====== Invasive pituitary neuroendocrine tumor molecular markers ====== There are few studies on the mechanism of pituitary neuroendocrine tumor (PA) destroying [[bone]]. Zhu et al. aimed to investigate the role of [[MEG8]]/[[miR-454-3p]]/[[TNFα]] in bone-invasive pituitary neuroendocrine tumors (BIPAs). In this study, they reported that [[lncRNA]] MEG8 and TNF-α are upregulated in BIPA tissues while miR-454-3p is downregulated, which is associated with poor [[progression-free survival]] (PFS). Functional assays revealed the role of up-regulated MEG8 and down-regulated miR-454-3p in promoting bone destruction. Mechanistically, MEG8 promotes TNF-α expression by sponging miR-454-3p, which ultimately leads to the occurrence of bone destruction. The mechanism is confirmed in vivo and in vitro. Therefore, this data illustrated a new regulatory mechanism of MEG8/miR-454-3p/TNF-α in BIPAs. It may provide a useful strategy for diagnosis and treatment for BIPA patients ((Zhu HB, Li B, Guo J, Miao YZ, Shen YT, Zhang YZ, Zhao P, Li CZ. LncRNA MEG8 promotes TNF-α expression by sponging miR-454-3p in bone-invasive pituitary neuroendocrine tumors. Aging (Albany NY). 2021 May 19;13. doi: 10.18632/aging.203048. Epub ahead of print. PMID: 34016788.)). ---- A review summarized the known molecular basis of the invasiveness of pituitary neuroendocrine tumors. The study pointed out that [[Hypoxia-inducible factor]]-1α, [[pituitary tumor transforming gene]], vascular endothelial growth factor, fibroblast growth factor-2, and matrix metalloproteinases (MMPs, mainly [[MMP-2]], and [[MMP-9]]) are core molecules responsible for the invasiveness of pituitary neuroendocrine tumors. The reason is that these molecules have the ability to directly or indirectly induce cell proliferation, epithelial-to-mesenchymal transition, angiogenesis, degradation, and remodeling of the extracellular matrix. HIF-1α induced by hypoxia or apoplexy inside the adenoma might be the initiating factor of invasive transformation, followed by angiogenesis for overexpressed [[VEGF]], [[EMT]] for overexpressed [[PTTG]], degradation of [[ECM]] for overexpressed MMPs, creating a suitable microenvironment within the tumor. Together, they form a complex interactive network. More investigations are required to further elucidate the mechanisms underlying the invasiveness of pituitary neuroendocrine tumors ((Yang Q, Li X. Molecular Network Basis of Invasive pituitary neuroendocrine tumor: A Review. Front Endocrinol (Lausanne). 2019 Jan 24;10:7. doi: 10.3389/fendo.2019.00007. Erratum in: Front Endocrinol (Lausanne). 2019 Sep 24;10:657. PMID: 30733705; PMCID: PMC6353782.)). ---- Prior attempts have been made to define morphologic features and [[molecular marker]]s more commonly associated with invasive adenoma or pituitary carcinoma to help predict tumor behavior and discriminate between the two prior to identification of metastatic disease. These include quantification of the degree of cytologic [[atypia]] and [[mitotic activity]], examination of proliferation markers such as [[Ki-67]] using the [[MIB-1]] antibody and cell-cycle molecules such as [[p27]] and galectin-3, and gene expression of [[p53]], [[MGMT]], and [[MMP-9]] ((Beatriz M, Lopes S, Scheithauer BW, et al. Pituitary carcinoma. Endocrine. 2005;28:115–121.)) ((Chacko G, Chacko AG, Kovacs K, et al. The clinical significance of MIB-1 labeling index in pituitary neuroendocrine tumors. Pituitary. 2010;13:337–344.)) ((Hussaini IM, Trotter C, Zhao Y, et al. Matrix metalloproteinase-9 is differentially expressed in nonfunctioning invasive and noninvasive pituitary neuroendocrine tumors and increases invasion in human pituitary neuroendocrine tumor cell line. Am J Pathol. 2007;170:356–365.)) ((Lau Q, Scheithauer B, Kovacs K, et al. MGMT immunoexpression in aggressive pituitary neuroendocrine tumor and carcinoma. Pituitary. 2010;13:367–379.)) ((Pernicone PJ, Scheithauer BW, Sebo TJ, et al. Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer. 1997;79:804–812.)). ---- The aim of a study in 2017 was to identify the differences in expression of molecular markers between primary and relapsed pituitary neuroendocrine tumors (as an aggressiveness indicator), as well as between secreting and non-secreting pituitary neuroendocrine tumors. Tumor fragments were collected from 51 patients with invasive pituitary neuroendocrine tumors. Of these, 10 cases were operated on a second time due to tumor recurrence. The tumor fragments were retrieved from the archives of the Department of Pathology, Emergency County Hospital, Cluj-Napoca, Romania. Immunohistochemical staining was performed for nine markers on 51 invasive pituitary neuroendocrine tumors: [[Ki-67]], [[beta-catenin]], [[E-cadherin]], [[Bcl-2]], [[galectin-3]], [[p53]], [[p27]], [[CD117]], and [[CD44]]. They compared the expression differences between two groups: the first one including primary and relapsed invasive pituitary neuroendocrine tumors, and another one including prolactin (PRL)-secreting and non-secreting invasive pituitary neuroendocrine tumors. Ki-67, p53, and Bcl-2 expressions were found significant in the PRL-secreting group. CD44 immunostaining was significant only in relapsed invasive pituitary neuroendocrine tumors. For the β-catenin, E-cadherin, galectin-3, p27, and CD117 expression levels were not registered statistically significant differences between these groups. This study is the first one to report a statistically significant difference between the expression of [[CD44]] in primary and relapsed invasive pituitary neuroendocrine tumors and it could be used as a negative impact prognostic marker ((Moldovan IM, Şuşman S, Pîrlog R, Jianu EM, Leucuţa DC, Melincovici CS, Crişan D, Florian IŞ. Molecular markers in the diagnosis of invasive pituitary neuroendocrine tumors - an immunohistochemistry study. Rom J Morphol Embryol. 2017;58(4):1357-1364. PMID: 29556628.)). ---- [[TNF]]-α and its related lncRNAs and MicroRNAs represent potential therapeutic targets for bone-invasive pituitary neuroendocrine tumors in the future ((Zhu H, Guo J, Shen Y, Dong W, Gao H, Miao Y, Li C, Zhang Y. Functions and mechanisms of tumor necrosis factor-α and noncoding RNAs in bone-invasive pituitary neuroendocrine tumors. Clin Cancer Res. 2018 Jul 6. pii: clincanres.0472.2018. doi: 10.1158/1078-0432.CCR-18-0472. [Epub ahead of print] PubMed PMID: 29980532. )).