R e vie w

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Junxia Zhang‡1,2, Anlin Zhang‡1,2, Yingyi Wang3, Ning Liu3, Yongping You3, Chunsheng Kang1,2 & Peiyu Pu*1,2 Department of Neurosurgery, Laboratory of Neuro-Oncology, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of China 2 Tianjin Key Laboratory of Nerve Injury, Variation & Regeneration, Tianjin 300052, People’s Republic of China 3 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China *Author for correspondence: [email protected] ‡ Authors contributed equally 1

STAT3 signaling has been linked to the development of various cancers and is widely recognized as a critical molecular target for cancer therapy. ncRNAs, especially miRNAs and lncRNAs, are acting as promising biomarkers and therapy targets implicated in tumor pathogenesis. This review focuses on the most up-todate knowledge of miRNAs and lncRNAs, and their involvement with STAT3 signaling. The important miRNAs involved in the STAT3 pathway are summarized in a complex interaction network. The lncRNAs’ potential for targeting STAT3 at post-transcriptional level was predicted based upon lncRNA–mRNA interaction. The current and potential STAT3-targeted therapeutics are also discussed.

STAT3 proteins were originally discovered as being members of a family of latent cytoplasmic transcription factors, which consists of seven members in mammals: STAT1, 2, 3, 4, 5a, 5b and 6. All of the family members share six structural domains: the oligomerization, coiledcoil, DNA-binding and Src homology 2 (SH2) domains, the conserved tyrosine residue (Tyr705 for STAT3) and the transcriptional activation domain [1,2] . The activation of STAT3 is an important event for the mediation of cytokineand growth factor-induced cellular and biological processes, including proliferation, differentiation, survival, development and inflammation. Aberration of the STAT3 pathway is intimately associated with human cancers such as glioma, pancreatic adenocarcinomas and prostate cancer [3–5] . Recently, a glioma-specific regulatory network has revealed that STAT3 is one of the key transcription factors necessary in human glioma cells for mesenchymal transformation and tumor aggression [3] . The reduction of STAT3 inhibits glioma cell growth, cell cycle progression, invasion, migration and cell differentiation. However, the biological mechanism of STAT3 in human cancers and the potential approaches to inhibit aberrant STAT3 are still unknown and under further investigation. As reported, the protein-coding genes account for, at most, 2% of the entire human genome, and the different orders of eukaryocytic organisms have nearly the same number of coding genes but widely different phenotypic patterns; therefore, researchers have begun to explore novel ncRNAs to characterize their potential roles in 10.2217/FON.12.52 © 2012 Future Medicine Ltd

biological processes and tumor development [6] . The human genome includes a diverse collection of ncRNAs, such as miRNAs, lncRNAs, piRNAs and snoRNAs [7–10] . The number of ncRNAs encoded within the human genome is still unclear; however, recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs. miRNAs are conserved, and short ncRNAs (22 nucleotides in length) are located in noncoding regions of the genome and the introns of protein-coding genes, and negatively regulate gene expression [11] . Extensive studies have indicated that miRNAs can function as oncogenic miRNA or tumor-suppressor miRNAs, playing crucial roles in transformation and carcinogenesis [12–14] . lncRNAs are considered to be nonprotein-coding transcripts over 200 nucleotides long, bearing many signatures of mRNA including 5´ capping, splicing and polyadenylation, but have few or no open reading frames and are pervasively transcribed from genomic loci. lncRNAs have been implicated in a number of important events, such as epigenetic, transcriptional and post-transcriptional regulation [7,15,16] . lncRNAs also exhibit unique profiles in various human cancer states [17,18] . The recent recognition that ncRNAs function in various aspects of cell biology has focused on their potential to contribute to tumor progress and development. A recent study showed that a miRNA–STAT3 complex network consisting of miR‑124, IL‑6 receptor, STAT3, miR‑24 and miR‑629 is critical for hepatocellular carcinogenesis [19] . The involvement of ncRNAs in STAT3 signaling Future Oncol. (2012) 8(6), 723–730

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Future Oncology

New insights into the roles of ncRNA in the STAT3 pathway

Keywords n

cancer n lncRNA n miRNA

n STAT3

part of

ISSN 1479-6694

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Zhang, Zhang, Wang et al.

