Research On The Expression Significance And Mechanism Of PRMT5 In Angioimmunoblastic T-cell Lymphoma

BackgroundAngioimmunoblastic T cell lymphoma（AITL）is a peripheral T cell lymphoma derived from follicular helper T cells,accounting for 18.5%of peripheral T cell lymphomas.AITL is more common in middle-aged and elderly patients,which is more aggressive than B-cell lymphoma,and more common in advanced patients with a high recurrence rate.Histone arginine methyltransferase 5（PRMT5）is a type Ⅱ arginine methylase that regulates target gene transcription through the symmetric dimethylation of histone arginine residues H4R3,H3R8,and H2AR3.PRMT5 is up-regulated in lymphoma,lung cancer,breast cancer,colorectal cancer and other malignant tumors,and has become an important biomarker.More and more studies have shown that the enhanced expression of PRMT5 can induce proliferation signal transduction and is positively correlated with disease progression and poor prognosis.PRMT5 acts through methylation of cytoplasm and nuclear substrates,including histones H3 and H4,Sm proteins,nucleolus proteins,and EGFR.Some non-histone proteins can also act as their substrates,such as p53 and PR,which are involved in regulating cell signaling pathways and mRNA splicing.PRMT5 expression is upregulated in hematological malignancies,including leukemia and lymphoma,where PRMT5 regulates gene expression to promote cancer cell proliferation.Reasonable design and combination of targeted therapy with PRMT5 inhibitors has become an effective cancer treatment strategy.There is no clear and standard treatment plan for AITL,and CHOP,a traditional chemical therapy,is still the most commonly used plan in clinical practice,but its efficacy is poor.Therefore,it is urgent to further explore new pathogenesis and find new anti-cancer strategies.MethodFrom June 2009 to June 2019,103 cases of Angioimmunoblastic T-cell lymphoma in Qilu Hospital of Shandong University were collected,and the relevant clinical case data and clinicopathological data were improved.Waffin blocks were collected and resected for IHC detection.The health status of the patients was followed up by telephone,and survival analysis was performed by GraphPad Prism 5,and correlation analysis was conducted for the collected clinical indicators such as gender,age and LDH.Cytoinhibitor dosing assay,flow cytometry assay,detection of the effect of knockdown of PRMT5 gene on the proliferation,apoptosis and cycle of tumor cells,Western blot and RT-qPCR were used to detect the knockdown efficiency of PRMT5 gene.Transcriptome sequencing was used to detect PRMT5 downstream signaling pathways.Result1.Immunohistochemical test of pathological sections:PRMT5 is highly expressed in Angioimmunoblastic T-cell lymphoma tissues and is low expressed in lymph node reactive hyperplasia tissues.2.Clinical data analysis:There was a correlation between PRMT5 protein and Ki67 protein expression in Angioimmunoblastic T-cell lymphoma,suggesting that PRMT5 may be related to the occurrence and development of cancer cells.3.Specific inhibitor:Two T lymphoma cell lines Jurkat and Hut78。In vitro cell dosing experiments revealed that PRMT5 specific inhibitor（GSK591）inhibited the expression of PRMT5 protein in lymphoma cells。4.Cell function test:Inhibition of PRMT5 protein expression resulted in decreased proliferation and increased apoptosis in T cell lymphoma cell lines,suggesting that PRMT5 may be a potential target for biological therapy。5.Transcriptome sequencing:PRMT5 may be involved in cell proliferation,apoptosis and cell cycle arrest through the P53 pathway。ConclusionPRMT5 protein was highly expressed in patients with Angioimmunoblastic T-cell lymphoma,and clinical analysis showed that PRMT5 protein was closely related to Ki67 proliferation index.In vitro experiments showed that PRMT5 specific inhibitor（GSK591）could inhibit the expression of PRMT5 protein in cancer cells,thereby inhibiting the proliferative activity of lymphoma cells and promoting the apoptosis of lymphoma cells.The expression and mechanism of PRMT5 in Angioimmunoblastic T-cell lymphoma may provide a potential target for the treatment of lymphoma.