DataSheet_1_Medication for Acromegaly Reduces Expression of MUC16, MACC1 and GRHL2 in Pituitary Neuroendocrine Tumour Tissue.docx

Acromegaly is a disease mainly caused by pituitary neuroendocrine tumor (PitNET) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogs (SSAs), that decrease tumor mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumor tissue from twelve patients with somatotropinomas, with half of the patients receiving SSA/DA treatment before surgery and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein–protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumor development promoting factors MUC16, MACC1, and GRHL2, were significantly downregulated in therapy administered PitNET tissue; this finding was supported by functional studies in GH3 cells. Protein–protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotropinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA significantly downregulated several factors involved in tumorigenesis, including MUC16, MACC1, and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumor suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumor effect of drug treatment.

肢端肥大症（Acromegaly）是一种主要由垂体神经内分泌肿瘤（pituitary neuroendocrine tumor, PitNET）过度分泌生长激素所引发的疾病。该病症的一线治疗药物为生长抑素类似物（somatostatin analogs, SSAs），其可缩小肿瘤体积并对PitNET细胞发挥抗增殖作用；若生长抑素类似物治疗无效，也可使用多巴胺激动剂（dopamine agonists, DAs）。本研究旨在明确经生长抑素类似物/多巴胺激动剂（SSA/DA）治疗后，PitNET组织中诱导产生的转录组特征差异。我们选取了12例生长激素瘤患者的肿瘤组织，其中半数患者在术前接受了SSA/DA治疗，另一半则为初治患者。随后通过转录组测序（transcriptome sequencing）鉴定差异表达基因（differentially expressed genes, DEGs）及其蛋白质相互作用，并进行通路分析。我们在接受SSA/DA治疗的患者样本中发现了34个上调差异表达基因与6个下调差异表达基因。3个肿瘤发生促进因子——MUC16、MACC1及GRHL2，在经治疗的PitNET组织中显著下调，该结果在GH3细胞系的功能实验中得到了验证。蛋白质相互作用与通路分析显示，细胞外基质（extracellular matrix）参与了此类药物治疗的抗增殖作用，且胶原调控过程发生了显著改变。本研究证实，可根据生长激素瘤经SSA/DA治疗后的转录谱对其进行区分，且SSA/DA治疗确实会引起基因表达的改变。SSA/DA治疗可显著下调多种肿瘤发生相关因子，包括MUC16、MACC1及GRHL2；而上调的基因则未对PitNET细胞的抗增殖功能产生直接影响。上述结果表明，SSA/DA治疗以抑瘤方式发挥作用，且富集到了胶原相关的相互作用与通路，提示细胞外基质参与了此类药物治疗的抗肿瘤效应。