The Key Regulator And The Mechanisms Of MEN1 In Neuroendocrine Differentiation Of Lung Cancer Cells

MEN1 is the gene related to the multiple endocrine neoplasia type 1(MEN1)syndrome,which also as a tumor suppressor of lung.High frequency mutation of MEN1 has been reported in lung NE tumors.However,the underling mechanism is still unclear.This study attempts to further clarify the vital functions of MEN1 in regulating the NE differentiation of lung cancer.By the detection of human lung cancer samples,this study found that there was a population of tumor with low menin expression,and the decrease of menin was positively correlated with the neuroendocrine differentiation of lung cancer,and poor prognosis or malignant degree of patients.In vivo and in vitro,further testified that menin inhibition of lung cancer cell neuroendocrine differentiation,the deficiency or low expression of menin,promote the occurrence of lung cancer and neuroendocrine differentiation,at the same time in mice model experiment proves that Men1 deficiency markedly accelerated KrasG12D mutation induced lung adenocarcinoma malignant progression and neuroendocrine differentiation,also significantly reduced of survival.Mechanically,this study found that the neuroendocrine differentiation regulation of menin in lung cancer was dependent on MLL and RB/p53 signaling pathway.Menin maintained genomic stability by upregulation of RB and p53,thereby inhibiting lung cancer and neuroendocrine differentiation.MEN1 deficiency leads to the inactivation of p53 and DNA damage repair dysfunction,further the accumulation of DNA damage leads to the occurrence and development of malignant tumors.Meanwhile,this study found that menin is closely related to the regulation of cell senescence.By regulating H3K4me3 on p16/p19 promoter,menin directly or indirectly up-regulates the expression of p16/p19,thus promoting cell senescence and further inhibiting the occurrence of lung cancer.In the low expression of menin,cells cannot enter the senescence progress,and thus become malignant lung cancer.Meanwhile,this study found that menin is necessary for the EMT process of lung cancer induced by Kras mutation.The absence of menin inhibited the EMT process of lung cancer induced by Kras mutation,significantly accelerated the initiation,progression,and neuroendocrine differentiation of lung cancer.And detection of fibrosis markers found that Men1 deficiency increased positive rate of collagen-I and?-sma,separately in mice lung tumors.In sum,MEN1 deficiency results in disorder of MLL-mediated H3K4me3 modification and RB/p53 signaling pathways inactivation,which induces accumulation of DNA damage and decreased genomic stability,and arrests of cells to enter senescence progress.On the other hand,inhibition EMT of tumor cells induced by KrasG12D mutation,further promote tumorigenesis and NE differentiation.In addition,accompany with fibrosis.