HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway
Abstract Background The Hypoxia inducible gene domain family member 2A (HIGD2A) protein is indispensable for the assembly of the mitochondrial respiratory supercomplex, which has been implicated in cell proliferation and cell survival under hypoxic conditions. Because the liver has a naturally low o...
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04105-7 |
| _version_ | 1827966102670409728 |
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| author | Kuiyuan Huang Ziying Liu Zhanglian Xie Xiaoran Li Haixing Zhang Yu Chen Yiran Wang Zimo Lin Chuanjiang Li Hongyan Liu Xiaoyong Zhang |
| author_facet | Kuiyuan Huang Ziying Liu Zhanglian Xie Xiaoran Li Haixing Zhang Yu Chen Yiran Wang Zimo Lin Chuanjiang Li Hongyan Liu Xiaoyong Zhang |
| author_sort | Kuiyuan Huang |
| collection | DOAJ |
| description | Abstract Background The Hypoxia inducible gene domain family member 2A (HIGD2A) protein is indispensable for the assembly of the mitochondrial respiratory supercomplex, which has been implicated in cell proliferation and cell survival under hypoxic conditions. Because the liver has a naturally low oxygen microenvironment, the role of HIGD2A in the development of hepatocellular carcinoma (HCC) remains largely unknown. Methods Gene expression data and clinical information were obtained from multiple public databases. A lentivirus-mediated gene knockdown approach was conducted to explore the function and mechanism of HIGD2A activity in HCC cells. In vivo and in vitro assays were performed to investigate the biological roles of HIGD2A. Results HIGD2A was overexpressed in HCC tissues and cell lines and was associated with a worse prognosis. Silencing HIGD2A expression significantly attenuated cell proliferation and migration, caused S-phase cell cycle arrest, and decreased tumor formation in nude mice. Mechanistically, HIGD2A depletion greatly decreased cellular ATP levels by disrupting mitochondrial ATP production. Moreover, HIGD2A knockdown cells displayed impaired mitochondrial function, such as mitochondrial fusion, increased expression of the mitochondrial stress response protein, and decreased oxygen consumption. Furthermore, knockdown of HIGD2A markedly attenuated the activation of the MAPK/ERK pathway. Conclusions HIGD2A promoted liver cancer cell growth by fueling mitochondrial ATP synthesis and activating the MAPK/ERK pathway, suggested that targeting HIGD2A may represent a new strategy for HCC therapy. |
| first_indexed | 2024-04-09T17:44:46Z |
| format | Article |
| id | doaj.art-2ec4af787a9440209e53b6fd55feab6a |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T17:44:46Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-2ec4af787a9440209e53b6fd55feab6a2023-04-16T11:23:48ZengBMCJournal of Translational Medicine1479-58762023-04-0121111810.1186/s12967-023-04105-7HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathwayKuiyuan Huang0Ziying Liu1Zhanglian Xie2Xiaoran Li3Haixing Zhang4Yu Chen5Yiran Wang6Zimo Lin7Chuanjiang Li8Hongyan Liu9Xiaoyong Zhang10State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityDivision of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical UniversityAbstract Background The Hypoxia inducible gene domain family member 2A (HIGD2A) protein is indispensable for the assembly of the mitochondrial respiratory supercomplex, which has been implicated in cell proliferation and cell survival under hypoxic conditions. Because the liver has a naturally low oxygen microenvironment, the role of HIGD2A in the development of hepatocellular carcinoma (HCC) remains largely unknown. Methods Gene expression data and clinical information were obtained from multiple public databases. A lentivirus-mediated gene knockdown approach was conducted to explore the function and mechanism of HIGD2A activity in HCC cells. In vivo and in vitro assays were performed to investigate the biological roles of HIGD2A. Results HIGD2A was overexpressed in HCC tissues and cell lines and was associated with a worse prognosis. Silencing HIGD2A expression significantly attenuated cell proliferation and migration, caused S-phase cell cycle arrest, and decreased tumor formation in nude mice. Mechanistically, HIGD2A depletion greatly decreased cellular ATP levels by disrupting mitochondrial ATP production. Moreover, HIGD2A knockdown cells displayed impaired mitochondrial function, such as mitochondrial fusion, increased expression of the mitochondrial stress response protein, and decreased oxygen consumption. Furthermore, knockdown of HIGD2A markedly attenuated the activation of the MAPK/ERK pathway. Conclusions HIGD2A promoted liver cancer cell growth by fueling mitochondrial ATP synthesis and activating the MAPK/ERK pathway, suggested that targeting HIGD2A may represent a new strategy for HCC therapy.https://doi.org/10.1186/s12967-023-04105-7Hepatocellular carcinomaHIGD2AMitochondriaATPThe MAPK/ERK pathway |
| spellingShingle | Kuiyuan Huang Ziying Liu Zhanglian Xie Xiaoran Li Haixing Zhang Yu Chen Yiran Wang Zimo Lin Chuanjiang Li Hongyan Liu Xiaoyong Zhang HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway Journal of Translational Medicine Hepatocellular carcinoma HIGD2A Mitochondria ATP The MAPK/ERK pathway |
| title | HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway |
| title_full | HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway |
| title_fullStr | HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway |
| title_full_unstemmed | HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway |
| title_short | HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway |
| title_sort | higd2a silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the mapk erk pathway |
| topic | Hepatocellular carcinoma HIGD2A Mitochondria ATP The MAPK/ERK pathway |
| url | https://doi.org/10.1186/s12967-023-04105-7 |
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