Abstract
Mismatch repair genes mutS homologs 6/2 (MSH6/2) expressions are involved in tumor growth and programmed cell death 1 ligand 1 (PD-L1) expression in tumor immunity, but the direct association with pituitary adenomas (PAs) is not well understood. We aimed to clarify the effects of MSH6/2 and PD-L1 expression on tumor proliferation and invasiveness in nonfunctioning (NF) PAs. We performed immunohistochemistry to classify the NFPAs into gonadotroph adenoma (GAs), silent corticotroph adenomas (SCAs), null cell adenoma (NCAs), and pituitary transcription factor 1 (PIT1) lineage PAs. We evaluated MSH6/2 and PD-L1 mRNA expressions in NFPAs by real-time PCR (n = 73), and statistically analyzed the expressions and clinicopathological factors. We also investigated the effect of MSH6 knockout on PD-L1 expression in AtT-20ins and GH3. MSH6/2 expressions were significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. MSH6/2 expressions were positively associated with PD-L1 expression. PD-L1 expression was significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. Although MSH6/2 expressions also tended to be lower in PIT1 lineage PAs than in GAs, PIT1 lineage PAs expressed PD-L1 equivalently to GA, which was unlike SCAs and NCAs. MSH6 knockout in AtT-20ins and GH3 significantly decreased PD-L1 expression (75% and 34% reduction, respectively) with cell proliferation promotion. In conclusion, differences in MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1-lineage PAs from those of GAs appear to contribute to their clinically aggressive characteristics, such as more proliferation and invasiveness.
Highlights
Pituitary adenomas (PAs) are common intracranial tumors comprising 15% to 20% of all brain tumors, which have been recently referred to as “pituitary neuroendocrine tumors” (Pit-NETs) [1,2]
We recently reported that reduced expression of mismatch repair (MMR) genes MSH6/MSH2 directly promotes pituitary tumor proliferation via the ataxia telangiectasia and Rad3-related-checkpoint kinase 1 (ATR-Chk1) pathway [11,12]
The expressions of mutS homologs 6/2 (MSH6/2) and programmed cell death 1 ligand 1 (PD-L1) were significantly lower in invasive non-functioning pituitary carcinomas (NFPAs) than in non-invasive NFPAs
Summary
Pituitary adenomas (PAs) are common intracranial tumors comprising 15% to 20% of all brain tumors, which have been recently referred to as “pituitary neuroendocrine tumors” (Pit-NETs) [1,2]. PAs are predominantly benign tumors, but they include highly proliferative and invasive tumors, such as aggressive PAs and pituitary carcinomas [3,4]. Regarding proliferation, when non-functioning pituitary carcinomas (NFPAs) are pathologically classified based on 2017 World Health Organization (WHO) classifications, null cell adenoma (NCA), silent corticotroph adenoma (SCA), and PIT1-lineage PA are reportedly highly proliferative and invasive [5,6,7,8,9]. We recently reported that reduced expression of mismatch repair (MMR) genes MSH6/MSH2 directly promotes pituitary tumor proliferation via the ataxia telangiectasia and Rad3-related-checkpoint kinase 1 (ATR-Chk1) pathway [11,12]. In PAs, MMR genes may be target molecules for future drug therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
