Abstract 2639: Insulin receptor alternative splicing during development and cancer

It has been shown that alternative splicing of some genes changes during development from embryogenesis to adulthood. Intriguingly, transformation of cells is also often accompanied by a reversion to the embryonic spliced isoforms. Insulin receptor (IN-R) undergoes alternative splicing to produce two isoforms: the full-length IN-RB isoform and the exon 11-skipped IN-RA isoform. The IN-RB isoform encodes a receptor with high affinity for insulin, while the IN-RA isoform has high affinity for both insulin & IGF2 growth hormones. IN-RAexploits the IGF pathway to accelerate growth, proliferation and angiogenesis. It is known that during embryogenesis the IN-R gets spliced to primarily express the INR-A form. Recently, the A isoform has has also been shown to be expressed in certain cancer types. Because the insulin receptor signaling converges on the mTOR/AKTpathway that is one of the most critical pathways for organismal development as well in cancer, it is important to understand the expression of these isoforms and their role in signaling and cellular fate. However, a tissue and a temporal description of the expression of these two isoforms is lacking. Towards this end we have shown that the mouse insulin receptor gene is spliced similarly to the human gene and have used the mouse model to study IR splicing during development. We harvested tissues from mice at different developmental stages (E10, E18, P1, P7, 3 months and 6 months) and performed RT-PCR for the insulin receptor gene. Our data confirmed that the whole embryos at embryonic day 10 (E10) express mostly IN-RA (90%). However, as the embryo develops and we can obtain discrete tissues we are able to detect tissue-specific profiles of IN-Rsplicing. For example, in bone at E18 as well as postnatal day P1 and 7, IN-RBis highly expressed (65%) and decreases to (40%) as the mouse reaches 6 months of age. Likewise, the liver and pancreas, which are primarily involved with metabolic functions, express mostly IN-RB(90%) from postnatal day P1 and into adult hood (6 months). In contrast, when we analyzed IR-splicing in human cancers, we find that in both liver cancer and cancers of the bone (osteosarcoma and Ewing’s sarcoma) there is a shift toward increased levels of the pro-proliferative isoform, IN-RA. We believe that understanding the molecular underpinnings of the splicing regulation during development will provide us with knowledge that will help us better understand the transformation process and how to control it, possibly through splicing corrective therapy.

Citation Format: Safiya Khurshid. Insulin receptor alternative splicing during development and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2639.