Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas
Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas
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DOI：
10.3892/or.2016.5132
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发表时间：
2016-11-01
期刊：
影响因子：
4.2
通讯作者：
Micci, Francesca
中科院分区：
文献类型：
--
作者：
Johannessen, Lene E.;Panagopoulos, Ioannis;Micci, Francesca
由位于同一染色体上邻近基因的外显子组合产生的融合转录本可能产生嵌合或新的蛋白质。这种通读转录本已经在不同的癌症中被检测到，在那里它们可能是致病的。在这项研究中，我们首次描述了可读转录物在胰岛素瘤（一种功能正常的胰腺神经内分泌肿瘤）中的表达。由胰岛素前体细胞（INS）和胰岛素样生长因子2 （IGF2）两个基因外显子组成的可读转录物INS-IGF2，都定位于染色体亚带11p15.5，在分析的两种胰岛素瘤中高表达。更准确地说，表达了版本2的INS-IGF2转录物，表明嵌合INS-IGF2蛋白可能表达。我们进一步在一个胰岛素瘤中发现了一种新的由INS3外显子1和IGF2外显子组成的INS-IGF2可读转录物的剪接变体。在同一肿瘤中，我们发现了INS3的高表达和SNP rs689的A等位基因的存在。SNP rs689先前已被描述为调节INS转录物的剪接，表明这种调节机制也影响INS- igf2的剪接。在肿瘤组织中特异性地发现了INS-IGF2读通转录物，而在正常胰腺组织中却没有，这表明INS-IGF2的高表达可能是肿瘤特异性的。这些结果可能具有潜在的临床应用，因为该可读转录物可作为胰岛素瘤患者的生物标志物。
Fusion transcripts arising from the combination of exons residing on neighboring genes on the same chromosome may give rise to chimeric or novel proteins. Such read-through transcripts have been detected in different cancers where they may be of pathogenetic interest. In this study, we describe for the first time the expression of a read-through transcript in insulinomas, a functioning neuroendocrine pancreatic neoplasm. The read-through transcript INS-IGF2, composed of exons from the two genes proinsulin precursor (INS) and insulin-like growth factor 2 (IGF2), both mapping to chromosomal subband 11p15.5, was highly expressed in the two insulinomas analyzed. More precisely, version 2 of the INS-IGF2 transcript was expressed, indicating possible expression of the chimeric INS-IGF2 protein. We further identified a novel splice variant of the INS-IGF2 read-through transcript in one of the insulinomas, composed of exon 1 of INS3 and exons of IGF2. In the same tumor, we found high expression of INS3 and the presence of the A allele at SNP rs689. SNP rs689 has been previously described to regulate splicing of the INS transcript, indicating that this regulatory mechanism also affects splicing of INS-IGF2. The identification of the INS-IGF2 read-through transcript specifically in tumor tissue but not in normal pancreatic tissue suggests that high expression of INS-IGF2 could be neoplasia-specific. These results may have potential clinical applications given that the read-through transcript could be used as a biomarker in insulinoma patients.