moreover, in the FFPE tissues, but not the frozen tissues, we found that a higher HOTAIR expression also correlated with the depth of myometrial invasion (p=0.019) and lymphovascular space invasion (p=0.015). More importantly, patients with a higher HOTAIR expression showed significantly poorer overall survival than those with lower HOTAIR expression (p<0.05). In conclusion, our results suggest that a high expression of HOTAIR is involved in the progression of cancer and may be a novel biomarker of poor prognosis in patients with EC. IntroductionEndometrial carcinoma (EC) is one of the most common malignancies of the female reproductive system in Western countries. In 2013, an estimated 49,500 new cases and 8,200 deaths due to EC are expected in the USA (1). With the increase in obesity and the decrease in physical activity, the incidence of EC is rising and shows a trend in younger women (2). EC is usually classified into two types to determine the risk of metastasis and recurrence (3). Generally, type I endometrioid endometrial carcinomas (EECs) have a good prognosis and account for 80-85% of the total cases of EC. By contrast, type II non-EECs are often associated with a worse outcome (3,4). However, the prognostic value of this classification is unsatisfactory, as approximately 20% of type I tumors recur, whereas 50% of type II tumors recur (5). A number of previous studies have demonstrated the utility of molecular alterations as prognostic markers, including p53 (6), phosphatase and tensin homolog (PTEN) (7) and ; however, their value is limited (9). Thus, a deeper understanding of the molecular mechanisms responsible for EC is required for risk stratification and a clinical decision regarding individualized treatment strategies.Recent studies have indicated that only 2% of transcripts are protein-coding RNAs, and ...

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Section: Discussionmentioning

confidence: 99%

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

Bao

et al. 2013

International Journal of Molecular Medicine

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“…Meanwhile on Xa, Tsix expression is believed to repress Xist through a combination of several mechanisms: titrating away PRC2, preventing its proper docking onto RepA/Xist; recruiting Dnmt3a, laying down DNA methylation (Ⓜ) to silence the Xist promoter; and/or directly base pairing with Xist RNA, becoming a substrate for Dicer-dependent processing into small RNAs. (Gupta et al 2010), liver (Z. , colorectal (Kogo et al 2011), gastrointestinal (Niinuma et al 2012), and pancreatic (Kim et al 2012) cancers and is proposed to increase tumor invasiveness and metastasis (Gupta et al 2010). MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), another lncRNA associated with various cancers and metastasis (Ji et al 2003;Lin et al 2011), is found to affect the transcriptional and post-transcriptional regulation of cytoskeletal and extracellular matrix genes (Tano et al 2010).…”

Section: Implications In Cancermentioning

confidence: 99%

Long Noncoding RNAs: Past, Present, and Future

2013

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Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years as a potentially new and crucial layer of biological regulation. lncRNAs of all kinds have been implicated in a range of developmental processes and diseases, but knowledge of the mechanisms by which they act is still surprisingly limited, and claims that almost the entirety of the mammalian genome is transcribed into functional noncoding transcripts remain controversial. At the same time, a small number of well-studied lncRNAs have given us important clues about the biology of these molecules, and a few key functional and mechanistic themes have begun to emerge, although the robustness of these models and classification schemes remains to be seen. Here, we review the current state of knowledge of the lncRNA field, discussing what is known about the genomic contexts, biological functions, and mechanisms of action of lncRNAs. We also reflect on how the recent interest in lncRNAs is deeply rooted in biology's longstanding concern with the evolution and function of genomes.T HE past several years have witnessed a steep rise of interest in the study of lncRNAs. Almost on a weekly basis, it seems that a new lncRNA is found to be up-or downregulated in a particular disease, or a new class of noncoding transcripts is uncovered by a transcriptomic study, or a new article heralds a paradigm shift that lncRNAs will bring to our understanding of biology. Without a doubt, the advent of sensitive, high-throughput genomic technologies such as microarrays and next-generation sequencing (NGS) has resulted in an unprecedented ability to detect novel transcripts, the vast majority of which seem not to be derived from annotated protein-coding genes. Despite this explosion of data, however, surprisingly little is known about how lncRNAs function, how many different types of lncRNAs exist, or even whether most of them carry biological significance.In this review, we focus on recently discovered lncRNAs of .200 nt, place these new discoveries in historical context, and outline areas where additional work is needed. The review does not cover "classic" ncRNAs such as ribosomal (r) RNAs, ribozymes, transfer (t)RNAs, small nuclear (sn)RNAs, small nucleolar (sno)RNAs, and telomere-associated RNAs (TERC, TERRA); nor does it cover small ncRNAs such as microRNAs (miRNAs), endogenous small interfering (endo-si)RNAs that participate in RNA interference (RNAi), and Piwi-associated (pi)RNAs. We refer readers to the many

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“…15,16 A very recent study reported that upregulation of miR199a was correlated with high-risk-grade and worse prognosis in patients with GISTs. 17 However, further analysis is needed to clarify the role of miRNAs in the development and progression of GIST.…”

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confidence: 99%

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor

2013

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MicroRNAs (miRNAs) are small, non-coding RNAs that are up-or downregulated in several types of cancer, and have an important role in the tumorigenesis and progression. To better understand the role of aberrantly expressed miRNAs and their target genes affecting the biology of gastrointestinal stromal tumor (GIST), we performed miRNA array in 19 cases of GIST, and found that several miRNAs, including miR-133b, were downregulated in high-grade GISTs. Subsequently, quantitative real-time reverse transcription-PCR revealed that fascin-1 mRNA was upregulated in accordance with miR-133b downregulation in high-grade GIST; this result was consistent with a previous report showing that fascin-1 might be a direct target of miR-133b. We then examined the fascin-1 protein expression by immunohistochemical staining in 147 cases of GIST, and found that fascin-1 overexpression was significantly correlated with shorter disease-free survival time and several aggressive pathological factors, including tumor size, mitotic counts, risk grade, blood vessel invasion and mucosal ulceration. Our results suggest that downregulation of miR-133b and overexpression of fascin-1 may have an important role in the progression of GIST, and that fascin-1 may be a useful biomarker to predict the aggressive behavior.

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Upregulation of miR-196a andHOTAIRDrive Malignant Character in Gastrointestinal Stromal Tumors

Cited by 332 publications

References 39 publications

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

The long non-coding RNA HOTAIR is upregulated in endometrial carcinoma and correlates with poor prognosis

Long Noncoding RNAs: Past, Present, and Future

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor

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