scholarly journals EBV LMP1-activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Properties

2021 ◽  
Author(s):  
Nannan Zhu ◽  
Qian Wang ◽  
Zhidong Wu ◽  
Yan Wang ◽  
Mu-Sheng Zeng ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Side Population ◽  
Nasopharyngeal Cancer ◽  
Chemotherapy Resistance ◽  
Cell Formation ◽  
Migration And Invasion ◽  
Tumor Initiation ◽  
Mesenchymal Transition ◽  
Mtorc1 Signaling

Epstein-Barr Virus (EBV) is associated with several malignant diseases, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC), certain types oflymphomas,and a portion of gastric cancers. Virus-encoded oncoprotein LMP1 induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring CSC characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 co-regulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients.

scholarly journals A Direct Negative Feedback Loop of miR-4721/FOXA1/Nanog Promotes Nasopharyngeal Cell Stem Cell Enrichment and Metastasis 

2021 ◽  
Author(s):  
Mengyang Zhao ◽  
Zibo Tang ◽  
Yijun Wang ◽  
Jiaojiao Ding ◽  
Ying Guo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Side Population ◽  
Nasopharyngeal Cancer ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Negative Feedback Loop ◽  
Linkage Mechanism

Abstract Objective: The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated. Methods: The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed.Results: In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells. Conclusion: These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC.

scholarly journals A direct negative feedback loop of miR-4721/FOXA1/Nanog promotes nasopharyngeal cell stem cell enrichment and metastasis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mengyang Zhao ◽  
Zibo Tang ◽  
Yijun Wang ◽  
Jiaojiao Ding ◽  
Ying Guo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Side Population ◽  
Nasopharyngeal Cancer ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Negative Feedback Loop ◽  
Linkage Mechanism

Abstract Objective The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated. Methods The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed. Results In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells. Conclusion These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC.

scholarly journals COX-2 Promotes Migration and Invasion by the Side Population of Cancer Stem Cell-Like Hepatocellular Carcinoma Cells

Medicine ◽  
2015 ◽  
Vol 94 (44) ◽  
pp. e1806 ◽  
Author(s):  
Zhe Guo ◽  
Jing-Hang Jiang ◽  
Jun Zhang ◽  
Hao-Jie Yang ◽  
Fu-Quan Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Side Population ◽  
Carcinoma Cells ◽  
Migration And Invasion ◽  
Hepatocellular Carcinoma Cells ◽  
Cox 2

scholarly journals Partial acquisition of stemness properties in tumorspheres obtained from interleukin-8-treated MCF-7 cells

Tumor Biology ◽  
2020 ◽  
Vol 42 (12) ◽  
pp. 101042832097943
Author(s):  
Natalia Ospina-Muñoz ◽  
Jean-Paul Vernot
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
First Generation ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Line ◽  
Interleukin 8 ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Sphere Formation ◽  
Mcf 7

The interleukin-8 is an important regulator of the tumor microenvironment, promoting the epithelial–mesenchymal transition and the acquisition of stem-like cell properties in cancer cells. The tumorsphere-formation assay has been used for the identification of cancer stem cell. Interleukin-8 induces the formation of larger tumorspheres in Michigan Cancer Foundation-7 (MCF-7) cells, suggesting cancer stem cell enrichment. In this work, we aimed to study the phenotypic and functional characteristics of the cells present within the tumorspheres of MCF-7 cells previously treated with interleukin-8. MCF-7 cells treated for 5 days or not with this cytokine were further cultivated in ultralow attachment plates for another 5 days to allow tumorspheres formation. We showed that the enhanced sphere formation by MCF-7 cells was not a consequence of higher cell proliferation by interleukin-8 stimulation. Despite maintaining an epithelial–mesenchymal transition phenotype with the presence of epithelial and mesenchymal markers, basic stemness properties were impaired in tumorspheres and in those treated with interleukin-8, while others were increased. Self-renewal capacity was increased in interleukin-8-treated cells only in the first generation of tumorspheres but was not sustained in consecutive assays. Accordingly, self-renewal and reprogramming gene expression, differentiation capacity to adipocytes, and clonogenicity were also impaired. We showed also that tumorspheres were enriched in differentiated luminal cells (EpCAM+/CD49f−). Nevertheless, cells were more quiescent and maintain a partial epithelial–mesenchymal transition, consistent with their increased resistance to Paclitaxel and Doxorubicin. They also presented higher migration and interleukin-8-directed invasion. Therefore, the breast cancer cell line MCF-7, having a low stemness index, might partially acquire some stem-like cell attributes after interleukin-8 stimulation, increasing its aggressiveness.

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