is becoming increasingly highlighted, particularly in the development of cancers. This review article will focus on the new insights into STAT3, preceded by a brief overview of STAT3 signaling, miRNAs and lncRNAs involved in the STAT3 pathway, as well as strategies for targeting the STAT3 pathway. A better understanding of the role of STAT3 will establish a novel developmental paradigm in the study of tumor pathogenesis and provide a foundation for patient-tailored approaches to their treatment in the future.

sequence of the HoxA9 gene, and modulation of miR‑126 led to regulation of HoxA9 levels in immortalized bone marrow cells [26] . miRNAs involved in the STAT3 pathway

Recent data have demonstrated that active interactions between miRNA and STAT3 signaling take place, thereby impacting on the cell biological process. Here, the important miRNAs involved in the STAT3 pathway are summarized, which is shown in Figure 1. miR‑17 family

Brief overview of STAT3 signaling

The canonical view of STAT3 signaling is as follows: upon binding to the extracellular domain of transmembrane cytokine or growth factor receptors, receptor-associated cytoplasmic kinases, such as JAKs, phosphorylate key tyrosine residues on the target receptor’s cytoplasmic tail, recruiting unactivated STAT3 protein via its SH2 domain [19,21] . The STAT3 protein is then phosphorylated at key tyrosine (Tyr705) residues to furnish the active STAT3 monomer. Phosphorylated STAT3 dissociates from the receptor and engages another Tyr705-phosphorylated STAT3 protein, forming a transcriptional active STAT3–STAT3 dimer through a reciprocal phosphorylated Tyr705–SH2 domain interaction. The activated STAT3 dimer translocates to the nucleus where it binds to specific DNA sequences in the promoters of multiple responsive genes. miRNA miRNA target sites

According to recent computational predictions, each miRNA has the potential to regulate approximately 200 target genes [22] . The widely accepted concept is that miRNAs recognize the 3´-untranslated region (UTR) of their mRNA targets through the sequence complementarity in two main ways: perfect complementarity, followed by mRNA degradation; and imperfect complementarity, blocking the translation of mRNA. Both of them result in the inhibition of the target gene expression. However, recent studies have reported that effective miRNA binding sites have also been identified in 5´-UTR or the coding regions [23,24] . Evidence of miRNAs targeting the 5´-UTR and the coding regions of mRNAs has been demonstrated experimentally. Tsai et al. found that miR‑346 targets the 5´-UTR of RIP140 mRNA and upregulates its protein expression [25] . An evolutionarily conserved miR‑126 target site exists in the coding 724

Future Oncol. (2012) 8(6)

The miR‑17 family of miRNA is comprised of three paralog clusters (miR‑17–92, miR‑106a–363 and miR‑106b–25). In humans, the miR‑17–92 cluster is located on chromosome 13q31.3 and contains six miRNAs (miR‑17, miR‑18a, miR‑19a, miR‑20a, miR‑19b‑1 and miR‑92a‑1). The miR‑106a–363 cluster is located on human chromosome Xq26.2 and contains six miRNAs (miR‑106a, miR‑18b, miR‑20b, miR‑19b-2, miR‑92a-2 and miR‑363), while miR‑106b-25 is located on human chromosome 7q22.1 and contains three miRNAs (miR‑106b, miR‑93 and miR‑25). The miR‑17 family has been shown to play an important role in STAT3 signaling. During embryonic lung development, miR‑17, miR‑20a and miR‑106b alter E-cadherin levels and distribution [27] . Moreover, STAT3 has been identified as a key direct target of miR‑17, miR‑20a and miR‑106b, and overexpression of STAT3 mimics the alteration of E-cadherin distribution observed after miR‑17, miR‑20a and miR‑106b downregulation. Furthermore, in pancreatic carcinoma cells, lentivirusmediated overexpression of miRNA-20a negatively regulated STAT3 protein expression in a dose-dependent manner, without changing the STAT3 mRNA level, and decreased the activity of a luciferase reporter construct containing the 3´-UTR of STAT3 [28] . In addition, overexpression of miR‑20b reduced levels of the nuclear HIF-1a subunit and STAT3 in breast cancer cells, and STAT3 nuclear accumulation is necessary for miR‑20b-mediated HIF-1a recruitment to the VEGF promoter under hypoxia-mimicking conditions (CoCl2 exposure) [29] . In multiple myeloma, miR‑19a and miR‑19b downregulated expression of SOCS1, a gene frequently silenced in multiple myeloma, which plays a critical role as an inhibitor of IL-6 growth signaling [30] , whereas STAT3 is activated via the IL-6–JAK pathway. As a key transcription factor, STAT3 has potential binding sites in the consensus sequence future science group


