Yufeng Ren

Methionine aminopeptidase 2 (METAP2), one of the two enzymes responsible for removing the N-terminal methionine from nascent proteins, has emerged as a potential drug target for cancer therapy. Yet, its role in ovarian cancer remains largely elusive. Here, we demonstrated that METAP2 is upregulated in ovarian cancer tissues and is associated with poor clinical outcomes. Consistently, METAP2 knockdown significantly suppresses the proliferation and migration of ovarian cancer cells in vivo and in vitro. Mechanistically, co-immunoprecipitation analysis identified YTHDF2 as a key interactor of METAP2. METAP2 interacts with YTHDF2 and attenuates its K48-linked ubiquitination at lysine 245, thereby preventing proteasomal degradation. Importantly, using AlphaFold3 algorithm, we elucidated and then experimentally validated that the Gln342 to Phe361 region of YTHDF2 interacts with the Thr240 to Gly358 region of METAP2. Furthermore, we identified BMF, LXRA, and HIVEP2 as functionally critical downstream targets of the METAP2-YTHDF2 axis, which are essential for ovarian cancer cells proliferation, migration and invasion. Additionally, we validated the therapeutic potential of the METAP2 inhibitor ZGN-1061 in ovarian cancer models. In conclusion, our findings reveal that METAP2 drives ovarian cancer progression by promoting YTHDF2-mediated mRNA decay of BMF/LXRA/HIVEP2, highlighting METAP2 as a potential therapeutic target for ovarian cancer.

Chemoresistance has long been a significant but unresolved issue in the treatment of various cancers, including the most deadly gynecological cancer, the high-grade serous ovary cancer (HGSOC). In this study, single nuclei transcriptome analyses were utilized to identify key cells and core networks for chemoresistance in HGSOC patients with different early responses to platinum-based chemotherapy at the single-cell level. Biomarkers for chemoresistance were also screened using bulk transcriptome data from independent cohorts with larger sample sizes. A total of 62,482 single cells from six samples were analyzed, revealing that chemoresistant cancer cells (Epithelial cells_0) pre-existed within individual patient before treatment. Two network modules formed with hub genes such as hormone-related genes (ESR1 and AR), insulin-related genes (INSR and IGF1R), and CTNNB1, were significantly overexpressed in these cells in the chemoresistant patient. BMP1 and TPM2 could be promise biomarkers in identifying chemoresistant patients before chemotherapy using bulk transcriptome data. Additionally, chemotherapy-induced fibroblasts (Fibroblasts_01_after) emerged as key stromal cells for chemoresistance. One network module containing one subnetwork formed by cholesterol biosynthesis-related genes and one subnetwork formed by cancer-related genes such as STAT3 and MYC, was significantly overexpressed in these cells in the chemoresistant patient. Notably, the NAMPT-INSR was the most prioritized ligand-receptor pair for cells interacting with Fibroblasts_01_after cells and Epithelial cells_0 cells to drive the up-regulation of their core genes, including IL1R1, MYC and INSR itself. Our findings deepen the understandings about mechanisms of early chemoresistance in HGSOC patients.

Although ovarian cancer, a gynecological malignancy, has the highest fatality rate, it still lacks highly specific biomarkers, and the differential diagnosis of ovarian masses remains difficult to determine for gynecologists. Our study aimed to obtain ovarian cancer-specific protein candidates from the circulating small extracellular vesicles (sEVs) and develop a protein panel for ovarian cancer screening and differential diagnosis of ovarian masses. In our study, sEVs derived from the serum of healthy controls and patients with cystadenoma and ovarian cancer were investigated to obtain a cancer-specific proteomic profile. In a discovery cohort, 1119 proteins were identified, and significant differences in the protein profiles of EVs were observed among groups. Then, 23 differentially expressed proteins were assessed using the parallel reaction monitoring in a validation cohort. Through univariate and multivariate logistic regression analyses, a novel model comprising three proteins (fibrinogen gamma gene (FGG), mucin 16 (MUC16), and apolipoprotein (APOA4)) was established to screen patients with ovarian cancer. This model exhibited an area under the receiver operating characteristic curve (AUC) of 0.936 (95% CI, 0.888–0.984) with 92.0% sensitivity and 82.9% specificity. Another panel comprising serum CA125, sEV-APOA4, and sEV-CD5L showed excellent performance (AUC 0.945 (95% CI, 0.890–1.000), sensitivity of 88.0%, specificity of 93.3%, and accuracy of 89.2%) to distinguish malignancy from benign ovarian masses. Altogether, our study provided a proteomic signature of circulating sEVs in ovarian cancer. The diagnostic proteomic panel may complement current clinical diagnostic measures for screening ovarian cancer in the general population and the differential diagnosis of ovarian masses.

