Abstract
Non-functional pituitary adenomas (NFPAs) are one of the most prevalent pituitary adenoma subtypes. The lack of reliable screening approach for NFPAs for the insidious clinical course usually leads to delays in medical therapy and consequently worse prognosis. Hence, we employed a sequence cohort (patient: control, 6:2) and a validation cohort (patient: control, 22:8) to develop a serum exosomal miRNA profile-based method for NFPA screening and prognosis prediction. We found that a total of 1,395 kinds of human miRNA were detected. Compared with healthy donors, 18 up-regulated and 36 down-regulated miRNAs showed significant expression alterations in NFPA patients. Target genes of differentially expressed miRNAs are mainly enriched in axonogenesis and cancer-associated terms. After validation, hsa-miR-486-5p, hsa-miR-151a-5p, hsa-miR-652-3p_R+1, and hsa-miR-1180-3p were promising biomarkers for NFPA, in which miR-486-5p was the most competent one. After a median of 33 months of prospective follow-up, exosomal hsa-miR-486-5p also was an efficient predictive biomarker for progression or relapse of NFPAs. By protein-protein interaction network construction of hsa-miR-486-5p targeted genes, the core modules revealed a high possibility that exosomal hsa-miR-486-5p regulated tumor progression by epigenetic regulation of MAPK signaling pathways. In conclusion, exosomal hsa-miR-486-5p, hsa-miR-151a-5p, hsa-miR-652-3p_R+1, and hsa-miR-1180-3p are candidate biomarkers for diagnosis and screening of NFPAs. More importantly, prospective follow-up reveals that hsa-miR-486-5p can be regarded as a significant predictor for prognosis of NFPAs.
Highlights
Pituitary adenoma (PA) is a heterogeneous entity derived from the adenohypophysis
Non-functional pituitary adenomas (NFPAs) were categorized into null cell, gonadotroph, plurihormonal, and corticotroph adenomas according to postoperative pathological studies (Lopes, 2017)
Western blotting data revealed that these particles expressed CD63 and TSG101, which were widely accepted markers of exosome (Figure 1E)
Summary
Based on the clinical manifestations, PAs are categorized into non-functional PAs and functional PAs (FPAs) which include growth hormone (GH)-secreting adenoma (GHPA), prolactinoma, thyrotropin (TSH)-secreting adenoma, and corticotropin (ACTH)-secreting adenoma (Tjörnstrand and Nyström, 2017). The diagnosis of NFPAs is drawn only after ruling out other subtypes of PAs. most PAs are benign, a significant number of PAs possess an aggressive clinical course (Di Ieva et al, 2014). Different from FPAs, owing to the absence of significant clinical clues, NFPAs tend to be invasive macroadenomas at diagnosis, which may exacerbate the therapeutic outcomes and medical costs. The development of novel screening and diagnostic method, especially non-invasive or microinvasive technique, for NFPAs would improve the accuracy of diagnosis and subsequent treatment strategy as well as the efficiency of postoperative management of NFPA patients
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