Investigator
Qilu Hospital Of Shandong University
PDIA6, which is regulated by TRPM2-AS/miR-424-5p axis, promotes endometrial cancer progression via TGF-beta pathway
AbstractPDIA6 have been reported to be involved in a variety of cancers, however, the underlying role in endometrial cancer is still unclear. In this study, we aimed to study the function of PDIA6 in endometrial cancer. Firstly, we verified that PDIA6 was significantly upregulated in endometrial cancer, which was correlated with the progression of endometrial cancer patients. Furthermore, we identified PDIA6 significantly altered the ability of endometrial cancer cells to proliferate and metastasize. In addition, our result illustrated the oncogene effects of PDIA6 in promoting malignant biological behavior of endometrial cancer cells by regulating TGF-β pathway and being modulated by TRPM2-AS/miR-424-5p axis for the first time. Taken together, this study suggested that PDIA6 may be a new candidate target for endometrial cancer therapy.
Loss of Krüppel‐like factor 9 facilitates stemness in ovarian cancer ascites‐derived multicellular spheroids via Notch1/slug signaling
AbstractThe ascites that develops in advanced OC, both at diagnosis and upon recurrence, is a rich source of multicellular spheroids/aggregates (MCSs/MCAs), which are the major seeds of tumor cell dissemination within the abdominal cavity. However, the molecular mechanism by which specific ascites‐derived tumor cells survive and metastasize remains largely unknown. In this study, we elucidated cancer stem cell (CSC) properties of ascites‐derived MCSs, concomitant with enhanced malignancy, induced EMT, and low KLF9 (Krüppel‐like factor 9) expression, compared with PTCs. KLF9 was also downregulated in OC cell line‐derived spheroids and the CD117+CD44+ subpopulation in MCSs. Functional experiments demonstrated that KLF9 negatively modulated stem‐like properties in OC cells. Mechanistic studies revealed that KLF9 reduced the transcriptional expression of Notch1 by directly binding to the Notch1 promoter, thereby inhibiting the function of slug in a CSL‐dependent manner. Clinically, expression of KLF9 was associated with histological grade and loss of KLF9 predicts poor prognosis in OC.
EIF5A2 enhances stemness of epithelial ovarian cancer cells via a E2F1/KLF4 axis
AbstractBackgroundOvarian cancer stem cells (OCSC), endowed with tumor-initiating and self-renewal capacity, would account not only for the tumor growth, the peritoneal metastasis, and the relapse, but also for the acquisition of chemotherapy resistance. Nevertheless, figuring out their phenotypical and functional traits has proven quite challenging, mainly because of the heterogeneity of ovarian cancer. A deeper understanding of OCSC mechanisms will shed light on the development of the disease. Therefore, we aim to explore it for the design of innovative treatment regimens which aim at the eradication of ovarian cancer through the elimination of the CSC component.MethodsIn this study, immunohistochemistry assay and western blot assay were used to detect protein expression in the primary tumor and peritoneal multi-cellular aggregates/spheroids (MCAs/MCSs). OCSCs induced from cell line SKOV3 and HO-8910 were enriched in a serum-free medium (SFM). The effect of EIF5A2 on CSC-like properties was detected by sphere-forming assays, re-differentiation assays, quantitative real-time polymerase chain reaction, western blotting, flow cytometry, cell viability assays, immunofluorescence staining, and in vivo xenograft experiments. RNA-sequencing (RNA-seq) was used to reveal the mechanism by which EIF5A2 positively modulates the stem-like properties of ovarian cancer cells.ResultsExpression of EIF5A2 was significantly higher in peritoneal MCAs/MCSs compared to matched primary tumors, and EIF5A2 was also unregulated in ovarian cancer cell line-derived spheroids. Knockdown of EIF5A2 reduced the expression of the stem-related markers (ALDH1A1 and OCT-4), inhibited self-renewal ability, improved the sensitivity to chemotherapeutic drugs, and inhibited tumorigenesis in vivo. Mechanistic studies revealed that EIF5A2 knockdown reduced the expression of KLF4, which could partially rescue stem-like properties abolished by EIF5A2 knockdown or strengthened by EIF5A2 overexpression, through the transcription factor E2F1, which directly bind to KLF4 promoter.ConclusionOur results imply that EIF5A2 positively regulates stemness in ovarian cancer cells via E2F1/KLF4 pathway and may serve as a potential target in CSCs-targeted therapy for ovarian cancer.
Overexpression of Stathmin 1 Predicts Poor Prognosis and Promotes Cancer Cell Proliferation and Migration in Ovarian Cancer
Purpose. The aim of this study was to investigate the expression of stathmin 1 (STMN1) in ovarian cancer and its effect on prognosis. The effect and mechanism of STMN1 on the proliferation and migration of ovarian cancer cells were also investigated. Methods. Expression of STMN1 was measured by immunohistochemical staining in ovarian cancer tissues. The effects of STMN1 on the proliferation and migration capacity of ovarian cancer were evaluated using Cell Counting Kit-8 (CCK-8) assays, colony formation assays, immunofluorescence staining, wound healing assays, and Transwell assays. Transcription factors were predicted by bioinformatic analysis of TCGA database. Results. STMN1 was upregulated in ovarian cancer tissues as compared to paracancerous tissues and associated with shorter overall survival. STMN1 expression significantly correlated with FIGO staging and tumor differentiation ( P < 0.05 ). Furthermore, STMN1 promoted proliferation and migration in ovarian cancer cell lines. Bioinformatic analysis revealed that STMN1 was potentially regulated by E2F transcription factors. Then, we found that E2F1 regulated the expression of STMN1 and affected proliferation. Conclusion. STMN1 is overexpressed in ovarian cancer, and its high expression suggests a poor prognosis. STMN1 promotes the proliferation and migration of ovarian cancer and is regulated by E2F1. Thus, STMN1 may serve as a negative prognostic factor and possible target for the treatment of ovarian cancer patients.
