ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization
Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with a poor prognosis, marked by a postoperative recurrence rate of 50–60% and a 5-year survival rate of 8–30%. Abnormal tumor metabolism, particularly, amino acid metabolism, plays a key role in malignant progression. Ho...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-025-03400-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850124683269111808 |
|---|---|
| author | Yanyu Gong Liwen Chen Hao Wang Dijie Zheng Futang Li Changhao Wu Yongning Li Yazhu Deng Zhiwei He Chao Yu |
| author_facet | Yanyu Gong Liwen Chen Hao Wang Dijie Zheng Futang Li Changhao Wu Yongning Li Yazhu Deng Zhiwei He Chao Yu |
| author_sort | Yanyu Gong |
| collection | DOAJ |
| description | Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with a poor prognosis, marked by a postoperative recurrence rate of 50–60% and a 5-year survival rate of 8–30%. Abnormal tumor metabolism, particularly, amino acid metabolism, plays a key role in malignant progression. However, the molecular mechanisms linking amino acid metabolism to ICC progression remain unclear. Methods Bioinformatics was used to identity the key amino acid metabolism related gene in ICC, qRT-PCR, western blotting and immunohistochemical (IHC) were used to detect the expression of ANXA1 in normal tissues or ICC tissues and cells at mRNA and protein levels. The effects of ANXA1 on the proliferation ability of ICC in vitro and in vivo were investigated using CCK8, cloning formation experiment, EdU, IHC, nude mice subcutaneous tumorigenesis model. Immunoprecipitation, mass spectrometry analysis, protein ubiquitin level detection test, immunofluorescence co-localization, and redox stress metabolite detection test were used to explore the metabolism-related regulatory mechanism of ANXA1. Results we employed bioinformatics analysis to classify ICC into metabolic subgroups with distinct prognoses and identified the associated biomarker Annexin A1(ANXA1), whose high expression is correlated with poor prognosis and promotes ICC development. Mass spectrometry analysis revealed that ANXA1 interacts with the key enzyme in glutamine metabolism, glutamic-oxaloacetic transaminase 1(GOT1). Through in vitro and in vivo experiments, overexpressed ANXA1 stabilizes GOT1 by recruiting the deubiquitinase USP5. This stabilization enhances glutamine uptake, as well as the production of aspartate and glutamate, which in turn reduces oxidative stress, thereby promoting tumor cell growth. Moreover, knockdown of ANXA1 combined with glutamine uptake inhibition significantly suppressed ICC cell proliferation and Inhibited subcutaneous tumor formation and growth. Conclusions These results suggest that the ANXA1/USP5/GOT1 axis promotes glutamine metabolism and ICC proliferation and growth. Inhibiting ANXA1 alongside glutamine uptake inhibition offers a promising strategy for treating ICC. |
| format | Article |
| id | doaj-art-930e94d1531444eba4bb9723535cef11 |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-930e94d1531444eba4bb9723535cef112025-08-20T02:34:15ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-05-0144112110.1186/s13046-025-03400-zANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilizationYanyu Gong0Liwen Chen1Hao Wang2Dijie Zheng3Futang Li4Changhao Wu5Yongning Li6Yazhu Deng7Zhiwei He8Chao Yu9Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical UniversityAbstract Background Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with a poor prognosis, marked by a postoperative recurrence rate of 50–60% and a 5-year survival rate of 8–30%. Abnormal tumor metabolism, particularly, amino acid metabolism, plays a key role in malignant progression. However, the molecular mechanisms linking amino acid metabolism to ICC progression remain unclear. Methods Bioinformatics was used to identity the key amino acid metabolism related gene in ICC, qRT-PCR, western blotting and immunohistochemical (IHC) were used to detect the expression of ANXA1 in normal tissues or ICC tissues and cells at mRNA and protein levels. The effects of ANXA1 on the proliferation ability of ICC in vitro and in vivo were investigated using CCK8, cloning formation experiment, EdU, IHC, nude mice subcutaneous tumorigenesis model. Immunoprecipitation, mass spectrometry analysis, protein ubiquitin level detection test, immunofluorescence co-localization, and redox stress metabolite detection test were used to explore the metabolism-related regulatory mechanism of ANXA1. Results we employed bioinformatics analysis to classify ICC into metabolic subgroups with distinct prognoses and identified the associated biomarker Annexin A1(ANXA1), whose high expression is correlated with poor prognosis and promotes ICC development. Mass spectrometry analysis revealed that ANXA1 interacts with the key enzyme in glutamine metabolism, glutamic-oxaloacetic transaminase 1(GOT1). Through in vitro and in vivo experiments, overexpressed ANXA1 stabilizes GOT1 by recruiting the deubiquitinase USP5. This stabilization enhances glutamine uptake, as well as the production of aspartate and glutamate, which in turn reduces oxidative stress, thereby promoting tumor cell growth. Moreover, knockdown of ANXA1 combined with glutamine uptake inhibition significantly suppressed ICC cell proliferation and Inhibited subcutaneous tumor formation and growth. Conclusions These results suggest that the ANXA1/USP5/GOT1 axis promotes glutamine metabolism and ICC proliferation and growth. Inhibiting ANXA1 alongside glutamine uptake inhibition offers a promising strategy for treating ICC.https://doi.org/10.1186/s13046-025-03400-zICCANXA1GOT1Glutamine metabolismOxidative stress |
| spellingShingle | Yanyu Gong Liwen Chen Hao Wang Dijie Zheng Futang Li Changhao Wu Yongning Li Yazhu Deng Zhiwei He Chao Yu ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization Journal of Experimental & Clinical Cancer Research ICC ANXA1 GOT1 Glutamine metabolism Oxidative stress |
| title | ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization |
| title_full | ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization |
| title_fullStr | ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization |
| title_full_unstemmed | ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization |
| title_short | ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization |
| title_sort | anxa1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through got1 stabilization |
| topic | ICC ANXA1 GOT1 Glutamine metabolism Oxidative stress |
| url | https://doi.org/10.1186/s13046-025-03400-z |
| work_keys_str_mv | AT yanyugong anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT liwenchen anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT haowang anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT dijiezheng anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT futangli anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT changhaowu anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT yongningli anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT yazhudeng anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT zhiweihe anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization AT chaoyu anxa1promotesintrahepaticcholangiocarcinomaproliferationandgrowthbyregulatingglutaminemetabolismthroughgot1stabilization |