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Distinct microRNA expression profiles in mouse renal cortical tissue after 177Lu-octreotate administration.

ABSTRACT: AIM:The aim of this study was to investigate the variation of the miRNA expression levels in normal renal cortical tissue after 177Lu-octreotate administration, a radiopharmaceutical used for treatment of neuroendocrine cancers. METHODS:Female BALB/c nude mice were i.v. injected with 1.3, 3.6, 14, 45, or 140 MBq 177Lu-octreotate, while control animals received saline. The animals were killed at 24 h after injection and total RNA, including miRNA, was extracted from the renal cortical tissue and hybridized to the Mouse miRNA Oligo chip 4plex to identify differentially regulated miRNAs between exposed and control samples. RESULTS:In total, 57 specific miRNAs were differentially regulated in the exposed renal cortical tissues with 1, 29, 21, 27, and 31 miRNAs identified per dose-level (0.13, 0.34, 1.3, 4.3, and 13 Gy, respectively). No miRNAs were commonly regulated at all dose levels. miR-194, miR-107, miR-3090, and miR-3077 were commonly regulated at 0.34, 1.3, 4.3, and 13 Gy. Strong effects on cellular mechanisms ranging from immune response to p53 signaling and cancer-related pathways were observed at the highest absorbed dose. Thirty-nine of the 57 differentially regulated miRNAs identified in the present study have previously been associated with response to ionizing radiation, indicating common radiation responsive pathways. CONCLUSION:In conclusion, the 177Lu-octreotate associated miRNA signatures were generally dose-specific, thereby illustrating transcriptional regulation of radiation responsive miRNAs. Taken together, these results imply the importance of miRNAs in early immunological responses in the kidneys following 177Lu-octreotate administration.

SUBMITTER: Schuler E

PROVIDER: S-EPMC4227842 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Distinct microRNA expression profiles in mouse renal cortical tissue after 177Lu-octreotate administration.

Schüler Emil E Parris Toshima Z TZ Helou Khalil K Forssell-Aronsson Eva E

PloS one 20141111 11

<h4>Aim</h4>The aim of this study was to investigate the variation of the miRNA expression levels in normal renal cortical tissue after 177Lu-octreotate administration, a radiopharmaceutical used for treatment of neuroendocrine cancers.<h4>Methods</h4>Female BALB/c nude mice were i.v. injected with 1.3, 3.6, 14, 45, or 140 MBq 177Lu-octreotate, while control animals received saline. The animals were killed at 24 h after injection and total RNA, including miRNA, was extracted from the renal corti ...[more]

PMID: 25386939

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Project description:UnlabelledThe kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity.MethodsC57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy.ResultsIn general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months.ConclusionDistinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm applicability of these genes as markers of radiation damage in kidney tissue.

Project description:BACKGROUND:Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs. METHODS:The development and validation of the PPQ was undertaken in three independent 177Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n?=?72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n?=?44), and Erasmus Medical Center, Rotterdam, Netherlands (n?=?42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n?=?28 (100% low grade, 100% GEP-NET); SSA cohort II, n?=?51 (98% low grade; 76% GEP-NET); and an untreated cohort, n?=?44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n?=?8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses. RESULTS:In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64-79%), the PPQ was 95% accurate (Bad Berka: PPQ?+?=97%, PPQ-?=?93%; Rotterdam: PPQ?+?=94%, PPQ-?=?100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p?<?0.0001). In the comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months). CONCLUSION:The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.

Dataset Information

Distinct microRNA expression profiles in mouse renal cortical tissue after 177Lu-octreotate administration.

Publications

Distinct microRNA expression profiles in mouse renal cortical tissue after 177Lu-octreotate administration.

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