IL‐6 expression promoted by Poly(I:C) in cervical cancer cells regulates cytokine expression and recruitment of macrophages
AbstractPoly(I:C) is a promising adjuvant for cancer treatment vaccines to enhance the host anti‐tumour immune response. However, the roles of poly(I:C) in the cervical cancer microenvironment and local immune reactions are not well understood. In this study, we investigated the roles of poly(I:C) in the cervical cancer. We analysed the cytokine transcription and secretion of cervical cancer cell lines and THP‐1–derived macrophages after poly(I:C) treatment, respectively. These results revealed that IL‐6 was significantly up‐regulated, and this up‐regulation was partly dose dependent. poly(I:C)‐stimulated supernatant of cervical cancer cells promoted M1‐type cytokine IL‐1β and IL‐6 expression of THP‐1–derived macrophages, but inhibited the expression of M2‐type cytokine, IL‐10 and CCL22. The recruitment of THP‐1–derived macrophages by poly(I:C)‐stimulated cervical cancer cell supernatant was also enhanced. Inhibition of IL‐6 expression in cervical cancer cells by siRNA transfection almost completely reversed the effects of poly(I:C) treatment. Finally, we found that phosphorylation of the NF‐κB signalling pathway in cervical cancer cells occurred quickly after poly(I:C) treatment. Moreover, the NF‐κB signalling pathway inhibitor PDTC significantly inhibited poly(I:C)‐induced IL‐6 expression. Taken together, these results suggest that poly(I:C) might regulate the effects of cervical cancer cells on tumour‐infiltrated macrophages, and subsequently promote a pro‐inflammatory tumour microenvironment.
Development of a Novel Deep Learning-Based Prediction Model for the Prognosis of Operable Cervical Cancer
Background. Cervical cancer ranks as the 4th most common female cancer worldwide. Early stage cervical cancer patients can be treated with operation, but clinical staging system is not a good predictor of patients’ survival. We aimed to develop a novel prognostic model to predict the prognosis for operable cervical cancer patients with better accuracy than clinical staging system. Methods. A total of 13,952 operable cervical cancer patients were retrospectively enrolled in this study. The whole dataset was randomly split into a training set ( n = 9,068 , 65%), validation set ( n = 2,442 , 17.5%), and testing set ( n = 2,442 , 17.5%). Cox proportional hazard (CPH) model and random survival forest (RSF) model were used as baseline models for the prediction of overall survival (OS). Then, a deep survival learning model (DSLM) was developed for OS prediction. Finally, a novel prognostic model was explored based on this DSLM. Results. The C-indexes for the CPH and RSF model were 0.731 and 0.753, respectively. DSLM, which had four layers that had 50 neurons in each layer, achieved a C-index of 0.782 in the validation set and a C-index of 0.758 in the testing set. The novel prognostic model based on DSLM showed better performances than the conventional clinical staging system (area under receiver operating curves were 0.826 and 0.689, respectively). Personalized survival curves for individual patient using this novel model also showed notably different survival slopes. Conclusions. Our study developed a novel, practical, personalized prognostic model for operable cervical cancer patients. This novel prognostic model may have the potential to provide a more prognostic information to oncologists.
RacGAP1 promotes the malignant progression of cervical cancer by regulating AP-1 via miR-192 and p-JNK
Abstract Cervical cancer (CC) is the most frequently diagnosed genital tract cancer in females worldwide. Rac GTPase-activating protein 1 (RacGAP1) is one of the specific GTPase-activating proteins. As a novel tumor protooncogene, overexpression of RacGAP1 was related to the occurrence of various tumors, but its function in CC is still unclear. In this study, bioinformatics analyses showed that RacGAP1 might be a key candidate gene in the progression of CC. RacGAP1 was significantly overexpressed in CC tissues. High RacGAP1 expression was positively associated with poor prognosis. Downregulating RacGAP1 significantly inhibited the proliferation, migration, and invasion of CC cells, while overexpressing RacGAP1 had the opposite effects. Further research showed that miR-192, which plays as a tumor suppressor in CC, was identified as a downstream target of RacGAP1 in CC cells. miR-192 inhibition could partially rescue the decrease in cell proliferation, migration, and invasion caused by RacGAP1 downregulation. In opposite, miR-192 overexpression could decrease the promotion of malignant progression caused by RacGAP1 upregulation. Mechanism studies revealed that RacGAP1 could regulate the expression and phosphorylation of c-Jun, which was the component of AP-1, via miR-192 and p-JNK separately. These findings suggested that RacGAP1 promoted tumorigenicity, migration, and invasion of CC. Therefore, it represented a potential novel prognostic marker in CC and may probably be a therapeutic target.
