The Role Of Long Non-Coding RNA H19 In Pituitary Tumorigenesis

Pituitary tumor is a common intracranial tumor,accounting for about 15% of all intracranial tumors.In recent years,the incidence of pituitary tumor showed an increasing trend.Although pituitary tumor is a benign tumor that does not pose a threat to the life of the patient,it can cause visual disturbances and severe clinical syndromes such as infertility and metabolic syndrome caused by abnormal hormones or tumors,which will seriously affect the quality of life of patients.Due to the lack of effective therapeutic targets and the complicated tumorigenesis mechanisms of pituitary tumor,it is a huge challenge for clinical treatment of pituitary tumor.Therefore,exploring the mechanisms of the initiation and development of pituitary tumors and identifying characteristic molecules involved in pituitary tumorigenesis will provide new avenues for the clinical prevention and treatment of pituitary tumors.Long chain non-coding RNA(lncRNA)that is recently discovered is a type of RNA longer than 200 nucleotides.Recently,it has been found that dysregulated expression of lncRNAs can affect cell growth,prolifertion,apoptosis and several other biological functions,leading to the occurrence of diseases,especially the development of tumors.lncRNA H19 is the first discovered lncRNA in human.It has been reported that its aberrant expression has been associated with both oncogenic and tumor suppressive activities in a variety of tumors.However,the role of lncRNA H19 in the development and progression of pituitary tumors and the underlying molecular mechanisms in pituitary tumorigenesis are still poorly understood.The purpose of this study was to investigate the role of lncRNA H19 in the pathogenesis and development of pituitary tumors and try to uncover the underlying molecular mechanisms involved.We found that expression of lncRNA H19 is frequently downregulated in human pituitary tumor tissue,and its expression level is negatively correlated with tumor progression.Through in vitro and in vivo studies,we confirmed that increasing lncRNA H19 expression can inhibit pituitary tumor cell proliferation in vitro and xenograft tumor growth in vivo.Mechanistically,we found that lncRNA H19 controls cell or tumor growth by selectively inhibiting the function of mTORC1 but not mTORC2.We further showed that lncRNA H19 specifically blocks mTORC1-mediated phosphorylation of 4E-BP1 without affecting S6K1 activation.At the molecular level,we showed that lncRNA H19 may specifically act on 4E-BP1 Tor signaling(TOS)motif and competitively inhibits the binding of 4E-BP1 to Raptor which is the scaffold protein of mTORC1,resulting in the selective inhibition of mTORC1-4E-BP1 signaling axis.In summary,our study uncovered a novel lncRNA H19-mTORC1-4E-BP1 signal axis which plays an important role in the regulation of pituitary tumor growth,which will be a potential therapeutic target for the treatment of human pituitary tumors.