Wentao Yue

LAPTM5 drives omental metastasis in high-grade serous ovarian cancer via TGF-β/Smad-mediated epithelial plasticity

International trends in ovarian cancer incidence from 1973 to 2012

Ovarian cancer is the 7th leading cancer diagnosis and the 8th leading cause of cancer death in women worldwide. We conducted this study to investigate the incidence of ovarian cancer internationally. The trends in ovarian cancer incidence were analyzed through the latest data of CI5 over the 40-year period from 21 populations in 4 continents using Joinpoint analysis, ASRs and proportions of different histological subtypes in those populations were also analyzed using volume XI of CI5. ASRs of ovarian cancer were from 7.0 to 11.6 per 100,000 in non-Asia populations during 2008-2012. In Asia, the ASR in Israel (Jews) were the highest, up to 8.1 per 100,000 in the same period. The international trends from 1973 to 2012 showed that ASRs of ovarian cancer were decreasing in 8 of 21 selected populations, whereas ASRs in Slovakia, Spain (Navarra) and China (Shanghai) were increasing. Meanwhile, there are certain differences in the main pathological classification patterns within different regions. In Asia, China (Hong Kong) and Japan both have a higher ASRs and proportions for clear cell and endometrioid carcinomas, while Japan has the highest ASRs and proportions for mucinous carcinomas. Although the reasons for those trends were not entirely clear, environmental, reproductive and genetic factors were likely to have led to these patterns. Meanwhile, more attention and further study should be given to the etiological factors of histology-specific ovarian cancer.

Single-cell transcriptomics in ovarian cancer identify a metastasis-associated cell cluster overexpressed RAB13

Abstract Background Metastasis, the leading cause of cancer-related death in patients diagnosed with ovarian cancer (OC), is a complex process that involves multiple biological effects. With the continuous development of sequencing technology, single-cell sequence has emerged as a promising strategy to understand the pathogenesis of ovarian cancer. Methods Through integrating 10 × single-cell data from 12 samples, we developed a single-cell map of primary and metastatic OC. By copy-number variations analysis, pseudotime analysis, enrichment analysis, and cell–cell communication analysis, we explored the heterogeneity among OC cells. We performed differential expression analysis and high dimensional weighted gene co-expression network analysis to identify the hub genes of C4. The effects of RAB13 on OC cell lines were validated in vitro. Results We discovered a cell subcluster, referred to as C4, that is closely associated with metastasis and poor prognosis in OC. This subcluster correlated with an epithelial–mesenchymal transition (EMT) and angiogenesis signature and RAB13 was identified as the key marker of it. Downregulation of RAB13 resulted in a reduction of OC cells migration and invasion. Additionally, we predicted several potential drugs that might inhibit RAB13. Conclusions Our study has identified a cell subcluster that is closely linked to metastasis in OC, and we have also identified RAB13 as its hub gene that has great potential to become a new therapeutic target for OC.

RAD51AP1 promotes progression of ovarian cancer via TGF‐β/Smad signalling pathway

AbstractOvarian cancer (OC) is one of the leading causes of female deaths. However, the molecular pathogenesis of OC has still remained elusive. This study aimed to explore the potential genes associated with the progression of OC. In the current study, 3 data sets of OC were downloaded from the GEO database to identify hub gene. Somatic mutation data obtained from TCGA were used to analyse the mutation. Immune cells were used to estimate effect of the hub gene to the tumour microenvironment. RNA‐seq and clinical data of OC patients retrieved from TCGA were used to investigate the diagnostic and prognostic values of hub gene. A series of in vitro assays were performed to indicate the function of hub gene and its possible mechanisms in OC. As a result, RAD51AP1 was found as a hub gene, which expression higher was mainly associated with poor survival in OC patients. Up‐regulation of RAD51AP1 was closely associated with mutations. RAD51AP1 up‐regulation accompanied by accumulated Th2 cells, but reduced CD4 + T cells and CD8 + T cells. Nomogram demonstrated RAD51AP1 increased the accuracy of the model. Down‐regulation of RAD51AP1 suppressed proliferation, migration and invasion capabilities of OC cells in vitro. Additionally, scatter plots showed that RAD51AP1 was positively correlated with genes in TGF‐β/Smad pathway. The above‐mentioned results were validated by RT‐qPCR and Western blotting. In conclusion, up‐regulation of RAD51AP1 was closely associated with mutations in OC. RAD51AP1 might represent an indicator for predicting OS of OC patients. Besides, RAD51AP1 might accelerate progression of OC by TGF‐β/Smad signalling pathway.

The Overexpression of Keratin 23 Promotes Migration of Ovarian Cancer via Epithelial‐Mesenchymal Transition

Background. Keratin 23 (KRT23) is a new member of the KRT gene family and known to be involved in the development and migration of various types of tumors. However, the role of KRT23 in ovarian cancer (OC) remains unclear. This study is aimed at investigating the function of KRT23 in OC. Methods. The expression of KRT23 in normal ovarian and OC tissues was determined using the Oncomine database and immunohistochemical staining. Reverse transcription quantitative polymerase chain reaction assay was used to analyze the expression of KRT23 in normal ovarian epithelial cell lines and OC cell lines. Small interfering RNA (siRNA), wound healing assay, and transwell assay were conducted to detect the effects of KRT23 on OC cell migration and invasion. Further mechanistic studies were verified by the Gene Expression Profiling Interactive Analysis platform, Western blotting, and immunofluorescence staining. Results. KRT23 was highly expressed in OC tissues and cell lines. High KRT23 expression could regulate OC cell migration and invasion, and the reduction of KRT23 by siRNA inhibited the migration and invasion of OC cells in vitro. Furthermore, KRT23 mediated epithelial‐mesenchymal transition (EMT) by regulating p‐Smad2/3 levels in the TGF‐β/Smad signaling pathway. Conclusions. These results demonstrate that KRT23 plays an important role in OC migration via EMT by regulating the TGF‐β/Smad signaling pathway.

Single-cell RNA-seq highlights a specific carcinoembryonic cluster in ovarian cancer

AbstractExpounding the heterogeneity for ovarian cancer (OC) with the cognition in developmental biology might be helpful to search for robust prognostic markers and effective treatments. In the present study, we employed single-cell RNA-seq with ovarian cancers, normal ovary, and embryo tissue to explore their heterogeneity. Then the differentiation process of clusters was explored; the pivotal cluster and markers were identified. Furthermore, the consensus clustering algorithm was used to explore the different clinical phenotypes in OC. At last, a prognostic model was construct and used to assess the prognosis for OCs. As a result, eight diverse clusters were identified, and the similarity existed in some clusters between embryo and tumours based on their gene expression. Meaningfully, a subtype of malignant epithelial cluster, PEG10+ EME, was associated with poor survival and was an intermediate stage of embryo to tumour. PEG10 was a CSC marker and might influence CSC self-renewal and promote cisplatin resistance via NOTCH pathway. Utilising specific gene profiles of PEG10+ EME based on public data sets, four phenotypes with different survival and clinical response to anti-PD-1/PD-L1 immunotherapy were identified. These insights allowed for the investigation of single-cell transcriptome of OCs and embryo, which advanced our current understanding of OC pathogenesis and resulted in promising therapeutic strategies.