Background: In this trial, we aimed to assess the efficacy and safety of radiotherapy with nedaplatin or cisplatin in patients with locally advanced cervical cancer.Methods: We conducted an open-label, non-inferiority, phase III, randomized, controlled trial. Eligible patients with stage IIB-IVA cervical carcinoma were randomly assigned to receive either nedaplatin or cisplatin for two cycles concurrently with radiotherapy. We reported the therapy-associated harms and survival. The study was registered with chictr.org.cn, number ChiCTR1800020527.Results: We randomly assigned 68 patients to nedaplatin-based or cisplatin-based concurrent chemoradiotherapy. Study treatment was stopped early after a data analysis found a higher number of patients suffered severe hematologic harms in the nedaplatin group than in the cisplatin group. Patients in the nedaplatin group had a significantly higher frequency of grade 3-4 neutropenia (19·4% vs. 13%; P < 0·001), severe thrombocytopenia (16·1% vs. 4·3%), and grade 1-2 anemia (51·6% vs. 43·5%) than patients in the cisplatin group. The 1-year PFS and OS in the nedaplatin and cisplatin groups were similar.Conclusion: Our findings showed that nedaplatin-based concurrent chemoradiotherapy expressed remarkably higher severe hematologic harms which were mortal. Though the results were negative, the experiences and lessons we learned from it were important.

Background: The incidence of anal squamous cell carcinoma (SCC) has been steadily growing globally in the past decade. Clinical data on anal SCC from China are rare. We conducted this study to describe the clinical and epidemiological characteristics of anal SCC in China and explore prognostic factors of outcomes among patients with anal SCC. Methods: We audited demographic characteristics, relevant symptoms, risk factors, treatment modalities and outcomes for patients diagnosed with anal SCC at 11 medical institutions in China between January 2007 and July 2018. Results: A total of 144 patients (109 females) were diagnosed with SCC during this period. Median age at initial diagnosis was 52.0 (interquartile range: 46.0–61.8) years. The most common symptoms were bleeding (n = 93, 64.6%), noticing a lump (n = 49, 34.0%), and pain (n = 47, 32.6%). The proportion of patients at the American Joint Committee on Cancer (AJCC) stages I-IV were 10 (6.9%), 22 (15.3%), 61 (42.4%) and 8 (5.6%), respectively, and AJCC stages in 43 (29.9%) patients were unknown. Thirty-six patients (25.0%) underwent abdominoperineal resection initially. Univariable analysis showed that T stage predicted recurrence-free survival (RFS) (Hazard ratio [HR] = 3.03, 95% Confidence interval [CI]: 1.10–8.37, p = 0.032), and age group (HR = 2.90, 95% CI: 1.12–7.49, p = 0.028), AJCC stage (HR = 4.56, 95% CI: 1.02–20.35, p = 0.046), and N stage (HR = 3.05, 95% CI: 1.07–8.74, p = 0.038) predicted overall survival (OS). Conclusions: T stage was identified as prognostic factor of RFS, and age, AJCC stage, and N stage were identified as prognostic factors of OS. Improving symptom awareness and earlier presentation among patients potentially at risk for anal SCC should be encouraged. Familiarity with the standard treatment among health care providers in China should be further improved.

Background: Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC. Methods: From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments. Results: C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pre-treated with a JAK2 inhibitor. Conclusions: Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression. Trial registration: ClinicalTrials.gov, NCT02425930, Registered 1st August 2013.

