PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummary
Background & Aims: Metastasis indicates a grave prognosis in patients with hepatocellular carcinoma (HCC). Our previous studies showed that RNA binding motif protein Y-linked (RBMY) is potentially a biomarker for poor survival in HCC patients, but its role in metastasis is largely unclear. M...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X22002090 |
| _version_ | 1797988223147835392 |
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| author | Huey-Huey Chua Mei-Hwei Chang Ya-Hui Chen Daw-Jen Tsuei Yung-Ming Jeng Po-Huang Lee Yen-Hsuan Ni |
| author_facet | Huey-Huey Chua Mei-Hwei Chang Ya-Hui Chen Daw-Jen Tsuei Yung-Ming Jeng Po-Huang Lee Yen-Hsuan Ni |
| author_sort | Huey-Huey Chua |
| collection | DOAJ |
| description | Background & Aims: Metastasis indicates a grave prognosis in patients with hepatocellular carcinoma (HCC). Our previous studies showed that RNA binding motif protein Y-linked (RBMY) is potentially a biomarker for poor survival in HCC patients, but its role in metastasis is largely unclear. Methods: A total of 308 male patients with primary HCC were enrolled. RBMY expression was traced longitudinally by immunostaining from the manifestation of a primary HCC tumor to the formation of a distant metastasis, and its upstream regulators were screened with a protein microarray. A series of metastasis assays in mouse models and HCC cell lines were performed to explore new functional insights into RBMY. Results: Cytoplasmic expression of RBMY was associated with rapid distant metastasis (approximately 1 year after resection) and had a predictive power of 82.4% for HCC metastasis. RBMY conferred high migratory and invasive potential upon phosphorylation by the provirus integration in Moloney 1 (PIM1) kinase. Binding of PIM1 to RBMY caused mutual stabilization and massive translocation of RBMY from nuclei to mitochondria, thereby preventing mitochondrial apoptosis and augmenting mitochondrial generation of adenosine triphosphate/reactive oxygen species to enhance cell motility. Depletion of RBMY suppressed Snail1/zinc finger E-box binding homeobox transcription factor 1–mediated epithelial–mesenchymal transition and dynamin-related protein 1–dependent mitochondrial fission. Inactivation and knockout of PIM1 down-regulated the expression of RBMY. In nude mice, cytoplasmic RBMY promoted liver-to-lung metastasis by increasing epithelial–mesenchymal transition, mitochondrial proliferation, and mitochondrial fission, whereas nuclear-restricted RBMY impeded the mitochondrial switch and failed to induce lung metastasis. Conclusions: This study showed the regulation of HCC metastasis by PIM1-driven cytoplasmic expression of RBMY and suggested a novel therapeutic target for attenuating metastasis. |
| first_indexed | 2024-04-11T08:00:39Z |
| format | Article |
| id | doaj.art-b4787e112e144172b784333c77889842 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-11T08:00:39Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-b4787e112e144172b784333c778898422022-12-22T04:35:44ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2023-01-01151121152PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummaryHuey-Huey Chua0Mei-Hwei Chang1Ya-Hui Chen2Daw-Jen Tsuei3Yung-Ming Jeng4Po-Huang Lee5Yen-Hsuan Ni6Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanDepartment of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanDepartment of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Surgery, E-DA Hospital, Kaohsiung, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; Medical Microbiota Center, College of Medicine, National Taiwan University, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Correspondence Address correspondence to: Yen-Hsuan Ni, MD, PhD, Department of Pediatrics, College of Medicine, National Taiwan University, 15F, No 8, Chung-Shan S Road, Zhongzheng District, Taipei City 100226, Taiwan.Background & Aims: Metastasis indicates a grave prognosis in patients with hepatocellular carcinoma (HCC). Our previous studies showed that RNA binding motif protein Y-linked (RBMY) is potentially a biomarker for poor survival in HCC patients, but its role in metastasis is largely unclear. Methods: A total of 308 male patients with primary HCC were enrolled. RBMY expression was traced longitudinally by immunostaining from the manifestation of a primary HCC tumor to the formation of a distant metastasis, and its upstream regulators were screened with a protein microarray. A series of metastasis assays in mouse models and HCC cell lines were performed to explore new functional insights into RBMY. Results: Cytoplasmic expression of RBMY was associated with rapid distant metastasis (approximately 1 year after resection) and had a predictive power of 82.4% for HCC metastasis. RBMY conferred high migratory and invasive potential upon phosphorylation by the provirus integration in Moloney 1 (PIM1) kinase. Binding of PIM1 to RBMY caused mutual stabilization and massive translocation of RBMY from nuclei to mitochondria, thereby preventing mitochondrial apoptosis and augmenting mitochondrial generation of adenosine triphosphate/reactive oxygen species to enhance cell motility. Depletion of RBMY suppressed Snail1/zinc finger E-box binding homeobox transcription factor 1–mediated epithelial–mesenchymal transition and dynamin-related protein 1–dependent mitochondrial fission. Inactivation and knockout of PIM1 down-regulated the expression of RBMY. In nude mice, cytoplasmic RBMY promoted liver-to-lung metastasis by increasing epithelial–mesenchymal transition, mitochondrial proliferation, and mitochondrial fission, whereas nuclear-restricted RBMY impeded the mitochondrial switch and failed to induce lung metastasis. Conclusions: This study showed the regulation of HCC metastasis by PIM1-driven cytoplasmic expression of RBMY and suggested a novel therapeutic target for attenuating metastasis.http://www.sciencedirect.com/science/article/pii/S2352345X22002090Drp1EMTMitochondriaSnail1ZEB1 |
| spellingShingle | Huey-Huey Chua Mei-Hwei Chang Ya-Hui Chen Daw-Jen Tsuei Yung-Ming Jeng Po-Huang Lee Yen-Hsuan Ni PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummary Cellular and Molecular Gastroenterology and Hepatology Drp1 EMT Mitochondria Snail1 ZEB1 |
| title | PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummary |
| title_full | PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummary |
| title_fullStr | PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummary |
| title_full_unstemmed | PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummary |
| title_short | PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma MetastasisSummary |
| title_sort | pim1 induced cytoplasmic expression of rbmy mediates hepatocellular carcinoma metastasissummary |
| topic | Drp1 EMT Mitochondria Snail1 ZEB1 |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X22002090 |
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