Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and the only cancer with an increasing incidence in the United States. Recent advances in sequencing technology have enabled detailed profiling of liver cancer genomes and revealed extensive inter- and intra-tumor heterogeneity...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/11/2589 |
| _version_ | 1797493965200556032 |
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| author | Takahiro Kodama Michiko Kodama Nancy A. Jenkins Neal G. Copeland Huanhuan Joyce Chen Zhubo Wei |
| author_facet | Takahiro Kodama Michiko Kodama Nancy A. Jenkins Neal G. Copeland Huanhuan Joyce Chen Zhubo Wei |
| author_sort | Takahiro Kodama |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and the only cancer with an increasing incidence in the United States. Recent advances in sequencing technology have enabled detailed profiling of liver cancer genomes and revealed extensive inter- and intra-tumor heterogeneity, making it difficult to identify driver genes for HCC. To identify HCC driver genes, we performed transposon mutagenesis screens in a mouse HBV model of HCC and discovered many candidate cancer genes (SB/HBV-CCGs). Here, we show that one of these genes, RNF125 is a potent anti-proliferative tumor suppressor gene in HCC. RNF125 is one of nine CCGs whose expression was >3-fold downregulated in human HCC. Depletion of RNF125 in immortalized mouse liver cells led to tumor formation in transplanted mice and accelerated growth of human liver cancer cell lines, while its overexpression inhibited their growth, demonstrating the tumor-suppressive function of RNF125 in mouse and human liver. Whole-transcriptome analysis revealed that RNF125 transcriptionally suppresses multiple genes involved in cell proliferation and/or liver regeneration, including Egfr, Met, and Il6r. Blocking Egfr or Met pathway expression inhibited the increased cell proliferation observed in RNF125 knockdown cells. In HCC patients, low expression levels of RNF125 were correlated with poor prognosis demonstrating an important role for RNF125 in HCC. Collectively, our results identify RNF125 as a novel anti-proliferative tumor suppressor in HCC. |
| first_indexed | 2024-03-10T01:27:33Z |
| format | Article |
| id | doaj.art-34f59b4930cf4086a4f14c1ee24a50d8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:27:33Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-34f59b4930cf4086a4f14c1ee24a50d82023-11-23T13:47:45ZengMDPI AGCancers2072-66942022-05-011411258910.3390/cancers14112589Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular CarcinomaTakahiro Kodama0Michiko Kodama1Nancy A. Jenkins2Neal G. Copeland3Huanhuan Joyce Chen4Zhubo Wei5Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USAHouston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USAHouston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USAHouston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USAThe Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USAHouston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USAHepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and the only cancer with an increasing incidence in the United States. Recent advances in sequencing technology have enabled detailed profiling of liver cancer genomes and revealed extensive inter- and intra-tumor heterogeneity, making it difficult to identify driver genes for HCC. To identify HCC driver genes, we performed transposon mutagenesis screens in a mouse HBV model of HCC and discovered many candidate cancer genes (SB/HBV-CCGs). Here, we show that one of these genes, RNF125 is a potent anti-proliferative tumor suppressor gene in HCC. RNF125 is one of nine CCGs whose expression was >3-fold downregulated in human HCC. Depletion of RNF125 in immortalized mouse liver cells led to tumor formation in transplanted mice and accelerated growth of human liver cancer cell lines, while its overexpression inhibited their growth, demonstrating the tumor-suppressive function of RNF125 in mouse and human liver. Whole-transcriptome analysis revealed that RNF125 transcriptionally suppresses multiple genes involved in cell proliferation and/or liver regeneration, including Egfr, Met, and Il6r. Blocking Egfr or Met pathway expression inhibited the increased cell proliferation observed in RNF125 knockdown cells. In HCC patients, low expression levels of RNF125 were correlated with poor prognosis demonstrating an important role for RNF125 in HCC. Collectively, our results identify RNF125 as a novel anti-proliferative tumor suppressor in HCC.https://www.mdpi.com/2072-6694/14/11/2589hepatocellular carcinomadriver genesRNF125tumor suppressoranti-proliferationwhole-transcriptome analysis |
| spellingShingle | Takahiro Kodama Michiko Kodama Nancy A. Jenkins Neal G. Copeland Huanhuan Joyce Chen Zhubo Wei Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma Cancers hepatocellular carcinoma driver genes RNF125 tumor suppressor anti-proliferation whole-transcriptome analysis |
| title | Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma |
| title_full | Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma |
| title_fullStr | Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma |
| title_full_unstemmed | Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma |
| title_short | Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma |
| title_sort | ring finger protein 125 is an anti proliferative tumor suppressor in hepatocellular carcinoma |
| topic | hepatocellular carcinoma driver genes RNF125 tumor suppressor anti-proliferation whole-transcriptome analysis |
| url | https://www.mdpi.com/2072-6694/14/11/2589 |
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