THU560 Serum miRNA-483 As A Diagnostic And Therapeutic Marker Of IGF-II-producing Non-islet Cell Tumor Hypoglycemia (NICTH)

Abstract

Abstract Disclosure: M. Okazaki-Hada: None. M. Nagao: Grant Recipient; Self; The Foundation for Growth Science. A. Asai: None. I. Fukuda: None. L. Eliasson: None. M. Iwabu: None. Objective: Non-islet cell tumor hypoglycemia (NICTH) is known as the second major cause of spontaneous hypoglycemia next to insulinoma. Abnormal higher molecular weight forms of insulin-like growth factor II (IGF-II), so-called “big IGF-II”, are frequently detected in the sera of patients with NICTH. Thus, the disease is referred to as IGF-II-producing NICTH. We have previously reported a significant elevation of serum microRNA (miRNA)-483-5p and -3p levels in patients with IGF-II-producing NICTH. The miRNA-483 family are encoded in an intron of IGF2 gene and thus suggested to be co-expressed with IGF-II. The aim of this study was to validate the usefulness of miRNA-483 family as a diagnostic and therapeutic marker of IGF-II producing NICTH, then to examine if the IGF-II-producing tumor tissues could be the source of these circulating miRNAs Design: Serum samples from patients who had been suspected to have IGF-II-producing NICTH (n = 134) were tested. The presence of big IGF-II was confirmed by Western blotting, and miRNA-483-5p and -3p levels were evaluated by quantitative PCR. IGF-II level was also analyzed by ELISA. In addition, IGF-II, miRNA-483-5p and -3p levels were compared before and after tumor removal in serum samples from surgically treated patients with IGF-II-producing NICTH (n=21). Expression levels of miRNA-483-5p and -3p were also analyzed in the big IGF-II-expressing tumor tissues and the surrounding surgical margins (n=9). Results: Big IGF-II was detected in the sera of 91 out of 134 patients. IGF-II, miRNA-483-5p and -3p levels were significantly higher in sera with big IGF-II than in those without. The area under the receiver operating characteristic curve of miRNA-483-5p (0.85) for IGF-II-producing NICTH were higher than those of miRNA-483-3p (0.75) and IGF-II (0.75). After tumor removal, serum miRNA-483-5p level decreased (P=0.0025), but serum miRNA-483-3p and IGF-II levels did not change significantly. The expression levels of miRNA-483-5p and -3p in the tumor tissues were significantly higher than those in the surgical margins (18 and 51 times for miRNA-483-5p and -3p, respectively). Conclusion: The present study confirms that miRNA-483-5p and -3p are elevated in sera of patients with IGF-II-producing NICTH and shows that miRNA-483-5p is significantly reduced after the surgical removal of big IGF-II-producing tumors. These results highlight the usefulness of the miRNA-483 family as a diagnostic and therapeutic marker for IGF-II-producing NICTH, and strongly suggest that the tumors produce miR-483-5p and -3p in parallel with the production of big IGF-II. Presentation: Thursday, June 15, 2023