UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1
Abstract Background Ubiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1278-9 |
| _version_ | 1818541605140824064 |
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| author | Hongze Chen Le Li Jisheng Hu Zhongjie Zhao Liang Ji Chundong Cheng Guangquan Zhang Tao zhang Yilong Li Hua Chen Shangha Pan Bei Sun |
| author_facet | Hongze Chen Le Li Jisheng Hu Zhongjie Zhao Liang Ji Chundong Cheng Guangquan Zhang Tao zhang Yilong Li Hua Chen Shangha Pan Bei Sun |
| author_sort | Hongze Chen |
| collection | DOAJ |
| description | Abstract Background Ubiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of cancer-related death and the underlying molecular mechanism of UBL4A and PDAC remains unknown. Methods First, the prognostic role of UBL4A and its expression in human PDAC patients and in pancreatic cancer cell lines were detected by survival analysis and qRT-PCR, western blotting, and immunohistochemistry. Next, the effects of UBL4A on proliferation and metastasis in pancreatic cancer were evaluated by functional assays in vitro and in vivo. In addition, chloroquine was introduced to determine the role of autophagy in UBL4A-related tumor proliferation and metastasis. Ultimately, coimmunoprecipitation was used to confirm the interaction between UBL4A and lysosome associated membrane protein-1 (LAMP1), and western blotting was performed to explore the UBL4A mechanism. Results We found that UBL4A was decreased in PDAC and that high levels of UBL4A correlated with a favorable prognosis. We observed that UBL4A inhibited tumor proliferation and metastasis through suppression of autophagy, a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions. UBL4A caused impaired autophagic degradation in vitro, a crucial process in autophagy, by disturbing the function of lysosomes and contributing to autophagosome accumulation. We found a positive correlation between UBL4A and LAMP1. Furthermore, UBL4A caused lysosomal dysfunction by directly interacting with LAMP1, and LAMP1 overexpression reversed the antitumor effects of UBL4A in pancreatic cancer. In addition, we demonstrated that UBL4A suppressed tumor growth and metastasis in a pancreatic orthotopic tumor model. Conclusions These findings suggest that UBL4A exerts an antitumor effect on autophagy-related proliferation and metastasis in PDAC by directly targeting LAMP1. Herein, we describe a novel mechanism of UBL4A that suppresses the progression of pancreatic cancer. UBL4A might be a promising target for the treatment and prognostication of PDAC. |
| first_indexed | 2024-12-11T22:11:28Z |
| format | Article |
| id | doaj.art-c9a285bbb35e44e8b3ee45f2f28cc46a |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-11T22:11:28Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-c9a285bbb35e44e8b3ee45f2f28cc46a2022-12-22T00:48:45ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-07-0138111810.1186/s13046-019-1278-9UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1Hongze Chen0Le Li1Jisheng Hu2Zhongjie Zhao3Liang Ji4Chundong Cheng5Guangquan Zhang6Tao zhang7Yilong Li8Hua Chen9Shangha Pan10Bei Sun11Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityKey Laboratory of Hepatosplenic Surgery, Ministry of EducationDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical UniversityAbstract Background Ubiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of cancer-related death and the underlying molecular mechanism of UBL4A and PDAC remains unknown. Methods First, the prognostic role of UBL4A and its expression in human PDAC patients and in pancreatic cancer cell lines were detected by survival analysis and qRT-PCR, western blotting, and immunohistochemistry. Next, the effects of UBL4A on proliferation and metastasis in pancreatic cancer were evaluated by functional assays in vitro and in vivo. In addition, chloroquine was introduced to determine the role of autophagy in UBL4A-related tumor proliferation and metastasis. Ultimately, coimmunoprecipitation was used to confirm the interaction between UBL4A and lysosome associated membrane protein-1 (LAMP1), and western blotting was performed to explore the UBL4A mechanism. Results We found that UBL4A was decreased in PDAC and that high levels of UBL4A correlated with a favorable prognosis. We observed that UBL4A inhibited tumor proliferation and metastasis through suppression of autophagy, a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions. UBL4A caused impaired autophagic degradation in vitro, a crucial process in autophagy, by disturbing the function of lysosomes and contributing to autophagosome accumulation. We found a positive correlation between UBL4A and LAMP1. Furthermore, UBL4A caused lysosomal dysfunction by directly interacting with LAMP1, and LAMP1 overexpression reversed the antitumor effects of UBL4A in pancreatic cancer. In addition, we demonstrated that UBL4A suppressed tumor growth and metastasis in a pancreatic orthotopic tumor model. Conclusions These findings suggest that UBL4A exerts an antitumor effect on autophagy-related proliferation and metastasis in PDAC by directly targeting LAMP1. Herein, we describe a novel mechanism of UBL4A that suppresses the progression of pancreatic cancer. UBL4A might be a promising target for the treatment and prognostication of PDAC.http://link.springer.com/article/10.1186/s13046-019-1278-9Ubiquitin-like protein 4A, UBL4ALysosome associated membrane protein-1, LAMP1AutophagyLysosome dysfunctionPancreatic ductal adenocarcinoma, PDACProliferation and metastasis |
| spellingShingle | Hongze Chen Le Li Jisheng Hu Zhongjie Zhao Liang Ji Chundong Cheng Guangquan Zhang Tao zhang Yilong Li Hua Chen Shangha Pan Bei Sun UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1 Journal of Experimental & Clinical Cancer Research Ubiquitin-like protein 4A, UBL4A Lysosome associated membrane protein-1, LAMP1 Autophagy Lysosome dysfunction Pancreatic ductal adenocarcinoma, PDAC Proliferation and metastasis |
| title | UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1 |
| title_full | UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1 |
| title_fullStr | UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1 |
| title_full_unstemmed | UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1 |
| title_short | UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1 |
| title_sort | ubl4a inhibits autophagy mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting lamp1 |
| topic | Ubiquitin-like protein 4A, UBL4A Lysosome associated membrane protein-1, LAMP1 Autophagy Lysosome dysfunction Pancreatic ductal adenocarcinoma, PDAC Proliferation and metastasis |
| url | http://link.springer.com/article/10.1186/s13046-019-1278-9 |
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