Abstract
Ileal neuroendocrine tumors (I-NETs) are the most common tumors of the small intestine. Although I-NETs are known for a lack of recurrently mutated genes, a majority of tumors do show loss of one copy of chromosome 18. Among the genes on chromosome 18 is MIR1-2, which encodes a microRNA, MIR1-3p, with high complementarity to the mRNA of CDK4. Here we show that transfection of neuroendocrine cell lines with MIR1-3p lowered CDK4 expression and activity, and arrested growth at the G1 stage of the cell cycle. Loss of copy of MIR1-2 in ileal neuroendocrine tumors associated with increased expression of CDK4. Genetic events that attenuated RB activity, including loss of copy of MIR1-2 as well as loss of copy of CDKN1B and CDKN2A, were more frequent in tumors from patients with metastatic I-NETs. These data suggest that inhibitors of CDK4/CDK6 may benefit patients whose I-NETs show loss of copy of MIR1-2, particularly patients with metastatic disease.
Highlights
Neuroendocrine cells are found throughout the body, from the pituitary to the rectum
Ileal neuroendocrine tumors (I-neuroendocrine tumors (NETs)), we examined this chromosome for the presence of potential tumor suppressor genes
We focused on potential activators of the RB1 tumor suppressor, because the RB1 pathway is associated with several types of NETs29–31 and because this pathway can be attenuated by loss of CDKN1B, which is the only gene that is recurrently mutated in I-NETs23,25,32
Summary
Neuroendocrine cells are found throughout the body, from the pituitary to the rectum. These hormone-producing cells are usually under tight growth regulation. As with many cell types, growth controls can go awry, allowing hyperplasias or even tumors to form. Because neuroendocrine tumors (NETs) often remain well-differentiated and continue to produce hormones, the first symptoms experienced by patients with NETs are often hormone-related. One of the most common sites of NETs is the ileum of the small intestine[1,2,3]. Ileal neuroendocrine tumors (I-NETs) are usually multifocal, well-differentiated tumors that produce the hormone serotonin. Overproduction of serotonin can lead to chronic diarrhea and skin flushing; these symptoms are part of a condition known as carcinoid
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