RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance
Abstract To identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-rela...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-07-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04036-5 |
| _version_ | 1797246973250633728 |
|---|---|
| author | Changhwan Yoon Jun Lu Sandra W. Ryeom M. Celeste Simon Sam S. Yoon |
| author_facet | Changhwan Yoon Jun Lu Sandra W. Ryeom M. Celeste Simon Sam S. Yoon |
| author_sort | Changhwan Yoon |
| collection | DOAJ |
| description | Abstract To identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-related gene in spheroids was phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, which functions in tumorigenesis and metastasis. In a human sarcoma microarray, PIK3R3 was also overexpressed by 4.1-fold compared with normal tissues. PIK3R3 inhibition using shRNA in the HT1080, SK-LMS-1, and DDLS8817 dedifferentiated liposarcoma in spheroids and in CD133+ cells (a CSC marker) reduced expression of CD133 and the stem cell factor Nanog and blocked spheroid formation by 61–71%. Mechanistic studies showed that in spheroid cells, PIK3R3 activated AKT and ERK signaling. Inhibition of PIK3R3, AKT, or ERK using shRNA or inhibitors decreased expression of Nanog, spheroid formation by 68–73%, and anchorage-independent growth by 76–91%. PIK3R3 or ERK1/2 inhibition similarly blocked sarcoma spheroid cell migration, invasion, secretion of MMP-2, xenograft invasion into adjacent normal tissue, and chemotherapy resistance. Together, these results show that signaling through the PIK3R3/ERK/Nanog axis promotes sarcoma CSC phenotypes such as migration, invasion, and chemotherapy resistance, and identify PIK3R3 as a potential therapeutic target in sarcoma. |
| first_indexed | 2024-04-24T19:51:18Z |
| format | Article |
| id | doaj.art-0625113d899f4955a7ef9d844d1be2e3 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-24T19:51:18Z |
| publishDate | 2021-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-0625113d899f4955a7ef9d844d1be2e32024-03-24T12:35:24ZengNature Publishing GroupCell Death and Disease2041-48892021-07-0112811110.1038/s41419-021-04036-5RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistanceChanghwan Yoon0Jun Lu1Sandra W. Ryeom2M. Celeste Simon3Sam S. Yoon4Department of Surgery, Memorial Sloan Kettering Cancer CenterDepartment of Surgery, Memorial Sloan Kettering Cancer CenterDepartment of Cancer Biology, University of PennsylvaniaAbramson Family Cancer Research Institute, Perelman School of Medicine, University of PennsylvaniaDepartment of Surgery, Memorial Sloan Kettering Cancer CenterAbstract To identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-related gene in spheroids was phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, which functions in tumorigenesis and metastasis. In a human sarcoma microarray, PIK3R3 was also overexpressed by 4.1-fold compared with normal tissues. PIK3R3 inhibition using shRNA in the HT1080, SK-LMS-1, and DDLS8817 dedifferentiated liposarcoma in spheroids and in CD133+ cells (a CSC marker) reduced expression of CD133 and the stem cell factor Nanog and blocked spheroid formation by 61–71%. Mechanistic studies showed that in spheroid cells, PIK3R3 activated AKT and ERK signaling. Inhibition of PIK3R3, AKT, or ERK using shRNA or inhibitors decreased expression of Nanog, spheroid formation by 68–73%, and anchorage-independent growth by 76–91%. PIK3R3 or ERK1/2 inhibition similarly blocked sarcoma spheroid cell migration, invasion, secretion of MMP-2, xenograft invasion into adjacent normal tissue, and chemotherapy resistance. Together, these results show that signaling through the PIK3R3/ERK/Nanog axis promotes sarcoma CSC phenotypes such as migration, invasion, and chemotherapy resistance, and identify PIK3R3 as a potential therapeutic target in sarcoma.https://doi.org/10.1038/s41419-021-04036-5 |
| spellingShingle | Changhwan Yoon Jun Lu Sandra W. Ryeom M. Celeste Simon Sam S. Yoon RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance Cell Death and Disease |
| title | RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance |
| title_full | RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance |
| title_fullStr | RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance |
| title_full_unstemmed | RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance |
| title_short | RETRACTED ARTICLE: PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance |
| title_sort | retracted article pik3r3 part of the regulatory domain of pi3k is upregulated in sarcoma stem like cells and promotes invasion migration and chemotherapy resistance |
| url | https://doi.org/10.1038/s41419-021-04036-5 |
| work_keys_str_mv | AT changhwanyoon retractedarticlepik3r3partoftheregulatorydomainofpi3kisupregulatedinsarcomastemlikecellsandpromotesinvasionmigrationandchemotherapyresistance AT junlu retractedarticlepik3r3partoftheregulatorydomainofpi3kisupregulatedinsarcomastemlikecellsandpromotesinvasionmigrationandchemotherapyresistance AT sandrawryeom retractedarticlepik3r3partoftheregulatorydomainofpi3kisupregulatedinsarcomastemlikecellsandpromotesinvasionmigrationandchemotherapyresistance AT mcelestesimon retractedarticlepik3r3partoftheregulatorydomainofpi3kisupregulatedinsarcomastemlikecellsandpromotesinvasionmigrationandchemotherapyresistance AT samsyoon retractedarticlepik3r3partoftheregulatorydomainofpi3kisupregulatedinsarcomastemlikecellsandpromotesinvasionmigrationandchemotherapyresistance |