Einspanier, Ralf

Hanisch, Carlos

Huber, Otmar

Kutz-Lohroff, Barbara

Sharbati, Jutta

Sharbati, Soroush

Cell Death and Disease

PubMed

Institutional Repository of the Freie Universität Berlin

OPENNews and CommentaryTrefoil factor 3 mediates resistance to apoptosis incolon carcinoma cells by a regulatory RNA axisCarlos Hanisch1, Jutta Sharbati1,2, Barbara Kutz-Lohroff1, Otmar Huber3, Ralf Einspanier1 and Soroush Sharbati*,1Cell Death and Disease (2017) 8, e2660; doi:10.1038/cddis.2017.84; published online 9 March 2017Trefoil factor family members (TFF1− 3) are small secretorypeptides on mucosal surfaces that regulate epithelial restitu-tion and wound healing by promoting cell migration andantagonising apoptosis. They have, in common, a structuraltrefoil motif that is stabilised by three disulphide bonds. TFFsare often co-secreted with mucins by mucin-producing cells,helping to maintain epithelial integrity in normal tissue.1 TFF3is constitutively expressed in the mammalian gastrointestinaltract; however, upregulation of TFF3 expression frequentlyobserved in human colorectal tumour cells exerts pro-invasiveactivity.2 Like other TFFs, TFF3 is regarded as a scatter factor,which interferes with AKT, EGFR and Wnt/β-cateninsignalling.3 There is increasing evidence that these pathwaystake an active part in progression of cancer 4 involvingnon-coding RNAs (ncRNAs).Only a few percent of themammalian genome are dedicatedto protein synthesis, but the remaining non-coding genomeeither harbours important regulatory regions or encodes aplethora of ncRNAs. The research on ncRNAs has incre-ased tremendously during the last two decades, revealingcontrol of central cellular processes such as proliferation orapoptosis in development and disease such as gastrointest-inal malignancies.5 Research on microRNAs unveiled manyunresolved regulatory mechanisms, and it is more than likelythat RNAseq-based discovery and annotation of longnon-coding RNAs (lncRNAs) will accelerate this progress inthe future. Along these lines, a further level of regulatory RNAnetworks governing cellular processes has been shown toexist by interactions between microRNAs and lncRNAs orpseudogenes.6Bearing this in mind, and because many TFF3-relevantsignalling pathways have been reported to be controlled byregulatory ncRNAs, we hypothesised that TFF3 may involveregulatory networks of ncRNAs to exert its effects as ascattering factor. In this context, in a recent study 7 we reportedthat TFF3 exerts resistance to TNF-α /IFN-γ-triggered apop-tosis in HT-29/B6 colorectal cancer cells by a signalling axisincluding ncRNAs. Based on specific RT-qPCR experiments,we identified several microRNAs and lncRNAs that weredifferentially regulated by the expression of TFF3. Amongothers, TFF3 reduces the expression of miR-491-5p in aPI3K/AKT-dependent fashion, which in turn is able to interactwith and downregulate the lncRNA PRINS. The miR-491-5p/PRINS-axis was shown to act as a master regulator ofapoptosis sensitivity in HT-29/B6 cells. PRINS detection byfluorescence in situ hybridisation (FISH) revealed certain focalsignals in nuclei of HT-29/B6 cells. In search for targets orinteraction partners of PRINS, gain-of-function aswell as loss-of-function experiments were performed, showing that thecellular concentration of PMAIP1 (NOXA) depends on PRINSavailability. PMAIP1 is a pro-apoptotic protein known to recruitMCL1 to mitochondria, causing its degradation. Interestinglyenough, in colorectal tumours PMAIP1 was detected both inthe cytosol and in the nuclei.8 Finally, combined immunofluor-escence and FISH experiments showed co-localised PRINSwith PMAIP1 in nuclei of HT-29/B6 cells. Pull-down of PMAIP1and co-precipitation of PRINS proved the interaction of bothmolecules, prompting their cooperative function in thenucleus. PRINS interacts either directly or together withribonucleoprotein complexes with PMAIP1. Experimentalreduction of PRINS causes PMAIP1 accumulation, suggest-ing that PRINS acts as a decoy to retain PMAIP1 in thenucleus, thereby prohibiting its pro-apoptotic activity inthe cytoplasm. Our ongoing studies are further resolving thenuclear function of PMAIP1.As mentioned above, TFF3 exerts its effects in a PI3K/AKT-dependent fashion. Currently, our knowledge about receptorsfor TFF peptides and how they trigger specific signalling islimited. Previously, CXCR4 has been described as a low-affinity TFF2 receptor.9 A more recent study reported thatCXCR4/7 heterodimers induce TFF3-dependent cellularmigration but not proliferation.10 Considering CXCR4 as apotential TFF3 receptor, diverse signalling pathways maycontribute to miR-491-5p/PRINS/PMAIP1-mediated regula-tion of apoptosis. Upon ligand binding CXCR4 may signalthrough the PI3K-PDK1 cascade, finally activating P70-S6Kdirectly or via AKT (Figure 1). In our study, recently publishedin Cell Death Discovery,7 we could show that chemicalinhibition of AKT resulted in increased expression ofmiR-491-5p. On the other hand, TFF3 overexpression didnot change the phosphorylation states of PDK1 and AKT, butchanged P70-S6K. Otherwise, CXCR4 activation in metasta-tic tumour cells was reported to activate small Rho-GTPasessuch as CDC42.11 In this context, TFF3-CXCR4-mediated1Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin, Oertzenweg 19b, Berlin 14163, Germany; 2Lise Meitner School ofScience, Rudower Strasse. 