Somatostatin Analogue Treatment Primarily Induce miRNA Expression Changes and Up-Regulates Growth Inhibitory miR-7 and miR-148a in Neuroendocrine Cells

Abstract

Somatostatin (SST) analogues are used to control the proliferation and symptoms of neuroendocrine tumors (NETs). MicroRNAs (miRNA) are small non-coding RNAs that modulate posttranscriptional gene expression. We wanted to characterize the miRNAs operating under the control of SST to elucidate to what extent they mediate STT actions. NCI-H727 carcinoid cell line was treated with either a chimeric SST/dopamine analogue; a SST or dopamine analogue for proliferation assays and for identifying differentially expressed miRNAs using miRNA microarray. The miRNAs induced by SST analogue treatment are investigated in carcinoid cell lines NCI-H727 and CNDT2 using in situ hybridization, qPCR and proliferation assays. SST analogues inhibited the growth of carcinoid cells more potently compared to the dopamine analogue. Principal Component Analysis (PCA) of the samples based on miRNA expression clearly separated the samples based on treatment. Two miRNAs which were highly induced by SST analogues, miR-7 and miR-148a, were shown to inhibit the proliferation of NCI-H727 and CNDT2 cells. SST analogues also produced a general up-regulation of the let-7 family members. SST analogues control and induce distinct miRNA expression patterns among which miR-7 and miR-148a both have growth inhibitory properties.

Treatment with somatostatin analogs induces differentially expressed let-7c-5p and mir-3137 in small intestine neuroendocrine tumors

“…The already characterized and published miRNAs (except let-7c), however, did not play a role in the present study. Regarding let-7c, our results are supported by Døssing et al who recently have shown that SSA leads to an upregulation of let-7 family members [42], which inhibits the growth of carcinoid cell lines [31]. Therefore, the alterations seen in the present study may in part be induced by SSA treatment and adds further information in assessing the role of miRNAs in neuroendocrine tumors.…”

“…SSTR type-2 (SSTR2) is abundantly expressed on the surface of well-differentiated GEP-NETs [8, 42]. In this respect, in silico target gene analyses revealed that mir-185-3p directly interacts with SSTR2.…”

Elevated miR-16-5p induces somatostatin receptor 2 expression in neuroendocrine tumor cells

“…Few studies have determined the expression patterns of SSA-related miRNAs. Recently, Døssing et al identified distinct dysregulation of miRNAs, including miR-7 and miR-148a, in the human neuroendocrine tumor cell line NCI-H727 after treatment with SSA [ 15 ]. Another study revealed that circulating miR-200a is involved in metastasis during SSA-treated small intestine NET progression [ 16 ].…”

MicroRNAs and Treatment with Somatostatin Analogs in Gastro- Entero-Pancreatic Neuroendocrine Neoplasms: Challenges in Personalized Medicine

“…Moreover, SSTRs are also expressed in human cancers, including GEP-NENs, with characteristic receptor profiles being described in certain tumors. However, the SSTR profiles vary considerably between tumor types and also between tumors of the same type, with 70-90% of GEP-NENs most frequently expressing SSTR2, followed by SSTR5 [22][23][24].…”