Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs

Meiping Chen; Lian Duan; Wei Sun; Zhengguang Guo; Hui Miao; Na Yu; Shengmin Yang; Linjie Wang; Fengying Gong; Yong Yao; Huijuan Zhu

doi:10.1159/000531200

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs

Neuroendocrinology. 2023;113(9):971-986. doi: 10.1159/000531200. Epub 2023 May 30.

Authors

Meiping Chen¹, Lian Duan¹, Wei Sun², Zhengguang Guo², Hui Miao¹, Na Yu¹, Shengmin Yang¹, Linjie Wang¹, Fengying Gong¹, Yong Yao³, Huijuan Zhu¹

Affiliations

¹ Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China.
² Proteomics Center, Core Instrument Facility, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
³ Department of Neurosurgery, Chinese Academy of Medical Science and Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China.

PMID: 37253344
DOI: 10.1159/000531200

Abstract

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.

Keywords: Biomarker; Cathepsin Z; Invasiveness; Proteomics; Somatotroph pituitary neuroendocrine tumours.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Neuroendocrine Tumors* / pathology
Phosphatidylinositol 3-Kinases / metabolism
Pituitary Neoplasms* / pathology
Proteomics
Somatotrophs* / metabolism

Substances

Phosphatidylinositol 3-Kinases