Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.
Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain.
Mol Oncol. 2022 Feb;16(3):764-779. doi: 10.1002/1878-0261.13107. Epub 2021 Oct 26.
Somatostatin receptor subtype 5 (SST ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.
生长抑素受体亚型 5（SST）是垂体（PitNETs）和胰腺（PanNETs）神经内分泌肿瘤的新兴生物标志物和可操作靶点。SSTR5 基因表达和 mRNA 生物发生的转录和表观遗传调控知之甚少。最近，发现了一种重叠的天然反义转录本 SSTR5-AS1，它可能调节 SSTR5 的表达。我们旨在阐明表观遗传过程是否有助于调节 PitNETs（生长激素瘤）和 PanNETs 中的 SSTR5 表达。我们通过定量实时 PCR（qPCR）在 27 例生长激素瘤、11 例正常垂体（NPs）和 15 例 PanNETs/配对相邻（对照）样本中分析了 SSTR5/SSTR5-AS1 人基因座，以鉴定 CpG 岛。我们评估了 SSTR5/SSTR5-AS1 基因中四个 CpG 岛的甲基化程度。结果表明，在 NP、生长激素瘤和 PanNET 样本中 SSTR5 和 SSTR5-AS1 直接相关。有趣的是，与 NPs 相比，选定的 CpG 岛在生长激素瘤中存在差异甲基化。在 PanNET 细胞系中，SSTR5-AS1 沉默下调 SSTR5 表达，改变侵袭性特征，并影响培高利特反应。这些结果表明，PitNETs 和 PanNETs 中的 SSTR5 表达可以通过 SSTR5-AS1 反义转录本的表观遗传调控，以及间接通过 DNA 甲基化来调控，这可能影响肿瘤行为和治疗反应。
