scholarly journals The Stress-Inducible BCL2A1 Is Required for Ovarian Cancer Metastatic Progression in the Peritoneal Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4577
Author(s):  
Rui Liang ◽  
Mingo M. H. Yung ◽  
Fangfang He ◽  
Peili Jiao ◽  
Karen K. L. Chan ◽  
...  

Emerging evidence indicates that hypoxia plays a critical role in governing the transcoelomic metastasis of ovarian cancer. Hence, targeting hypoxia may be a promising approach to prevent the metastasis of ovarian cancer. Here, we report that BCL2A1, a BCL2 family member, acts as a hypoxia-inducible gene for promoting tumor progression in ovarian cancer peritoneal metastases. We demonstrated that BCL2A1 was induced not only by hypoxia but also other physiological stresses through NF-κB signaling and then was gradually reduced by the ubiquitin-proteasome pathway in ascites-derived ovarian cancer cells. The upregulated BCL2A1 was frequently found in advanced metastatic ovarian cancer cells, suggesting its clinical relevance in ovarian cancer metastatic progression. Functionally, BCL2A1 enhanced the foci formation ability of ovarian cancer cells in a stress-conditioned medium, colony formation in an ex vivo omental tumor model, and tumor dissemination in vivo. Under stress conditions, BCL2A1 accumulated and colocalized with mitochondria to suppress intrinsic cell apoptosis by interacting with the BH3-only subfamily BCL2 members HRK/BAD/BID in ovarian cancer cells. These findings indicate that BCL2A1 is an early response factor that maintains the survival of ovarian cancer cells in the harsh tumor microenvironment.

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Jiawen Zhang ◽  
Jing Zhang ◽  
Yingze Wei ◽  
Qingxian Li ◽  
Qingying Wang

Abstract Enhanced glycolysis has been identified as a hallmark of cancer. As a novel oncogene, ACTL6A is aberrantly amplified in several types of human cancers and has been shown to regulate tumor growth and progression. However, the roles of ACTL6A in the development of ovarian cancer and the regulation of cancer glucose metabolism are mostly unknown. Here we show that ACTL6A is overexpressed in ovarian cancers compared with adjacent non-tumor tissues, and that ACTL6A overexpression correlates with poor prognosis. Silencing of ACTL6A in vitro inhibits proliferation, clonal growth, and migration, and decreases glucose utilization, lactate production, and pyruvate levels of ovarian cancer cells. We found a positive correlation between ACTL6A and PGK1 expression in ovarian cancer tissues. Enforced ACTL6A expression increased PGK1 expression, whereas knockdown of ACTL6A had the opposite effect. Altered ACTL6A expression inhibits the tumorigenicity of ovarian cancer cells in vivo by downregulating PGK1. In addition, the expression of ACTL6A is regulated by follicle-stimulating hormone (FSH) stimulation via PI3K/AKT pathway. Importantly, ACTL6A regulates FSH-enhanced glycolysis in ovarian cancer. Taken together, our findings highlight the critical role of ACTL6A in ovarian cancer development and identify its contribution to glucose metabolism of cancer cells.


2021 ◽  
Vol 7 (9) ◽  
pp. eabb0737
Author(s):  
Zhengnan Yang ◽  
Wei Wang ◽  
Linjie Zhao ◽  
Xin Wang ◽  
Ryan C. Gimple ◽  
...  

Ovarian cancer represents a highly lethal disease that poses a substantial burden for females, with four main molecular subtypes carrying distinct clinical outcomes. Here, we demonstrated that plasma cells, a subset of antibody-producing B cells, were enriched in the mesenchymal subtype of high-grade serous ovarian cancers (HGSCs). Plasma cell abundance correlated with the density of mesenchymal cells in clinical specimens of HGSCs. Coculture of nonmesenchymal ovarian cancer cells and plasma cells induced a mesenchymal phenotype of tumor cells in vitro and in vivo. Phenotypic switch was mediated by the transfer of plasma cell–derived exosomes containing miR-330-3p into nonmesenchymal ovarian cancer cells. Exosome-derived miR-330-3p increased expression of junctional adhesion molecule B in a noncanonical fashion. Depletion of plasma cells by bortezomib reversed the mesenchymal characteristics of ovarian cancer and inhibited in vivo tumor growth. Collectively, our work suggests targeting plasma cells may be a novel approach for ovarian cancer therapy.


2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Shourong Wang ◽  
Zixiang Wang ◽  
Jieyin Li ◽  
Junchao Qin ◽  
Jianping Song ◽  
...  

AbstractAberrant expression of splicing factors was found to promote tumorigenesis and the development of human malignant tumors. Nevertheless, the underlying mechanisms and functional relevance remain elusive. We here show that USP39, a component of the spliceosome, is frequently overexpressed in high-grade serous ovarian carcinoma (HGSOC) and that an elevated level of USP39 is associated with a poor prognosis. USP39 promotes proliferation/invasion in vitro and tumor growth in vivo. Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells. We further demonstrated that USP39 colocalizes with spliceosome components in nuclear speckles. Transcriptomic analysis revealed that USP39 deletion led to globally impaired splicing that is characterized by skipped exons and overrepresentation of introns and intergenic regions. Furthermore, RNA immunoprecipitation sequencing showed that USP39 preferentially binds to exon-intron regions near 5′ and 3′ splicing sites. In particular, USP39 facilitates efficient splicing of HMGA2 and thereby increases the malignancy of ovarian cancer cells. Taken together, our results indicate that USP39 functions as an oncogenic splicing factor in ovarian cancer and represents a potential target for ovarian cancer therapy.


2019 ◽  
Vol 8 (11) ◽  
pp. e1649971 ◽  
Author(s):  
Noémie Joalland ◽  
Laura Lafrance ◽  
Thibauld Oullier ◽  
Séverine Marionneau-Lambot ◽  
Delphine Loussouarn ◽  
...  

2015 ◽  
Vol 96 (1) ◽  
pp. 37-48 ◽  
Author(s):  
Yanyan Ma ◽  
Zengtao Wei ◽  
Robert C Bast ◽  
Zhanying Wang ◽  
Yan Li ◽  
...  

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770550 ◽  
Author(s):  
Yi Li ◽  
Ming Xiao ◽  
Fangchun Guo

SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.


2021 ◽  
Vol 17 (13) ◽  
pp. 3493-3507
Author(s):  
Miao Bai ◽  
Mengqi Cui ◽  
Mingyue Li ◽  
Xinlei Yao ◽  
Yulun Wu ◽  
...  

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