1,721,005 research outputs found
Abstract 3355: Identification of a novel network of miRNAs that regulate stemness in colorectal cancer
No full textAbstract
Background and Aims: Accumulating evidence suggests that a subset of cancer cells also known as the “cancer stem cells” (CSCs) influence various clinical outcomes in cancer, including tumor recurrence, metastasis and resistance to chemotherapy. Recently stemness has been recognized as a dynamic state governed by epigenetic modifiers including miRNAs. Despite identification of several self-renewal associated miRNAs, miRNA profile of CSCs remains unclear. Herein, we characterized miRNA expression of CSCs with high vs. low CD44v6 expression through RNA-Seq. Subsequently, we investigated the clinical significance of a novel miRNA identified from this systematic discovery approach.
Methods: Colorectal CSCs from HCT116 and HT29 cells were grown as spheroid-derived cancer stem cells (SDCSCs). CD44v6+ and CD44v6- CSCs were subdivided by FACS and characterized by small RNA-Seq. Differentially expressed miRNAs were subsequently confirmed in CD44v6+ CSCs and chemoresistant cells. The expression of one such candidate, miR-1246, was assessed in a clinical cohort (n = 144) by qRT-PCR.
Results: MiRNA profiling identified a unique overall pattern of CD44v6+ SDCSCs indicative of high self-renewal capacity. We noted that a panel of established self-renewal suppressive-miRNAs were downregulated (including miR-34a, 101 and 200 family) in CD44v6+ CSCs, and discovered upregulation of previously unreported miRNAs (miR-1246, 3605, 3182 and 4284). KEGG pathway analysis indicated that these miRNAs regulate Akt-MAPK and Wnt signaling pathways. Subsequently, we selected miR-1246 and validated its expression in CD44v6+ SDCSCs and chemoresistant cells. Clinically, the expression of miR-1246 was significantly elevated in CRC tissues compared to corresponding normal mucosa, and this occurred in a stage-dependent manner in primary CRCs. Furthermore, the expression of CD44v6 positively correlated with miR-1246 in CRC tissues. High miR-1246 expression resulted in poor disease free and overall survival.
Conclusion: Using a systematic and comprehensive approach, we have identified a unique network of dysregulated miRNAs in CD44v6 CSCs indicative of high degree of stemness features in cancer. In particular, we identified miR-1246 to be frequently overexpressed in CSCs as well as chemoresistant cells and its expression was associated with poor prognosis in CRC patients. Collectively, we have identified a unique group of previously unreported miRNAs which appear to have important mechanistic roles in CSCs and could serve as a promising predictive biomarkers for recurrence and prognosis in patients with CRC.
Citation Format: Shusuke Toden, Takatoshi Matsuyama, Elizabeth Hutchins, Kendall Jensen, Ajay Goel. Identification of a novel network of miRNAs that regulate stemness in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3355. doi:10.1158/1538-7445.AM2017-3355</jats:p
The Holy Grail of Curcumin and its Efficacy in Various Diseases: Is Bioavailability Truly a Big Concern?
No full textAbstract 4311: Oligomeric proanthocyanidins inhibit Hippo-YAP pathway and prevent colorectal cancer stem cell formation
No full textAbstract 3356: Novel evidence for <i>AZIN1</i> RNA editing-mediated oncogenic role in colorectal cancer
No full textAbstract
Introduction: Colorectal cancer (CRC) is the third most frequent malignancy in males and second most common disease in females worldwide. CRC pathogenesis is intimately associated to lifestyles, such as diet, obesity, and smoking. Multiple evidences have revealed that these risk factors can trigger specific epigenetic alterations and subsequently promote carcinogenesis. Recently, adenosine (A)-to-inosine (I) RNA editing has been shown to be a potential epigenetic event in human cancers. One of the most important RNA editing gene targets is the antizyme inhibitor 1 (AZIN1), and edited AZIN1 promotes accumulation of ornithine decarboxylase and polyamines, leading to promotion and development of carcinogenesis. However, the oncogenic role and the clinical significance of RNA editing in CRC has not been investigated, which led us to undertake this present study.
Materials and methods: We systematically and comprehensively investigated RNA editing in the AZIN1 gene using the RNA editing site specific PCR (RESSqPCR) in CRC patients. We further validates these results using multiple independent cohorts of CRC patients comprising of 329 colorectal cancer and adenoma patients. In addition, we performed a series of functional assays to elucidate the functional role of AZIN1 RNA editing in CRC pathogenesis.
Results: Using RESSqPCR, AZIN1 RNA editing levels were analyzed in two CRC cohorts. AZIN1 editing levels were significantly higher in cancer tissues at all stages (I thru IV) compared with normal mucosa. Additionally, AZIN1 was highly edited in colorectal adenoma tissues compared to adjacent normal mucosa, suggesting this epigenetic event to be critical in normal-adenoma-carcinoma cascade. Additionally, the expression of RNA editing enzyme (ADAR1) was also upregulated in cancerous tissues compared to normal mucosa, and positively correlated with AZIN1 editing levels. To interrogate whether AZIN1 editing has an oncogenic role, overexpression of edited-AZIN1 in CRC cell lines resulted in increased cell proliferation, invasion, migration, and stemness. More importantly, AZIN1 editing was significantly enhanced in cancer stem cells, suggesting its importance for the development and maintenance of stemness features. Finally, establishment of xenograft tumors in an animal model resulted in significantly larger tumors in edited vs. wild type-AZIN1 groups. Taken together, these results highlight the oncogenic role of AZIN1 RNA editing in CRC.
Conclusion: Our systematic and comprehensive study, which is first of its kind, reveals that AZIN1 RNA editing is novel epigenetic alteration that promotes an oncogenic behavior in colorectal cancer. In addition to its functional role, AZIN1 editing levels may be one of the important facilitators of adenoma-carcinoma sequence in CRC and serve as an important clinical biomarker in this disease.
Citation Format: Kunitoshi Shigeyasu, Shusuke Toden, Yoshinaga Okugawa, Jinsei Miyoshi, Takeshi Nagasaka, Toshiyoshi Fujiwara, Leilei Chen, Ajay Goel. Novel evidence for AZIN1 RNA editing-mediated oncogenic role in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3356. doi:10.1158/1538-7445.AM2017-3356</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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