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IL-6

Cytokine

IL-6R P

P JAK

P

JAK P

P

P

miR-124

3 AT ST

3 AT ST

ST AT 3

JAK

ST AT 3

P JAK

P IL-6

STAT3 P

HNF4α

SOCS3

P STAT3

SOCS1 STAT3

miR-204

miR-155 miR-20b

let-7a

miR-203 miR-19a/b miR-106b/125b

miR-21

miR-17/20a

miR-24/629

STAT3 P P STAT3

miR-21

miR-17

miR-20a

miR-181b-1 ...

Figure 1. Interaction network between miRNAs and STAT3 signaling. IL-6R: IL-6 receptor.

upstream of the transcription start site of the miR‑17 family. Direct transcriptional regulation of the miR‑17 family by STAT3 has been reported. Activation of STAT3 upregulates the preliminary transcript C13orf25 and the mature miR‑20a [31] . A highly conserved STAT3-binding site has been located in the promoter region of the miR‑17–92 gene (C13orf25). Further promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. In lung cancer, constitutively active STAT3 upregulated miR‑17 expression and knockdown of STAT3 expression downregulated the expression of miR‑17 [32] . These events represent a feedback loop between STAT3 and the miR‑17 family, particularly with miR‑20a and miR‑17. miR‑155

The miR‑155 locus is located within a region known as the B‑cell integration cluster, which was originally thought to be a proto-oncogene associated with lymphoma. miR‑155 functions as an oncogenic miRNA in human cancers, including breast, lung and pancreatic cancers [33–35] . Jiang et al. reported that the tumor-suppressor gene SOCS1 is an evolutionarily conserved target of miR‑155 in breast cancer cells [36] . RNAi silencing of SOCS1 recapitulates the oncogenic effects of miR‑155, whereas restoration future science group

of SOCS1 expression attenuates the protumorigenesis function of miR‑155, suggesting that miR‑155 exerts its oncogenic role by negatively regulating SOCS1. In addition, overexpression of miR‑155 in breast cancer cells leads to constitutive activation of STAT3 through the JAK–STAT pathway, and stimulation of breast cancer cells by the inflammatory cytokine IL-6 significantly upregulates miR‑155 expression, suggesting the existence of a positive feedback loop (STAT3–miR‑155–SOCS1–STAT3). let-7a

As one member of the let-7 family, let-7a has been recognized as a tumor suppressor by targeting the oncogenes such as RAS and myc [37,38] . Recent data have identified STAT3 as being a novel target of let-7a in hepatocellular carcinoma. The introduction of let-7a into cells containing wild-type STAT3 3´-UTR reporter construct resulted in significantly lower reporter activity compared with cells carrying the mutant STAT3 3´-UTR reporter [39] . Furthermore, a significant reduction of the endogenous STAT3 transcript and protein expression was detected when the let-7a precursor was introduced. This evidence suggests that let-7a physically interacts with the 3´-UTR of STAT3 to negatively regulate its cellu lar expression. A subsequent study showed that www.futuremedicine.com

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let-7a reduced levels of the IL-6 protein through targeting IL-6 mRNA 3´-UTR, thereby resulting in the inhibition of VEGF, a direct transcriptional target of STAT3 [40] . Furthermore, let-7a could inhibit IL-6 expression indirectly through the Ras–NF-kB pathway. miR‑21

miR‑21 is located in 17q23.2 and conserved in vertebrates including humans. miR‑21 is confirmed to be overexpressed in brain, breast, colon, lung, and head and neck cancer. Several sets of data have proven that miR‑21 is a transcriptional target of STAT3 in carcinogenesis and heart diseases. The first study regarding miR‑21 transcriptional activation by STAT3 was reported in multiple myeloma cells [41] . STAT3 activation by IL‑6 induces the transcription of the miR‑21 gene (pre-miR‑21 and mature miR‑21). A further reporter assay showed that miR‑21 transcription is controlled by an upstream enhancer containing strictly conserved STAT3-binding sites, confirmed by other studies [42–44] . Interestingly, the authors’ data found that repression of miR‑21 triggered a reduction in STAT3 expression and phosphorylation levels [45] , showing a potential feedback loop between STAT3 and miR‑21. However, the mechanism by which miR‑21 modulates STAT3 signaling warrants further investigation. miR‑124, miR‑24 & miR‑629

