Argonaute proteins: key players in RNA silencing

Hutvágner, György; Simard, Martin J.

doi:10.1038/nrm2321

Cited by 1,176 publications

(945 citation statements)

References 136 publications

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“…Proteins with Piwi domains have been described as components of ribonucleoprotein complexes that act in the microRNA/ RNA interference pathway of gene silencing (Fetzer et al, 2002, Lingel et al, 2005. Recently, it was shown that the Piwi gene family are associated with a new class of small RNAs socalled 'piwi-interacting RNAs' (piRNAs) in mammalian spermatogenesis (Hall et al, 2005, Houwing et al, 2007, Hutvagner et al, 2008, Peters et al, 2007, which is one of gene expressing regulatory small non-coding RNAs (ncRNAs). Small ncRNAs are naturally conserved regulators of gene expression described in almost all eukaryotic species including humans (Elbashir et al, 2001, Meister et al, 2004, Sana et al, 2012.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Hiwi Promotes Growth of Human Breast Cancer Cells

Wang¹,

Wang²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The Piwi subfamily comprises two argonaute (Ago) family proteins, which are defined by the presence of PAZ and Piwi domains, with well known roles in RNA silencing. Hiwi, a human Piwi subfamily member, has been shown to play essential roles in stem cell self-renewal and gametogenesis. Recently, accumulating reports have indicated that abnormal hiwi expression is associated with poorer prognosis of multiple types of human cancers, including examples in the breast. However, little is known about details of the oncogenic role of hiwi in breast cancers. In present study, we confirmed overexpression of hiwi in breast cancer specimens and breast cancer cell lines at both mRNA and protein levels. Thus both RT-qPCR and Western blot data revealed significantly higher hiwi in intratumor than peritumor specimens, overexpression being associated with tumor size, lymph node metastasis and histological grade. Hiwi overexpression was also identified in breast cancer cell lines, MDA-MB-231 and MCF-7, and gain-of-function and loss-of-function strategies were adopted to identify the role of hiwi in the MCF-7 cell growth. Results demonstrated that hiwi expression in MCF-7 cells was significantly up-or down-regulated by the two strategies. We next evaluated the influence of hiwi overexpression or knockdown on the growth of breast cancer cells. Both cell count and colony formation assays confirmed promoting roles of hiwi in MCF-7 cells, which could be inhibited by hiwi specific blockage by siRNAs. In summary, the present study confirmed overexpression of hiwi in breast cancer specimens and breast cancer cell lines, and provided evidence of promotion by hiwi of cell growth. The results imply an oncogenic role of hiwi in breast cancers.

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Section: Discussionmentioning

confidence: 99%

Overexpression of Hiwi Promotes Growth of Human Breast Cancer Cells

Wang¹,

Wang²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Recent studies indicate that CSCs which are self-renewing and differentiate into heterogeneous tumor cells, are responsible for the drug resistance and tumor relapse (Yu et al, 1995). Hiwi gene, a human homologue of the Piwi family which plays an important role in stem cell self-renewal (Cox et al, 1998;Hutvagner et al, 2008), had been shown to be highly expressed in a variety of human cancers (Liu et al, 2006;Grochola et al, 2008). Moreover, recent data suggested that Hiwi gene was required to maintain the stemness of hematopoietic stem cells (Sharma et al, 2001).…”

Section: Hiwi Knockdown Inhibits the Growth Of Lung Cancer In Nude Micementioning

confidence: 99%

Hiwi Knockdown Inhibits the Growth of Lung Cancer in Nude Mice

Liang

Dong²,

Hu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Hiwi, a human homologue of the Piwi family, plays an important role in stem cell self-renewal and is overexpressed in various human tumors. This study aimed to determine whether an RNA interference-based strategy to suppress Hiwi expression could inhibit tumor growth in a xenograft mouse model. A rare population of SSC lo Alde br cells was isolated and identified as lung cancer stem cells in our previous study. Plasmids containing U6 promoter-driven shRNAs against Hiwi or control plasmids were successfully established. The xenograft tumor model was generated by subcutaneously inoculating with lung cancer stem cell SSC lo Alde br cells. After the tumor size reached about 8 mm in diameter, shRNA plasmids were injected into the mice via the tail vein three times a week for two weeks, then xenograft tumor growth was assessed. In nude mice, intravenously delivery of Hiwi shRNA plasmids significantly inhibited tumor growth compared to treatment with control scrambled shRNA plasmids or the vehicle PBS. No mice died during the experiment and no adverse events were observed in mice administered the plasmids. Moreover, delivery of Hiwi shRNA plasmids resulted in a significant suppressed expression of Hiwi and ALDH-1 in xenograft tumor samples, based on immunohistochemical analysis. Thus, shRNA-mediated Hiwi gene silencing in lung cancer stem cells by an effective in vivo gene delivery strategy appeared to be an effective therapeutic approach for lung cancer, and may provide some useful clues for RNAi gene therapy in solid cancers.

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“…RNA silencing is a small regulatory RNA-mediated biological process conserved in plants and animals (Tomari & Zamore, 2005;Patel et al, 2006;Hutvagner & Simard, 2008). In plants, RNA silencing is believed to be an ancient immune response triggered against viral double-stranded RNAs (dsRNAs; Ding & Voinnet, 2007).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for RNA‐silencing suppression by Tomato aspermy virus protein 2b

et al. 2008

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The 2b proteins encoded by cucumovirus act as post-transcriptional gene silencing suppressors to counter host defence during infection. Here we report the crystal structure of Tomato aspermy virus 2b (TAV2b) protein bound to a 19 bp small interfering RNA (siRNA) duplex. TAV2b adopts an all a-helix structure and forms a homodimer to measure siRNA duplex in a length-preference mode. TAV2b has a pair of hook-like structures to recognize simultaneously two a-helical turns of A-form RNA duplex by fitting its a-helix backbone into two adjacent major grooves of siRNA duplex. The conserved p-stackings between tryptophan and the 5 0 -terminal base of siRNA duplex from both ends enhance the recognition. TAV2b further oligomerizes to form a dimer of dimers through the conserved leucine-zipper-like motif at its amino-terminal a-helix. Biochemical experiments suggest that TAV2b might interfere with the post-transcriptional gene silencing pathway by directly binding to siRNA duplex.

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Argonaute proteins: key players in RNA silencing

Cited by 1,176 publications

References 136 publications

Overexpression of Hiwi Promotes Growth of Human Breast Cancer Cells

Overexpression of Hiwi Promotes Growth of Human Breast Cancer Cells

Hiwi Knockdown Inhibits the Growth of Lung Cancer in Nude Mice

Structural basis for RNA‐silencing suppression by Tomato aspermy virus protein 2b

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