Protein arginine methyltransferase (PRMT) can methylate a variety of proteins,including histones and non-histones,affecting a variety of cellular processes such as transcription,RNA splicing,DNA repair,and cell cycle control.The activity of PRMT is affected by a variety of regulatory mechanisms,and its abnormal expression plays an important role in the development of the diseases,especially in tumors such as breast cancer and leukemia.PRMT has a unique value in the diagnosis or treatment of tumors.With the further exploration of PRMT methylation mechanism,PRMT selective inhibitors have made some progress.PRMT-specific inhibitors are expected to be targeted drugs for the treatment of tumors.

Objective To describe the natural history of cervical intraepithelial neoplasia(CIN)Ⅰand the biologic factors associated with the progression of CINⅠ and to analyze the predictive values of p16INK4a protein for the progression of CINⅠ. Methods From August 2010 to July 2013, 104 patients referred for abnormal cytology [≤ low-grade squamous intraepithelial lesion (LSIL); including negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASCUS), LSIL] and high-risk (HR) HPV positive,and were diagnosed CINⅠ by colposcopy-assisted biopsy and followed at 1-year intervals in the First Affiliated Hospital of Nanjing Medical University. In order to analyze the relationship between the progression of CINⅠ with clinical biologic factors, including patient age, cervical cytology before colposcopy, loads of HR HPV, HPV L1 capsid protein, p16INK4a protein,χ2 tests was used to compare the different frequencies of factors in groups of progressed and persisted/regressed CINⅠ, then five factors with progressed CINⅠwere processed into binary logistic regression analysis. Results (1) In the first year of follow-up, among 104 patients(including 15 cases NILM,78 cases ASCUS,11 cases LSIL), 52 cases of them were NILM and HR HPV negative, 30 cases were negative for intraepithelial lesion, 10 cases were CINⅠ, 5 cases were CINⅡand 7 cases were CINⅢ. In total, 82 cases (78.8%,82/104) cases had regressed, 10 cases (9.6%,10/104) persisted, 12 cases (11.5%,12/104) progressed [including 5 cases (4.8%,5/104) progressed to CIN Ⅱ, 7 cases (6.7%,7/104) progressed to CIN Ⅲ, none progressed to invasive cancer]. (2) All patients, 88 cases of them accepted immunohistochemical detection the expression of p16INK4a protein. The result shown that 30 cases (34%,30/88) were positive and 58 cases (66%,58/88) were negative. And 94 cases accepted immunocytochemical detection the expression of HPV L1 capsid protein, 49 cases (52%,49/94) were positive and 45 cases (48%,45/94) were negative. (3) Univariate analysis showed that age of the patient, loads of HR HPV, cervical cytology before colposcopy and the expression of HPV L1 capsid protein were not risk factors of the progression of CINⅠ(all P>0.05) except for the expression of p16INK4a protein (P<0.05). Multivariable analysis found that p16INK4a protein positive was associated with progression of CINⅠ(OR=5.1,95%CI:1.162-22.387,P=0.031). (4) Thirty-one cases were p16INK4a protein positive, 8 cases (27%,8/30) of them progressed,while 4 cases (7%,4/58) of 58 cases with p16INK4a protein negative progressed,in which there were significant difference (P<0.05). The sensitivity was 75%, the specificity was 71%, the positive predictive value was 27%and the negative predictive value was 93%for progression to CINⅡ-Ⅲof p16INK4a protein staining. Conclusions The progression rate of CINⅠwith abnormal cytology (≤LSIL) and HR HPV positive was lower, and there was no progression to invasion at 1-year intervals. Immunostaining of p16INK4a protein as the risk factors of CINⅠprogression could have a role in prediction of CINⅠand the management of high-risk CINⅠ.

Objective To examine the anticancer effect of a novel histone deacetylase inhibitor (HDACi), JZ004, on colon cancer cells HCT-8 and HT-29, and to investigate the molecular mechanisms of proliferation inhibition and apoptosis induction of cancer cells treated by JZ 004.Methods Colon cancer cells were treated with a series of concentrations of JZ004 .MTT assay was used to detect the proliferation of cancer cells .The cell cycle distribution and apoptosis were deter-mined by flow cytometry .Rhodamine 123 and DCFH-DA were applied to detect the mitochondrial membrane potential (ΔΨm) and reactive oxygen species ( ROS) production.The protein expressions of acetyl-histone H3, p21, cyclin-dependent kinase(CDK)4, Bcl-2, Mcl-1 and Bax were assayed by Western blotting .Results JZ004 was found to inhibit proliferation and induce apoptosis of colon cancer cells in a time-and dose-dependent manner , accompanied by a dose-dependent hyperacetylation of histone H3.JZ004 induced the cancer cell arrest in G 0/G1 phase by increasing the expres-sion level of p21 while CDK4 was downregulated .JZ004 also increased cellular ROS production and reduced ΔΨm by regu-lating the expressions of Bcl-2 family proteins .Conclusion As a novel HDACi , JZ004 effectively inhibits proliferation and increases ROS production to induce apoptosis of colon cancer cells .The results indicate that JZ004 is a potential compound to be developed as an anti-colon cancer agent for clinic application .