Nucleolin Protein Interacts with Microprocessor Complex to Affect Biogenesis of MicroRNAs 15a and 16

Pickering, Brian F.; Yu, Dihua; Dyke, Michael W. Van

doi:10.1074/jbc.m111.265439

Cited by 67 publications

(79 citation statements)

References 41 publications

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“…In line with its role in RNA processing, a previously published study (Pickering et al, 2011) and our data suggest a direct involvement of NCL in miRNA biogenesis. In this study, we demonstrated that abrogation of NCL expression affects the biogenesis of a specific cohort of miRNAs, including miR-10a, miR-21, miR-103, miR-221, and miR-222.…”

Section: Discussionsupporting

confidence: 72%

“…component of the DROSHA-DGCR8 microprocessor complex (Shiohama et al, 2007). Although the role of NCL and the DROSHA-DGCR8 microprocessor complex in ribosomal RNA biogenesis is well characterized (Srivastava and Pollard, 1999;Wu et al, 2000;Fukuda et al, 2007;Jalal et al, 2007), only recently has its ability to modulate processing from primary miRNA (pri-miRNA) structures to precursor forms been reported (Pickering et al, 2011).…”

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confidence: 99%

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In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

Pichiorri¹,

Palmieri²,

Luca³

et al. 2013

J Cell Biol

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Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCLtargeting aptamers for the modulation of miRNA expression in the treatment of breast cancer.

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 99%

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

Pichiorri¹,

Palmieri²,

Luca³

et al. 2013

J Cell Biol

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“…[63][64][65] Recently, nucleolin was reported to interact with the microprocessor complex and thereby regulated the biogenesis of the protumorigenic microRNAs miR-15a and miR-16. 66 It is likely that GAST mRNA. The gastrointestinal hormone gastrin, responsible for gastric acid secretion, is highly expressed in malignancies such as pancreatic and colorectal cancers.…”

Section: Nucleolin Target Transcriptsmentioning

confidence: 99%

RNA-binding protein nucleolin in disease

2012

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“…Because NCL has been shown to associate with DGCR8, one of the components of the micro-RNA microprocessor complex (19,35,36), we evaluated the effects of 4LB5 on this interaction in HeLa cells expressing FLAG-tagged DGCR8 and myc-tagged NCL. Fig.…”

Section: Significancementioning

confidence: 99%

Human anti-nucleolin recombinant immunoagent for cancer therapy

Palmieri

Richmond

Piovan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Nucleolin (NCL) is a nucleocytoplasmic protein involved in many biological processes, such as ribosomal assembly, rRNA processing, and mRNA stabilization. NCL also regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and aggressiveness. Interestingly, NCL is expressed on the surface of actively proliferating cancer cells, but not on their normal counterparts. Therefore, NCL is an attractive target for antineoplastic treatments. Taking advantage of phage-display technology, we engineered a fully human single-chain fragment variable, named 4LB5. This immunoagent binds NCL on the cell surface, it is translocated into the cytoplasm of target cells, and it abrogates the biogenesis of NCLdependent miRNAs. Binding of 4LB5 to NCL on the cell surface of a variety of breast cancer and hepatocellular carcinoma cell lines, but not to normal-like MCF-10a breast cells, dramatically reduces cancer cell viability and proliferation. Finally, in orthotopic breast cancer mouse models, 4LB5 administration results in a significant reduction of the tumor volume without evident side effects. In summary, here we describe, to our knowledge, the first anti-NCL single-chain fragment variable displaying antineoplastic activity against established solid tumors, which could represent the prototype of novel immunebased NCL-targeting drugs with clinical potential as diagnostic and therapeutic tools in a wide variety of human cancers.is one of the most abundant nonribosomal proteins in the nucleolus (1), first identified in ribosomal RNA processing (2). Additional studies have demonstrated that NCL is a multifunctional nucleocytoplasmic protein, involved in ribosomal assembly, chromatin decondensation, transcription, nucleo-cytoplasmic import/export, and chromatin remodeling (3, 4). NCL is frequently up-regulated in cancer and in cancerassociated endothelial cells compared with normal tissues (5, 6), where it is also present on the cell surface (7,8). Altered NCL expression and localization results in oncogenic effects, such as stabilization of AKT, Bcl-2, Bcl-XL, and IL-2 mRNAs (9-11). Moreover, surface-NCL acts as a receptor for several oncogenic ligands (12-15) and viruses (16). Recently, we reported that NCL has a critical protumorigenic function regulating the biogenesis of selected microRNAs (miRNAs), a class of noncoding single-stranded RNAs 19-22 nt in length (17) that regulate gene expression at the posttranscriptional level by targeting mRNAs in a sequence-specific manner (18). In fact, NCL enhances the maturation of specific miRNAs (including miR-21, miR-221, and miR-222) causally involved in cancer pathogenesis and resistance to several antineoplastic treatments (19-23). Our findings demonstrated that NCL modulates the biogenesis of these miRNAs at the posttranscriptional level, enhancing their maturation from pri-to premiRNAs, identifying a novel NCL-dependent oncogenic mechanism (19).Because of its oncogenic role and specific expression on cancer cells surface, NCL represents an attractive target f...

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Nucleolin Protein Interacts with Microprocessor Complex to Affect Biogenesis of MicroRNAs 15a and 16

Cited by 67 publications

References 41 publications

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

RNA-binding protein nucleolin in disease

Human anti-nucleolin recombinant immunoagent for cancer therapy

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