Oncogenic role of p53 is suppressed by si-RNA bicistronic construct of uPA, uPAR and cathepsin-B in meningiomas both in vitro and in vivo
Authors: Andrew J Tsung
Jasti S Rao
Sanjeeva Mohanam
Jeffrey D Klopfenstein
Venkateswara Rao Gogineni
Chandramu Chetty
Reshu Gupta
Arun Kumar Nalla
Journal: International Journal of Oncology (2011)
Discipline: CLINICAL MEDICINE
Keywords: Meningiomas; radiation therapy; DNA repair; cell survival; cell proliferation
Affiliations: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, IL 61605 , USA.

Abstract:  Meningiomas are the most commonly occurring intracranial tumors and account for approximately 15-20% of central nervous system tumors. Patients whose tumors recur after surgery and radiation therapy have limited therapeutic options. It has also been reported recently that radiation triggers DNA repair, cell survival and cell proliferation, and reduces apoptosis via the induction of cellular protective mechanisms. Earlier studies have reported that proteases such as uPA, uPAR and cathepsin B play important roles in tumor progression. In the present study, we attempted to determine the effectiveness of two bicistronic siRNA constructs pUC (uPAR/cathepsin B) and pU2 (uPA/uPAR) either alone or in combination with radiation, both in in vitro and in vivo models. Transfection of a plasmid vector expressing double-stranded RNA for uPA, uPAR and cathepsin B significantly induced the sub-G0-G1 cell population by the mitochondrial intrinsic apoptotic pathway. Results showed that pUC efficiently enhanced sub-G0-G1 phases compared to pU2 and was more effective. Interestingly, we observed that in IOMM-Lee cell lines, combined treatment of radiation with pUC and pU2 is more effective in comparison to SF-3061 and MN cell lines. We showed that apoptosis caused by these bicistronic constructs involves Bcl-2, Bcl-xL, p53 inactivation, cytochrome c release from mitochondria and caspase-9 activation, followed by the activation of caspase-3. We also determined that apoptosis caused by pUC and pU2 involves a mechanism which includes inactivation of p53 by its translocation from nucleus to cytoplasm as confirmed by immunofluorescence, which shows the oncogenic potential of p53 in meningiomas. However, the simultaneous RNAi-mediated targeting of uPAR and cathepsin B (pUC), in combination with irradiation, has greater potential application for the treatment of human meningioma in comparison to pU2 by decreasing p53 expression both in vitro and in vivo. 

Retracted: Yes

PubPeer comments:
 Figure 1B. In the bottom panel, two adjacent lanes look unexpectedly similar to each other. Highlighted here in red. ![file] , 
 Figure 2B: two of the GAPDH panels look unexpectedly similar to GAPHD panels in Figure 1B representing a different experiment. Shown with green and blue rectangles. ![file] , 
 Figure 3A shows some panels (shown in orange and purple pink) that look very similar to panels in other figures by these authors, but representing different experiments. The blue panel from Figure 1 and 2 also appears to appear again. The other 2 papers are: * International Journal of Oncology 38: 733-744, DOI: 10.3892 ijo.2010.883 * PLoS ONE 6(2): e17123, 2011, DOI: 10.1371 journal.pone.0017123 ![file] , 
 Figure 7D. Could the authors please explain how the same group of cells appears to be visible in the top 2 panel sets, as shown here in blue? And how the stretching appears to be different and not matching the Merged images? Also, can the authors provide some explanation of the possible double appearance of the same group of cells in the 2nd from the top p53 merged photos, as shown in yellow? ![file] , 
 February 8, 2021 retraction: https: www.spandidos-publications.com 10.3892 ijo.2021.5186 Following the publication of the above paper, we were contacted by the University of Illinois at Chicago, to request the retraction of the above article. Following a formal institutional investigation, the investigation panel concluded that the images in question had falsifying elements. Regarding the above study, the specific allegations that were investigated were that of falsifying elements of Fig. 1B, bottom panel, columns 2 and 3; Fig. 4A, top panel, columns 4, 5 and 6, and middle panel, columns 1, 2 and 3; and Fig. 7D, row 1, column 1 and row 2, column 1. Following a review of this paper conducted independently by the Editor of International Journal of Oncology, the Editor concurred with the conclusions of the investigation panel, and therefore the above paper has been retracted from the publication. We also tried to contact the authors, but did not receive a reply. The Editor apologizes to the readership for the inconvenience caused. Paper first reported to the journal in February 2016. , 
 See also https: retractionwatch.com 2021 03 15 falsifying-elements-prompt-retraction-of-three-more-papers-by-former-peorian-of-the-year ,