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Abstract Background Radioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in radiation and drug resistance. We aimed to explore the biological function and clinical significance of 5-methylcytosine (m5C) in cervical cancer radiosensitivity. Methods The abundance of RNA modification in radiotherapy-resistant and sensitive CC specimens was quantified by liquid chromatography-tandem mass spectrometry. The essential RNA modification-related genes involved in CC radiosensitivity were screened via RNA sequencing. The effect of NSUN6 on radiosensitivity was verified in CC cell lines, cell-derived xenograft (CDX), and 3D bioprinted patient-derived organoid (PDO). The mechanisms of NSUN6 in regulating CC radiosensitivity were investigated by integrative m5C sequencing, mRNA sequencing, and RNA immunoprecipitation. Results We found a higher abundance of m5C modification in resistant CC samples, and NSUN6 was the essential m5C-regulating gene concerning radiosensitivity. NSUN6 overexpression was clinically correlated with radioresistance and poor prognosis in cervical cancer. Functionally, higher NSUN6 expression was associated with radioresistance in the 3D PDO model of cervical cancer. Moreover, silencing NSUN6 increased CC radiosensitivity in vivo and in vitro. Mechanistically, NDRG1 was one of the downstream target genes of NSUN6 identified by integrated m5C-seq, mRNA-seq, and functional validation. NSUN6 promoted the m5C modification of NDRG1 mRNA, and the m5C reader ALYREF bound explicitly to the m5C-labeled NDRG1 mRNA and enhanced NDRG1 mRNA stability. NDRG1 overexpression promoted homologous recombination-mediated DNA repair, which in turn led to radioresistance in cervical cancer. Conclusions Aberrant m5C hypermethylation and NSUN6 overexpression drive resistance to radiotherapy in cervical cancer. Elevated NSUN6 expression promotes radioresistance in cervical cancer by activating the NSUN6/ALYREF-m5C-NDRG1 pathway. The low expression of NSUN6 in cervical cancer indicates sensitivity to radiotherapy and a better prognosis.

Background Ovarian clear cell carcinoma (OCCC) is a rare and chemo-resistant subtype of ovarian cancer. While immunotherapy has demonstrated effectiveness in some OCCC cases, the mechanisms for heterogeneous immunoreactivity and potential combinatory strategies remain unclear.Methods Tumor samples from 13 patients with OCCC underwent single-cell mRNA-seq and TCR-seq to generate 1 40 683 cells transcriptome, while additionally 31 formalin-fixed paraffin-embedded samples were used for immunohistochemistry. Spatial transcriptomics of two OCCC samples and bulk RNA-seq of 58 patients were incorporated for spatial and interpatient level explorations. Serum tumor markers and radiologic images of three patients with OCCC who received combinatory VEGF and PD-1 inhibition were retrospectively analyzed.Results OCCC exhibited a dynamic immune architecture shaped by genetic and therapeutic pressure. ARID1A mutation linked to baseline immune activation, correlated with an enrichment of neoantigen-reactive CXCL13+ CTLA4+ CD8+ T cells (p

Abstract Background Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. Methods This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. Results Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). Conclusions Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

Abstract Background The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. Methods IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. Results We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF. Conclusions Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.

Aim: The purpose of this study was to analyze the incidence, clinical characteristics, prognostic factors and survival of ovarian cancer patients with liver metastases upon initial diagnosis.Methods: Patients with ovarian cancer liver metastases upon initial diagnosis between 2010 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic regression was performed to identify the predictors of the presence of liver metastases in newly diagnosed ovarian cancer patients. Overall survival (OS) was assessed using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression was conducted to determine the independent prognostic factors for OS.Results: A total of 1,744 ovarian cancer patients with liver metastases was identified from the SEER database, accounting for 6.7% of the entire ovarian cancer patients. As to the unique distant organ provided by SEER, liver was the most common metastatic site of ovarian cancer (4.65%). Age, race, laterality, histology, pathological grade, extrahepatic sites, stage of tumor were the predictors of the presence with liver metastases revealed by multivariable logistic regression model. Median OS for the patients with liver metastases at initial diagnosis of ovarian cancer was 16.0 months. Multivariate Cox regression model confirmed race, histology, extrahepatic metastatic sites, surgery and marital status were independent prognostic factors for OS.Conclusion: The study provided population-based estimates of the incidence and prognosis of newly diagnosed ovary cancer patients with liver metastases, which could be potentially used for the risk assessment and individualized treatment.

Background. In general, younger age is associated with better survival in patients with colon cancer. In this study, we aim to analyze the impact of age on cancer-specific survival (CSS) in patients with signet-ring cell carcinoma (SRCC) of the colon, a particularly aggressive type of colon cancer. Methods. Information on patients with SRCC of the colon with no distant metastasis was extracted from the US Surveillance, Epidemiology, and End Results (SEER) database. An X-tile plot was used to determine the optimal cutoff age at diagnosis. Results. A total of 776 patients were included in data analysis. The X-tile program revealed an optimal cutoff at 35 years of age. A higher percentage of stage III disease and a higher percentage of N2 disease were observed in patients ≤ 35 years of age. The multivariate Cox proportional model demonstrated that patients ≤ 35 years of age were more likely to have a poorer survival outcome compared with patients aged >35 years (HR 1.411, 95% CI 1.032–1.929, and P=0.031). Conclusion. In contrast to the association of younger age with better survival in colon cancer patients, younger age (≤35 years) is associated with poorer survival outcome in patients with SRCC of the colon without distant metastasis.

The activity of CO2 methanolization depends on the realization of metal–oxide interactions with different strengths. The CuO/La0.25CeOx catalyst (La content: 25%) demonstrated superior catalytic activity under the reaction conditions of 260 °C, with a methanol space–time yield (STY) of 0.281 gCH3OH·gcat−1h−1 and a methanol selectivity of 83.3%. This study elucidates the correlation of the metal–support interactions in CuO/LaCeOx catalysts and the promotion of catalytic activity, which mainly shows that the introduction of La leads to enhanced conversion of Ce4+ into Ce3+ in the catalyst, facilitates oxygen vacancy generation, and activates the formate reaction pathway of CO2 hydrogenation. Thus, this study has considerable significance for the progress of efficient and new catalysts for CO2 methanolization.