Recent data have shown that a complex miRNA–STAT3 feedback loop consisting of HNF4a, miR‑124, IL-6 receptor, STAT3, miR‑24 and miR‑629 is essential for hepatocellular carcinogenesis [19] . Transient inhibition of HNF4a initiates a reduction of miR‑124, which targets IL‑6 receptor expression. Subsequently, IL‑6–STAT3 activation induces miR‑24 and miR‑629 expression at the transcriptional level, thereby directly repressing HNF4a expression. This complex feedback loop maintaining the hepatocyte-transformed phenotype indicates a promising approach for treating liver cancer. miR‑125b & miR‑203

miR‑125b and miR‑203 target STAT3 signaling. STAT3 has been identified as a target gene of miR‑125b [46] , and miR‑203 inhibits SOCS3 expression by targeting the binding site of SOCS3 3´‑UTR [47] . miR‑181b-1, miR‑204 & miR‑23a

miR‑181b-1, miR‑204 and miR‑23a are regulated by STAT3 signaling. The presence 726


of STAT3-binding sites in the promoter of miR‑181b-1 was confirmed by a chromatin immunoprecipitation experiment. STAT3 directly activates miR‑181b-1, subsequently inhibiting CYLD tumor suppressors, leading to increased NF-kB activity, which is required to maintain the transformed state [41] . Also, STAT3 activation suppresses miR‑204 expression, and miR‑204 directly targets SHP2 expression, thereby activating the Src kinase and NFAT [48] . Finally, in hepatocellular carcinoma, activation of IL‑6–STAT3 signaling causes the upregulation of miR‑23a expression by activating its promoter, which directly targets PGC‑1a and G6PC, leading to decreased glucose production [49] . lncRNA

To date, over 3000 lncRNAs have been identified but fewer than 1% have been characterized in the human genome. The majority of lncRNAs can be classified into one or more of the seven broad categories: sense, antisense, bidirectional, intronic, intergenic, promoter-associated or 3´-UTR-associated. The targeting mechanism of lncRNAs is still unclear and under investigation. Here, the authors propose a possible basepairing and structure-guiding scheme of lncRNA for targeting DNA, mRNA, miRNA and protein. n Base pairing: perfect or imperfect sequence complementarity can facilitate lncRNA to specifically interact with DNA, mRNA or miRNA, thereby forming the complex to regulate gene expression. Structure guiding: the secondary and tertiary structures of RNA molecules play a crucial role in determining RNA function. Thus, base pairing within a lncRNA molecule may form the secondary structures, such as stem-loops and hairpins, and further folding forms the tertiary structures. These structures can connect with distant sequences to create a novel binding model including binding sequences for DNA, mRNA and miRNA and binding domains for proteins, which do not exist in the primary structure. There are no reports regarding lncRNAs involved in STAT3 signaling. However, based on the interaction models described above, especially lncRNA–mRNA interactions, the authors predicted the potential for lncRNAs to target STAT3 by computational docking and screening. Briefly, the sequence of STAT3 mRNA was compared with the sequences of a lncRNA database using the BLAST® program [50] . Then RNAplex, a tool for RNA–RNA interaction search, was employed n

future science group


to further screen the potential lncRNAs interacting with STAT3 mRNA based on the minimal free energy. Finally, it was found that 120 lncRNAs contain the binding sites (>100 bp length and >80% identity) for STAT3 mRNA (Table 1) . Thus, the authors proposed that these lncRNAs may regulate STAT3 at the post-transcriptional level. Strategy for targeting STAT3

Since the significant role of the STAT3 pathway in human diseases is well recognized and hence is considered to be an exciting and high-value target for molecular therapeutics, drug discovery for targeting the STAT3 pathway is being explored. The inhibitors of STAT3 can be divided into six generalized categories: peptidic, peptidomimetic, oligonucleotides, rationally designed small molecules, small molecules identified through highthroughput screening of compound libraries and metal complexes. Two key functional domains of STAT3 were identified as targets for molecular inhibition; the SH2 domain and the DNAbinding domain. Blocking the SH2 domain and the DNA-binding domain could suppress STAT3 protein dimerization and inhibit DNA binding, respectively. Using a structure-based drug design, several novel STAT3 inhibitors have been successfully developed, including STA-21, FLLL32 and FLLL31 for the SH2 domain [51–53] ; and the platinum compound IS3 295 and STAT3 decoy oligodeoxynucleotide for the DNA-binding domain [54–57] . Given the roles of miRNAs and lncRNAs, targeting miRNAs and lncRNAs related to STAT3 signaling will be a novel and attractive way to inhibit STAT3 signaling. To date, the approaches to specifically inhibit miRNAs include antisense oligonucleotides, locked nucleic acids and antagomirs [58–60] , while siRNA is

