ABSTRACT
Endometrial cancer (EC) is women's fourth most common malignant tumor. Neddylation plays a significant role in many diseases; however, the effect of neddylation and neddylation-related genes (NRGs) on EC is rarely reported. In this study, we first used MLN4924 to affect the activation of neddylation in different cell lines (Ishikawa and HEC-1-A) and determined the critical role of neddylation-related pathways for EC progression. Subsequently, we screened 17 prognostic NRGs based on expression files of the TCGA-UCEC cohort. Based on unsupervised consensus clustering analysis, patients with EC were classified into two neddylation patterns (C1 and C2). In terms of prognosis, substantial differences were observed between the two patterns. Compared with C2, C1 exhibited low levels of immune infiltration and promoted tumor progression. More importantly, based on the expression of 17 prognostic NRGs, we transformed nine machine-learning algorithms into 89 combinations. The random forest (RSF) was selected to construct the neddylation-related risk score according to the average C-index of different cohorts. Notably, our score had important clinical implications for EC. Patients with high scores have poor prognoses and a cold tumor state. In conclusion, neddylation-related patterns and scores can distinguish tumor microenvironment (TME) and prognosis and guide personalized treatment in patients with EC.
ABSTRACT
OBJECTIVE: To describe the natural history of cervical intraepithelial neoplasia (CIN) I and the biologic factors associated with the progression of CIN I and to analyze the predictive values of p16(INK4a) protein for the progression of CIN I. 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 CIN I 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 CIN I with clinical biologic factors, including patient age, cervical cytology before colposcopy, loads of HR HPV, HPV L1 capsid protein, p16(INK4a) protein, χ(2) tests was used to compare the different frequencies of factors in groups of progressed and persisted/regressed CIN I, then five factors with progressed CIN I were 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 CIN I, 5 cases were CIN II and 7 cases were CIN III. 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 p16(INK4a) 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 CIN I (all P>0.05) except for the expression of p16(INK4a) protein (P<0.05). Multivariable analysis found that p16(INK4a) protein positive was associated with progression of CIN I (OR=5.1, 95%CI: 1.162-22.387, P=0.031). (4) Thirty-one cases were p16(INK4a) protein positive, 8 cases (27%, 8/30) of them progressed, while 4 cases (7%, 4/58) of 58 cases with p16(INK4a) 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 CIN II-III of p16(INK4a) protein staining. CONCLUSIONS: The progression rate of CIN I with abnormal cytology (≤LSIL) and HR HPV positive was lower, and there was no progression to invasion at 1-year intervals. Immunostaining of p16(INK4a) protein as the risk factors of CIN I progression could have a role in prediction of CIN I and the management of high-risk CIN I.