Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma
Hepatoblastoma is the most common primary liver tumor in children, but treatment has not changed significantly in the past 20 years. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia (PIM) kinases promote tumorigenesis in hepatoblastoma. Stem cell-like cancer...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-02-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523318304327 |
| _version_ | 1811323815843594240 |
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| author | Laura L. Stafman Adele P. Williams Evan F. Garner Jamie M. Aye Jerry E. Stewart Karina J. Yoon Kimberly Whelan Elizabeth A. Beierle |
| author_facet | Laura L. Stafman Adele P. Williams Evan F. Garner Jamie M. Aye Jerry E. Stewart Karina J. Yoon Kimberly Whelan Elizabeth A. Beierle |
| author_sort | Laura L. Stafman |
| collection | DOAJ |
| description | Hepatoblastoma is the most common primary liver tumor in children, but treatment has not changed significantly in the past 20 years. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia (PIM) kinases promote tumorigenesis in hepatoblastoma. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to be responsible for chemoresistance, metastasis, relapse, and recurrence. The aim of this study was to identify SCLCCs in hepatoblastoma and determine the role of PIM kinases in SCLCCs. Hepatoblastoma cells were separated into CD133-enriched and CD133-depleted populations and the frequency of SCLCCs was assessed. CD133 expression was determined in the presence or absence of the PIM inhibitor, AZD1208. The effects of AZD1208 on proliferation, apoptosis, and motility were assessed in vitro and the effect of AZD1208 on tumor growth was examined in vivo. We identified CD133 as a marker for SCLCCs in hepatoblastoma and showed that PIM kinases promote a SCLCC phenotype. PIM kinase inhibition with AZD1208 decreased proliferation, migration, and invasion and increased apoptosis in both SCLCCs and non-SCLCCs in a long-term passaged hepatoblastoma cell line and patient-derived xenograft. Additionally, tumor growth in mice implanted with hepatoblastoma SCLCCs was decreased with PIM inhibition such that 57% of the tumors regressed. These findings identify CD133 as a marker for SCLCCs in hepatoblastoma and provide evidence that inhibition of PIM kinases decreases stemness and tumorigenicity of SCLCCs in hepatoblastoma, making them potential therapeutic targets for the treatment of hepatoblastoma. |
| first_indexed | 2024-04-13T14:02:07Z |
| format | Article |
| id | doaj.art-50eba423670a4f4380c1edd4eb9fdaa0 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-04-13T14:02:07Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-50eba423670a4f4380c1edd4eb9fdaa02022-12-22T02:44:01ZengElsevierTranslational Oncology1936-52332019-02-01122200208Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in HepatoblastomaLaura L. Stafman0Adele P. Williams1Evan F. Garner2Jamie M. Aye3Jerry E. Stewart4Karina J. Yoon5Kimberly Whelan6Elizabeth A. Beierle7Department of Surgery, University of Alabama at Birmingham, Birmingham, ALDepartment of Surgery, University of Alabama at Birmingham, Birmingham, ALDepartment of Surgery, University of Alabama at Birmingham, Birmingham, ALDepartment of Pediatrics, University of Alabama at Birmingham, Birmingham, ALDepartment of Surgery, University of Alabama at Birmingham, Birmingham, ALDepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, ALDepartment of Pediatrics, University of Alabama at Birmingham, Birmingham, ALDepartment of Surgery, University of Alabama at Birmingham, Birmingham, AL; Address all correspondence to: Elizabeth A. Beierle, University of Alabama at Birmingham, 1600 7th Avenue South, Lowder, Room 300, Birmingham, AL 35233.Hepatoblastoma is the most common primary liver tumor in children, but treatment has not changed significantly in the past 20 years. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia (PIM) kinases promote tumorigenesis in hepatoblastoma. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to be responsible for chemoresistance, metastasis, relapse, and recurrence. The aim of this study was to identify SCLCCs in hepatoblastoma and determine the role of PIM kinases in SCLCCs. Hepatoblastoma cells were separated into CD133-enriched and CD133-depleted populations and the frequency of SCLCCs was assessed. CD133 expression was determined in the presence or absence of the PIM inhibitor, AZD1208. The effects of AZD1208 on proliferation, apoptosis, and motility were assessed in vitro and the effect of AZD1208 on tumor growth was examined in vivo. We identified CD133 as a marker for SCLCCs in hepatoblastoma and showed that PIM kinases promote a SCLCC phenotype. PIM kinase inhibition with AZD1208 decreased proliferation, migration, and invasion and increased apoptosis in both SCLCCs and non-SCLCCs in a long-term passaged hepatoblastoma cell line and patient-derived xenograft. Additionally, tumor growth in mice implanted with hepatoblastoma SCLCCs was decreased with PIM inhibition such that 57% of the tumors regressed. These findings identify CD133 as a marker for SCLCCs in hepatoblastoma and provide evidence that inhibition of PIM kinases decreases stemness and tumorigenicity of SCLCCs in hepatoblastoma, making them potential therapeutic targets for the treatment of hepatoblastoma.http://www.sciencedirect.com/science/article/pii/S1936523318304327 |
| spellingShingle | Laura L. Stafman Adele P. Williams Evan F. Garner Jamie M. Aye Jerry E. Stewart Karina J. Yoon Kimberly Whelan Elizabeth A. Beierle Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma Translational Oncology |
| title | Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma |
| title_full | Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma |
| title_fullStr | Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma |
| title_full_unstemmed | Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma |
| title_short | Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma |
| title_sort | targeting pim kinases affects maintenance of cd133 tumor cell population in hepatoblastoma |
| url | http://www.sciencedirect.com/science/article/pii/S1936523318304327 |
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