垂体和胰腺神经内分泌肿瘤中生长抑素受体亚型 5 (SST5) 的表观遗传和转录后调控,Molecular Oncology

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垂体和胰腺神经内分泌肿瘤中生长抑素受体亚型 5 (SST5) 的表观遗传和转录后调控
Molecular Oncology ( IF 5.0 ) Pub Date : 2021-10-03 , DOI: 10.1002/1878-0261.13107
Sergio Pedraza-Arevalo _{1,

2,

3,

4} , Alejandro Ibáñez-Costa _{1,

2,

3,

4} , Ricardo Blázquez-Encinas _{1,

2,

3,

4} , Miguel R Branco ₅ , Mari C Vázquez-Borrego _{1,

2,

3,

4} , Aura D Herrera-Martínez _{1,

6} , Eva Venegas-Moreno ₇ , Raquel Serrano-Blanch _{1,

8} , Álvaro Arjona-Sánchez _{1,

9} , María A Gálvez-Moreno _{1,

6} , Marta Korbonits ₁₀ , Alfonso Soto-Moreno ₇ , Manuel D Gahete _{1,

2,

3,

4} , Marika Charalambous ₁₁ , Raúl M Luque _{1,

2,

3,

4} , Justo P Castaño _{1,

2,

3,

4}

Affiliation

Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.
Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.
Reina Sofia University Hospital, Córdoba, Spain.
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain.
Metabolism and Nutrition Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain.
Medical Oncology Service, Reina Sofia University Hospital, Córdoba, Spain.
Surgery Service, Reina Sofia University Hospital, Córdoba, Spain.
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Developmental Epigenetics group, Department of Medical and Molecular Genetics, King's College of London, London, UK.

生长抑素受体亚型 5 (SST ₅ ) 是垂体 (PitNETs) 和胰腺 (PanNETs) 神经内分泌肿瘤中新兴的生物标志物和可操作靶标。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，鉴定了一种重叠的天然反义转录物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。我们在计算机中分析了SSTR5 / SSTR5-AS1人类基因座以识别 CpG 岛。SSTR5通过定量实时 PCR (qPCR) 在 27 个生长激素瘤、11 个正常垂体 (NPs) 和 15 个 PanNETs/配对相邻（对照）样本中评估SSTR5 -AS1 的表达。我们评估了SSTR5 / SSTR5-AS1基因中四个 CpG 岛的甲基化等级。结果显示，SSTR5和SSTR5-AS1在 NP、生长激素瘤和 PanNET 样本中直接相关。有趣的是，与 NP 相比，选定的 CpG 岛在生长激素瘤中的甲基化程度不同。在 PanNETs 细胞系中，SSTR5-AS1沉默下调SSTR5表达，改变攻击性特征，并影响帕瑞肽反应。这些结果提供了证据表明PitNETs 和 PanNETs 中的SSTR5表达可以通过SSTR5-AS1反义转录物进行表观遗传调节，并间接通过 DNA 甲基化调节，从而影响肿瘤行为和治疗反应。

"点击查看英文标题和摘要"

Epigenetic and post-transcriptional regulation of somatostatin receptor subtype 5 (SST5) in pituitary and pancreatic neuroendocrine tumors

Somatostatin receptor subtype 5 (SST₅) 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.

更新日期：2021-10-03

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