Purpose: To explore a quantitative predictive model for the risk of chemotherapy-induced severe liver damage (CISLD). Materials and methods: In total, 3870 consecutive cancer patients initially treated with chemotherapy were retrospectively collected and randomly assigned to a training (n=2580) or internal validation (n=1290) set in a 2:1 ratio to construct and validate the model. Additional external validation was performed using another data set (n=413). A total of 486 patients were prospectively enrolled to assess the clinical significance of the model. CISLD was defined as grade ≥3 hepatotoxicity. Results: CISLD was found in 255 (9.9%), 128 (9.9%) and 36 (8.7%) patients in the training, internal and external validation sets, respectively. Serum triglyceride, body mass index and history of hypertension formed the basis of the score model. Patients could be stratified into low, intermediate and high-risk groups with 30% CISLD occurrence, respectively. This model displayed a concordance index (C-index) of 0.834 and was validated in both the internal (C-index, 0.830) and external (C-index, 0.817) sets. The incidence of CISLD was significantly reduced in those who received preventive hepatoprotective drugs compared to those who did not among patients assessed as the intermediate risk group (8.9% vs 17.5%, p=0.042) and the high risk group (15.6% vs 55.8%, p=0.043). Conclusions: The new score model can be used to accurately predict the risk of CISLD in cancer patients undergoing chemotherapy. Clinically, this can be translated into a reference tool for oncologists in the clinical decision-making process before chemotherapy to provide appropriate prevention and interventions for patients with a high risk of CISLD.

Objective: To facilitate decision-making support for individual patients, development and external validation of a nomogram was undertaken to reveal prognostic factors and predict the value of concurrent chemoradiotherapy (CCRT) compared with radiotherapy (RT) for stage-II nasopharyngeal carcinoma (NPC) patients. Methods: Clinical data of 419 and 309 patients with American Joint Committee on Cancer (2017) stage-II NPC in two institutions in China were collected retrospectively. Overall survival (OS) and progression-free survival were compared using Kaplan–Meier estimates. Cox regression analysis was used to identify the prognostic factors for building the nomogram. Predictive accuracy and discriminative ability were measured using the Concordance Index. Results: Finally, there were 24 and 20 deaths in the development and validation group, respectively. Patients with stage T2N1, N1 stage, involvement of retropharyngeal and unilateral cervical lymph nodes, and who had RT alone had worse OS (P=0.019, 0.035, 0.003 and 0.010, respectively; log-rank test) than patients with stage T1N1 and T2N0, N0 stage, involvement of retropharyngeal or unilateral cervical lymph nodes, and CCRT, respectively. After multivariate analysis of the training set, age, neutrophil-to-lymphocyte ratio, therapy type, and pretreatment plasma concentration of Epstein–Barr virus DNA were independent prognostic factors of OS. A nomogram was established externally by involving all the factors stated above. The Concordance Index for the established nomogram to predict the OS of the training set was 0.793 (95% CI 0.689–0.897), and 0.803 (95% CI 0.696–0.910) in the validation set. Conclusion: These data suggest that the nomogram was validated externally, could predict long-term outcome accurately, and enable accurate stratification of risk groups for stage-II NPC. Our model facilitated individualized care of NPC patients.

Baseline C-reactive protein (CRP) has been determined as a prognostic factor in nasopharyngeal carcinoma (NPC). This study was designed to further evaluate the impact of CRP kinetics on NPC patients. Thousand three hundred and seventy eight NPC patients from February 2001 to June 2011 were retrospectively reviewed. CRP were measured at beginning, middle, and the end of the treatment. The endpoints were overall survival (OS) and distant metastasis free survival (DMFS). Patients were divided into three groups according to baseline CRP and CRP kinetics: (1) continuously normal group: patients whose baseline CRP normal and never elevated, (2) ever-elevated group: patients whose CRP ever elevated regardless time points, (3) continuously elevated group: patients whose baseline CRP elevated and never normalized. Baseline CRP, CRP after treatment, and CRP kinetics were correlated with TNM stage, T stage, and N stage. Univariate and multivariate analysis identified that elevated baseline CRP and CRP after treatment had significant association with worse survival than normal CRP. Oppositely, elevated CRP during treatment was not associated with survival. Patients with continuously elevated CRP significantly had poor OS and DMFS (HR:2.610, 95%CI: 1.592–4.279, p < 0.001; HR:2.816, 95%CI: 1.486–5.302, p = 0.001, respectively). In multivariate analysis, CRP kinetics assessment is an independent prognostic factor for OS and DFMS in NPC patients (HR:2.512, 95%CI: 1.452–4.346, p = 0.001; HR:3.389, 95%CI: 1.734–6.625, p = 0.001, respectively). In conclusion, elevated CRP at baseline and after treatment are predictive factors of poor prognosis for NPC. The study of CRP kinetics shows that continuously elevated CRP during treatment might indicate an unfavorable prognosis for NPC.