184, Berlin 12351, Germany and 3Institute of Biochemistry II, Jena University Hospital, Nonnenplan 2, Jena 07743, Germany*Corresponding author: Soroush Sharbati, Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin, Oertzenweg 19b, Berlin 14163,Germany. Tel: +403083862576; Fax: +493083862584; E-mail: soroush.sharbati@fu-berlin.deCitation: Cell Death and Disease (2017) 8, e2660; doi:10.1038/cddis.2017.84Ofﬁcial journal of the Cell Death Differentiation Associationwww.nature.com/cddisactivation of small Rho-GTPases could have an effect on theobserved regulatory axis by PAK1-dependent activation ofMAPK.12 Moreover, since in our study TFF3 also influencedcellular levels of PLCG2, a potential role of CXCR4-dependentPLCG/PKC signalling has to be taken into account (Figure 1).Furthermore, silencing of CXCR7 was shown to induceapoptosis in a β-arrestin- and ERK-dependent fashion.13However, whether β-arrestin and ERK pathway are involved inTFF3-dependent regulation of apoptosis in colon cancerprogression and metastasis has still to be addressed.In conclusion, our study7 provides further evidence thatnetworks of ncRNAs together with involved ribonucleoproteincomplexes present a wealth of unprecedented mechanismsthat persistently revolutionise our understanding of importantcellular processes, such as apoptosis and autophagy.Moreover, translational research on ncRNAs will providetargets for novel therapeutic strategies to combat, for example,resistance of malignancies to TRAIL-directed therapies ormulti-drug-resistant bacterial infections.Conflict of InterestThe authors declare no conflict of interest.Acknowledgements. This study was supported by the German ResearchFoundation (DFG) through SFB 852 Project B4, the H. Wilhelm Schaumann Stiftungand partly by the GRACE project (‘GMO Risk Assessment and Communication ofEvidence’), financially supported by the 7th Framework Program of the EuropeanCommission for Research, Technological Development and Demonstration Activities(FP7), Grant Agreement No. 311957. We acknowledge support by the GermanResearch Foundation and the Open Access Publication Funds of the FreieUniversität, Berlin.1. Scholven J et al. Cell Physiol Biochem 2009; 23: 143–156.2. Rivat C et al. Cancer Res 2005; 65: 195–202.3. Rodrigues S et al. Oncogene 2003; 22: 4488–4497.4. Hu T, Li C. Mol Cancer 2010; 9: 236.5. Jiang HJ, Wang S, Ding Y. Am J Stem Cells 2014; 3: 63–73.6. Salmena L et al. Cell 2011; 146: 353–358.7. Hanisch C et al. Cell Death Discov 2017; 3: 16106.8. Jansson AK et al. Oncogene 2003; 22: 4675–4678.9. Dubeykovskaya Z et al. J Biol Chem 2009; 284: 3650–3662.10. Dieckow J et al. Invest Ophthalmol Vis Sci 2016; 57: 56–65.11. Gassmann P et al. Neoplasia 2009; 11: 651–661.12. Qing H et al. Tumour Biol 2012; 33: 985–994.13. Li XX et al. Int J Oncol 2014; 45: 1649–1657.Cell Death and Disease is an open-access journalpublished by Nature Publishing Group. This work islicensed under a Creative Commons Attribution 4.0 InternationalLicense. The images or other third party material in this article areincluded in the article’s Creative Commons license, unless indicatedotherwise in the credit line; if the material is not included under theCreative Commons license, users will need to obtain permission fromthe license holder to reproduce the material. To view a copy of thislicense, visit http://creativecommons.org/licenses/by/4.0/r The Author(s) 2017Figure 1 Model of potential TFF3-induced signalling pathways mediating miR-491-5p/PRINS-axis. Based on our results and data from literature the following modes of TFF3action can be postulated. Potential binding of TFF3 to CXCR4 is considered to signal through PI3K/AKT, small Rho-GTPases, PLCG/PKC or β-arrestin-ERK. While our studieshave demonstrated PI3K/AKT to act via miR-491-5p/PRINS to trigger apoptosis, other CXCR4-dependent signalling cascades remain to be exploredNews and Commentary2Cell Death and Disease

Trefoil factor 3 mediates resistance to apoptosis in colon carcinoma cells by
a regulatory RNA axis

Carlos Hanisch

Jutta Sharbati

Barbara Kutz-Lohroff

Otmar Huber

Ralf Einspanier

Soroush Sharbati

Crossref

Trefoil factor 3 mediates resistance to apoptosis in colon carcinoma cells by a regulatory RNA axis

https://refubium.fu-berlin.de/bitstream/fub188/20245/1/cddis201784a.pdf

Trefoil factor 3 mediates resistance to apoptosis in colon carcinoma cells by a regulatory RNA axis

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