INTRODUCTION Somatotroph pituitary neuroendocrine tumours (PitNETs) are characterized by complex and variable biological behaviours with unpredictable patterns of growth and invasiveness. The molecular mechanisms and reliable predictors of biological markers of invasiveness remain unknown. METHODS Seventy-two acromegaly patients were consecutively enrolled. Data-independent acquisition-based proteomics and ingenuity pathway analysis were conducted between invasive and noninvasive somatotroph PitNETs. The expression of selected biomarkers was verified in PitNET tissue, and its correlation with various clinical indicators and outcomes of these tumours was assessed. The invasive phenotypes of GH3 cells were validated in vitro. RESULTS Patients with invasive somatotroph PitNETs were significantly younger at onset and diagnosis, with significantly higher secretion and faster growth and a lower long-term biochemical response rate than patients with noninvasive somatotroph PitNETs. Proteomic data were evaluated in a consecutively collected sample of 19 (10 invasive and 9 noninvasive somatotroph PitNETs) tumours and indicated a distinct proteomic pattern. The enriched and important pathways included IL-4, PDGF, PTEN, VEGF, PI3K/AKT, FAK, and other pathways that were significantly associated with tumour proliferation, migration, and invasion. High cathepsin Z (CTSZ) expression was found in invasive somatotroph PitNETs and significantly positively correlated with parameters of tumour invasion and growth. In Ctsz-overexpressing GH3 cells, cell proliferation, invasion, and migration were consequently increased. CONCLUSION It is more difficult for patients with invasive somatotroph PitNETs to achieve remission than those with noninvasive somatotroph PitNETs, and proteomic data analysis has revealed the high expression of CTSZ as a contributing factor to invasive transformation and poor prognosis in somatotroph PitNETs for the first time.

中文翻译：

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侵入性和非侵入性生长激素 PitNET 的临床和基于蛋白质组学的分子特征。

引言 生长激素垂体神经内分泌肿瘤（PitNET）具有复杂多变的生物学行为以及不可预测的生长和侵袭模式。侵袭性生物标志物的分子机制和可靠的预测因子仍然未知。方法连续纳入72例肢端肥大症患者。在侵入性和非侵入性生长激素 PitNET 之间进行了基于数据独立采集的蛋白质组学和独创性路径分析。在 PitNET 组织中验证了所选生物标志物的表达，并评估了其与这些肿瘤的各种临床指标和结果的相关性。GH3细胞的侵袭表型在体外得到验证。结果 与非侵入性生长激素 PitNET 患者相比，侵入性生长激素 PitNET 患者在发病和诊断时明显更年轻，分泌量明显更高，生长更快，长期生化反应率更低。在连续收集的 19 个肿瘤样本（10 个侵袭性生长激素 PitNET 和 9 个非侵袭性生长激素 PitNET）中评估了蛋白质组数据，并表明了独特的蛋白质组模式。丰富且重要的通路包括IL-4、PDGF、PTEN、VEGF、PI3K/AKT、FAK以及其他与肿瘤增殖、迁移和侵袭显着相关的通路。在侵袭性生长激素 PitNET 中发现组织蛋白酶 Z (CTSZ) 高表达，并且与肿瘤侵袭和生长参数显着正相关。在 Ctsz 过表达 GH3 细胞中，细胞增殖、侵袭和迁移因此增加。结论 侵袭性生长激素 PitNET 患者比非侵袭性生长激素 PitNET 患者更难获得缓解，蛋白质组数据分析首次揭示 CTSZ 高表达是生长激素 PitNET 侵袭性转化和不良预后的影响因素。