Review

employed in the majority of lncRNA inhibition [61,62] . Although satisfying results have been reported with these agents, the major challenge for in vivo studies used in preclinical research is the high cost. Recently, Parisien and Major have proposed a new RNA structure prediction method based on the nucleotide cyclic motif, implemented as a pipeline of two computer programs: MC-Fold and MC-Sym [63] . This method has successfully been used to accurately predict the structure of several pre-miRNAs (let-7c, miR‑19 and miR‑29a). This allows us to arrive at better models of the 3D structure of ncRNAs. Therefore, using a structure-based drug design including computational docking and screening a small-molecule database could discover the novel ncRNA small-molecule inhibitors for STAT3 signaling. Conclusion

In summary, this review highlights the recent progress of miRNAs and lncRNAs and their involvement with STAT3 signaling, and the strategy for targeting STAT3. Analyzing the signature of miRNAs and lncRNAs, including summarizing and integrating the miRNA–STAT3 interaction network, and predicting the lncRNAs potentially targeting STAT3 based on lncRNA– mRNA interaction, will gain a clearer picture of the involvement of miRNAs and lncRNAs in STAT3 signaling and provide more information about approaches for targeting STAT3. Future perspective

Although STAT3 signaling has been studied during the past few years, the molecular mechanism of the STAT3 pathway is complex and still incompletely known. Regulation of the key components of the STAT3 pathway by ncRNAs – especially

Table 1. Top ten lncRNAs that potentially interact with STAT3 mRNA. lncRNA

Identity (%)

Aligned length

STAT3 start

STAT3 end

lncRNA start

lncRNA end

RNAplex evaluation

AK097323

88.33

240

3152

3386

1320

1081

6.00 × 1064

AL137382

88.60

228

3144

3367

799

573

1.00 × 1061

CR749373

87.04

247

3144

3386

1867

1621

6.00 × 1061

AK128732

89.04

219

3152

3366

1120

903

6.00 × 1061

BC019031

87.61

234

3154

3383

1730

1497

2.00 × 1060

AK130735

86.17

253

3147

3386

1018

767

2.00 × 1057

AK022050

87.95

224

3148

3367

300

78

9.00 × 1057

AK091499

87.45

239

3153

3386

2639

2402

3.00 × 1056

BC041477

87.89

223

3152

3370

1116

895

3.00 × 1056

AK056606

86.50

237

3154

3386

1323

1087

5.00 × 1055


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miRNAs and lncRNAs – will not only reveal increased complexity of STAT3 signaling, but also enable identification of increased crosstalk between STAT3 signaling and other pathways. Moreover, the small-molecule inhibitors targeting ncRNAs will offer a novel and promising approach to cancer treatment. In conclusion, the authors believe that an improved understanding of the genetics and biology of STAT3 signaling will provide insights into the development of novel chemopreventive and therapeutic strategies for cancer.

Financial & competing interests disclosure

This work was supported by the China Natural Science Foundation (81072078, 81101915 and 81101901) and National High Technology Research and Development Program 863 (2012AA02A508). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the sub‑ ject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary Background The activation of STAT3 is an important event for cancer development. ncRNAs have been implicated in carcinogenesis, especially miRNAs and lncRNAs. miRNA miRNAs target 3´‑untranslated region, 5´‑untranslated region and the coding regions of their target’s mRNA. miRNAs involved in the STAT3 pathway are summarized in an interaction network. lncRNA More attention has been paid to the signature of the lncRNAs involved in cancer. The lncRNA potential for regulating STAT3 at the post-transcriptional level was predicted based on a lncRNA–mRNA interaction model. Strategy for targeting STAT3 Two key functional domains of STAT3 were identified as targets for molecular inhibition. Using a structure-based drug design, including computational docking and screening in a small-molecule database, could aid discovery of novel ncRNA small-molecule inhibitors for STAT3 signaling.

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