Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroids
Background: High-grade serous ovarian cancer (HGSOC) accounts for 70–80% of all ovarian cancer-related deaths. Multiple studies have suggested that the fallopian tube epithelium (FTE) serves as the cell of origin of HGSOC. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss is s...
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Elsevier
2025-01-01
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| Series: | Cancer Pathogenesis and Therapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949713224000223 |
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| author | Angela Russo Junlone Moy Manead Khin Timothy R. Dorsey Alfredo Lopez Carrero Joanna E. Burdette |
| author_facet | Angela Russo Junlone Moy Manead Khin Timothy R. Dorsey Alfredo Lopez Carrero Joanna E. Burdette |
| author_sort | Angela Russo |
| collection | DOAJ |
| description | Background: High-grade serous ovarian cancer (HGSOC) accounts for 70–80% of all ovarian cancer-related deaths. Multiple studies have suggested that the fallopian tube epithelium (FTE) serves as the cell of origin of HGSOC. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss is sufficient to induce numerous tumorigenic changes in FTE, including increased migration, formation of multicellular tumor spheroids (MTSs), and ovarian colonization. In murine oviductal epithelial (MOE) cells (the equivalent of human FTE) loss of PTEN results in the upregulation of transcripts associated with the extracellular matrix, with a specific focus on the elevation of lysyl oxidase-like 2 (LOXL2). Although LOXL2 is known to drive transformation and invasion in solid tumors and is associated with a poor prognosis in ovarian cancer, its specific role in the tumorigenesis of ovarian cancer originating from FTE remains unclear. Therefore, we aim to investigate whether LOXL2 mediates tumorigenesis from the fallopian tube epithelium. Methods: In this study, we utilized clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (CAS9) technology to delete LOXL2 in PTEN-deficient MOE cells to understand its role in mediating the oncogenic effects of PTEN loss. In addition, CRISPR-CAS9 was used to delete LOXL2 in OVCAR8 ovarian cancer cells. We monitored the changes in tumorigenic properties, such as migration, invasion, and growth of three-dimensional (3D) spheroids, to assess whether the loss of LOXL2 resulted in any changes. Results: We found that a reduction in LOXL2 expression did not significantly change the migration or invasive capabilities of PTEN-depleted MOE or human ovarian cancer cells. However, we found that a reduction in LOXL2 expression resulted in a significant reduction in 3D MTS formation and survival in both lines. Conclusions: These results reveal for the first time that PTEN loss in FTE cells increases LOXL2 expression through downregulation of Pax2, and LOXL2 deletion blocks 3D spheroid formation. |
| format | Article |
| id | doaj-art-efec79189f624e3cafddf2f068ab2f35 |
| institution | Kabale University |
| issn | 2949-7132 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Cancer Pathogenesis and Therapy |
| spelling | doaj-art-efec79189f624e3cafddf2f068ab2f352025-01-06T04:09:10ZengElsevierCancer Pathogenesis and Therapy2949-71322025-01-01316875Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroidsAngela Russo0Junlone Moy1Manead Khin2Timothy R. Dorsey3Alfredo Lopez Carrero4Joanna E. Burdette5Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60607, USA; Corresponding author: Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60607, USA.College of Pharmacy, University of Illinois, Chicago, IL 60612, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60607, USACollege of Pharmacy, University of Illinois, Chicago, IL 60612, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60607, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60607, USABackground: High-grade serous ovarian cancer (HGSOC) accounts for 70–80% of all ovarian cancer-related deaths. Multiple studies have suggested that the fallopian tube epithelium (FTE) serves as the cell of origin of HGSOC. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss is sufficient to induce numerous tumorigenic changes in FTE, including increased migration, formation of multicellular tumor spheroids (MTSs), and ovarian colonization. In murine oviductal epithelial (MOE) cells (the equivalent of human FTE) loss of PTEN results in the upregulation of transcripts associated with the extracellular matrix, with a specific focus on the elevation of lysyl oxidase-like 2 (LOXL2). Although LOXL2 is known to drive transformation and invasion in solid tumors and is associated with a poor prognosis in ovarian cancer, its specific role in the tumorigenesis of ovarian cancer originating from FTE remains unclear. Therefore, we aim to investigate whether LOXL2 mediates tumorigenesis from the fallopian tube epithelium. Methods: In this study, we utilized clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (CAS9) technology to delete LOXL2 in PTEN-deficient MOE cells to understand its role in mediating the oncogenic effects of PTEN loss. In addition, CRISPR-CAS9 was used to delete LOXL2 in OVCAR8 ovarian cancer cells. We monitored the changes in tumorigenic properties, such as migration, invasion, and growth of three-dimensional (3D) spheroids, to assess whether the loss of LOXL2 resulted in any changes. Results: We found that a reduction in LOXL2 expression did not significantly change the migration or invasive capabilities of PTEN-depleted MOE or human ovarian cancer cells. However, we found that a reduction in LOXL2 expression resulted in a significant reduction in 3D MTS formation and survival in both lines. Conclusions: These results reveal for the first time that PTEN loss in FTE cells increases LOXL2 expression through downregulation of Pax2, and LOXL2 deletion blocks 3D spheroid formation.http://www.sciencedirect.com/science/article/pii/S2949713224000223LOXL2PTENPAX2Fallopian tubeOvarian cancer |
| spellingShingle | Angela Russo Junlone Moy Manead Khin Timothy R. Dorsey Alfredo Lopez Carrero Joanna E. Burdette Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroids Cancer Pathogenesis and Therapy LOXL2 PTEN PAX2 Fallopian tube Ovarian cancer |
| title | Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroids |
| title_full | Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroids |
| title_fullStr | Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroids |
| title_full_unstemmed | Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroids |
| title_short | Loss of phosphatase and tensin homolog (PTEN) increases Lysyl oxidase-like 2 (LOXL2) expression enhancing the growth of fallopian tube epithelial cells as three-dimensional spheroids |
| title_sort | loss of phosphatase and tensin homolog pten increases lysyl oxidase like 2 loxl2 expression enhancing the growth of fallopian tube epithelial cells as three dimensional spheroids |
| topic | LOXL2 PTEN PAX2 Fallopian tube Ovarian cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2949713224000223 |
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