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Silencing Intersectin 1 Slows Orthotopic Neuroblastoma Growth in Mice

Harris, Jamie MD*; Herrero-Garcia, Erika PhD†,‡; Russo, Angela PhD†,‡; Kajdacsy-Balla, Andre MD§; O’Bryan, John P. PhD†,‡,∥; Chiu, Bill MD

Journal of Pediatric Hematology/Oncology: November 2017 - Volume 39 - Issue 8 - p e413–e418
doi: 10.1097/MPH.0000000000000931
Online Articles: Original Articles
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Neuroblastoma accounts for 15% of all pediatric cancer deaths. Intersectin 1 (ITSN1), a scaffold protein involved in phosphoinositide 3-kinase (PI3K) signaling, regulates neuroblastoma cells independent of MYCN status. We hypothesize that by silencing ITSN1 in neuroblastoma cells, tumor growth will be decreased in an orthotopic mouse tumor model. SK-N-AS neuroblastoma cells transfected with empty vector (pSR), vectors expressing scrambled shRNA (pSCR), or shRNAs targeting ITSN1 (sh#1 and sh#2) were used to create orthotopic neuroblastoma tumors in mice. Volume was monitored weekly with ultrasound. End-point was tumor volume >1000 mm3. Tumor cell lysates were analyzed with anti-ITSN1 antibody by Western blot. Orthotopic tumors were created in all cell lines. Twenty-five days post injection, pSR tumor size was 917.6±247.7 mm3, pSCR was 1180±159.9 mm3, sh#1 was 526.3±212.8 mm3, and sh#2 was 589.2±74.91 mm3. sh#1-tumors and sh#2-tumors were smaller than pSCR (P=0.02), no difference between sh#1 and sh#2. Survival was superior in sh#2-tumors (P=0.02), trended towards improved survival in sh#1-tumors (P=0.09), compared with pSCR-tumors, no difference in pSR tumors. Western blot showed decreased ITSN1 expression in sh#1 and sh#2 compared with pSR and pSCR. Silencing ITSN1 in neuroblastoma cells led to decreased tumor growth in an orthotopic mouse model. Orthotopic animal models can provide insight into the role of ITSN1 pathways in neuroblastoma tumorigenesis.

*Department of Surgery, Rush University Medical Center

Department of Pharmacology, College of Medicine, University of Illinois at Chicago

Jesse Brown VA Medical Center

Departments of § Pathology

Surgery, University of Illinois at Chicago

University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL

Supported by the Warren and Clara Cole Career Development Award and NIH Award to B.C. (NS094218); a Merit Review Award (1I01BX002095) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service and NIH award to J.P.O. (CA116708). The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.

The authors declare no conflict of interest.

Reprints: Bill Chiu, MD, Department of Surgery, University of Illinois at Chicago, 840 S. Wood Street, Suite 416, Chicago, IL 60612 (e-mail: bchiumd@uic.edu).

Received January 6, 2017

Accepted July 10, 2017

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