Dataset Information

Loss of Kruppel-like factor 9 facilitates stemness in ovarian cancer ascites-derived multicellular spheroids via Notch1/slug signaling.

ABSTRACT: The 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.

SUBMITTER: Wang K

PROVIDER: S-EPMC8486214 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Loss of Krüppel-like factor 9 facilitates stemness in ovarian cancer ascites-derived multicellular spheroids via Notch1/slug signaling.

Wang Kun K Liu Shujie S Dou Zhiyuan Z Zhang Shuo S Yang Xingsheng X

Cancer science 20210820 10

The 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, a ...[more]

PMID: 34363722

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Project description:The lethality of epithelial ovarian cancer (OC) is largely due to a high rate of recurrence and development of chemoresistance, which requires synergy between cancer cells and the tumor microenvironment (TME) and is thought to involve cancer stem cells. Our analysis of gene expression microarray data from paired primary and recurrent OC tissues revealed significantly elevated expression of the gene encoding periostin (POSTN) in recurrent OC compared to matched primary tumors (p = 0.015). Secreted POSTN plays a role in the extracellular matrix, facilitating epithelial cell migration and tissue regeneration. We therefore examined how elevated extracellular POSTN, as we found is present in recurrent OC, impacts OC cell functions and phenotypes, including stemness. OC cells cultured with conditioned media with high levels of periostin (CMPOSTNhigh) exhibited faster migration (p = 0.0044), enhanced invasiveness (p = 0.006), increased chemoresistance (p < 0.05), and decreased apoptosis as compared to the same cells cultured with control medium (CMCTL). Further, CMPOSTNhigh-cultured OC cells exhibited an elevated stem cell side population (p = 0.027) along with increased expression of cancer stem cell marker CD133 relative to CMCTL-cultured cells. POSTN-transfected 3T3-L1 cells that were used to generate CMPOSTNhigh had visibly enhanced intracellular and extracellular lipids, which was also linked to increased OC cell expression of fatty acid synthetase (FASN) that functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors. Additionally, POSTN functions in the TME were linked to AKT pathway activities. The mean tumor volume in mice injected with CMPOSTNhigh-cultured OC cells was larger than that in mice injected with CMCTL-cultured OC cells (p = 0.0023). Taken together, these results show that elevated POSTN in the extracellular environment leads to more aggressive OC cell behavior and an increase in cancer stemness, suggesting that increased levels of stromal POSTN during OC recurrence contribute to more rapid disease progression and may be a novel therapeutic target. Furthermore, they also demonstrate the utility of having matched primary-recurrent OC tissues for analysis and support the need for better understanding of the molecular changes that occur with OC recurrence to develop ways to undermine those processes.

Dataset Information

Loss of Kruppel-like factor 9 facilitates stemness in ovarian cancer ascites-derived multicellular spheroids via Notch1/slug signaling.

Publications

Loss of Krüppel-like factor 9 facilitates stemness in ovarian cancer ascites-derived multicellular spheroids via Notch1/slug signaling.

Similar Datasets

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