RNAi-mediated downregulation of urokinase plasminogen activator and its receptor in human meningioma cells inhibits tumor invasion and growth
Authors: Shakuntala Kondraganti
Jasti S Rao
Meena Gujrati
Dzung H Dinh
Christopher S Gondi
William C Olivero
Ian McCutcheon
Journal: International Journal of Oncology (2006)
Discipline: CLINICAL MEDICINE
Keywords: RNA interference; siRNA; proteases; gliomas; meningiomas
Affiliations: Program of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Peoria, IL 61656, USA.

Abstract:  In recent years, RNA interference (RNAi) has emerged as an effective method to target specific genes for silencing. Several groups are actively exploring the use of small interfering RNA (siRNA) for therapeutic applications to treat cancer. Our previous studies have demonstrated the inhibition of various proteases, including serine proteases, cysteine proteases and matrix metalloproteases, via RNA interference (RNAi) in gliomas. Similar to gliomas, malignant meningiomas also exhibit elevated protease levels in comparison to normal brain and benign meningiomas. Here, we used siRNA to simultaneously target urokinase plasminogen activator (uPA) and its receptor, uPAR. A human CMV promoter-driven mammalian expression vector (pU2) was used to produce hairpin double-stranded RNA (hp RNA) to target uPA and uPAR. As determined by Western blotting and fibrin zymography, pU2 effectively inhibited uPAR protein levels and uPA enzymatic activity in meningioma cells (IOMM-Lee). In vitro studies (Matrigel invasion and spheroid migration) revealed reduced meningioma cell invasion and migration. Intratumoral injections of the plasmid vector expressing siRNA for uPA and uPAR resulted in regression of pre-established, subcutaneous tumors in mice. In addition, in vivo studies of mice injected with pU2-transfected meningioma cells revealed inhibition of intracranial tumor formation. These findings suggest that siRNA can be used as a potent and specific therapeutic tool for the treatment of malignant meningiomas in humans. 

Retracted: No

PubPeer comments:
 Figure 1 shows an interesting phenomenon not discussed in the text. ![file] Maybe the authors could comment on the excess of discharged patients during the first wave indicated by the yellow circle? Is this a data error or a true effect? Do the authors really believe [in a steroid effect as  game changer ] by the publication dates of their references? Could the authors please check their numbers also? Having digitized FIG 1 + 2, I count only 36.700 patients in this study while the official RKI report speaks of 50,457 patients in 2020. What is correct? ![file] , 
 As the plots in the letter do not really illustrate the message of the paper that the proportion of hospitalised patients requiring ICU treatment steadily dropped from 30% during the period of our previous analysis (ie, discharge up to week 23) to 14% in December (weeks 49u201352) here is more adequate plot from [a new government report](chrome-extension: oemmndcbldboiebfnladdacbdfmadadm https: www.bundesgesundheitsministerium.de fileadmin Dateien 3_Downloads C Coronavirus Analyse_Leistungen_Ausgleichszahlungen_2020_Corona-Krise.pdf)  Analysen zum Leistungsgeschehen der Krankenhu00e4user und zur Ausgleichspauschale in der Corona-Krise p15 ![file] So number of hospitalization increases in the second wave while ICU treatment doesn t. Looks like overtreatment in the first wave. , 
 #1 Dear colleague, thanks for reading our paper so carefully. Bringing clarity into this important topic is really not so easy. It is important to understand, however, that there are two separate sources of data for ICU treatments of COVID-19 patients in Germany: (1) The so called DIVI register, which uses daily reporting by all ICU units ( 1000) in Germany, mainly reporting on current numbers of COVID patients, other patients and available beds. They also count  finished cases which however cannot be taken as discharged or dead as patients might be moved from normal ward to intensive care several times during their hospitalisation (or from one ICU to the other), and are counted twice. Unfornately, the RKI is using these data for its reports. And yes, they report around 50,000 for 2020. (2) The second source are the routine discharge statistics, which in  normal years would be available only much later. Since 2020, hospitals are required to submit these to InEK, the German Hospital Payment Institute, three times a year, last for December 31, 2020. These numbers show that  only around 38,000 COVID patients have been treated in ICUs. Both the  government report which you cite (I am actually the author of that section) and our article in LRM uses these data. In the former we use the week of admission, in the latter the week of discharge. As you point out, if one uses the latter, there is a clear effect of those dying to do so relatively earlier that those surving ICU. I hope this clarifies! Reinhard Busse and Christian Karagiannidis , 
 Thank you so much for the additional explanation (unfortunately the DIVI register never validated, refined and extended the data collection for more qualified studies despite excessive funding. IMHO an ICU registry shouldn t be used as guidepost for politics - do we really intentionally want to fill ICUs?) So we agree on the discrepancy of basic numbers - approx 38,000 COVID cases @InEK in this paper and 50,000 @DIVI as reported by RKI. Unfortunately hospital COVID-19 readmission rates are high - for example 29% in [GB] and 20% in [US] while I couldn t find any number of ICU re-admissions in Germany. Using the back of an envelope and subtracting just those 13,000 ICU deaths of the 38,000 ICU cases who cannot be re-admitted - numbers in this paper or @DIVI are off target. It would mean that every discharged ICU patient would have been readmitted to reach 50,000 ICU admissions @DIVI. Sorry, also the difference introduced by week of admission and discharge does not explain that. BTW I see also a deficit of 500 ICU deaths in this paper... Glad that you also do not repeat the steroid effect as  game changer and that do not reject my assumption of ICU overtreatment. ,