MFN2 suppresses clear cell renal cell carcinoma progression by modulating mitochondria-dependent dephosphorylation of EGFR
Li Luo
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
These authors contributed equally.
Search for more papers by this authorDenghui Wei
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
These authors contributed equally.
Search for more papers by this authorYihui Pan
Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, P. R. China
These authors contributed equally.
Search for more papers by this authorQiu-Xia Wang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorJian-Xiong Feng
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorBing Yu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorTiebang Kang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorCorresponding Author
Junhang Luo
Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
Correspondence
Song Gao, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.
Email: [email protected]
Jiefeng Yang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China.
Email: [email protected]
Junhang Luo, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jiefeng Yang
Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
Correspondence
Song Gao, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.
Email: [email protected]
Jiefeng Yang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China.
Email: [email protected]
Junhang Luo, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China
Email: [email protected]
Search for more papers by this authorCorresponding Author
Song Gao
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Correspondence
Song Gao, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.
Email: [email protected]
Jiefeng Yang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China.
Email: [email protected]
Junhang Luo, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China
Email: [email protected]
Search for more papers by this authorLi Luo
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
These authors contributed equally.
Search for more papers by this authorDenghui Wei
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
These authors contributed equally.
Search for more papers by this authorYihui Pan
Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, P. R. China
These authors contributed equally.
Search for more papers by this authorQiu-Xia Wang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorJian-Xiong Feng
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorBing Yu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorTiebang Kang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Search for more papers by this authorCorresponding Author
Junhang Luo
Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
Correspondence
Song Gao, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.
Email: [email protected]
Jiefeng Yang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China.
Email: [email protected]
Junhang Luo, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jiefeng Yang
Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
Correspondence
Song Gao, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.
Email: [email protected]
Jiefeng Yang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China.
Email: [email protected]
Junhang Luo, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China
Email: [email protected]
Search for more papers by this authorCorresponding Author
Song Gao
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
Correspondence
Song Gao, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.
Email: [email protected]
Jiefeng Yang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China.
Email: [email protected]
Junhang Luo, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China
Email: [email protected]
Search for more papers by this authorAbstract
Background
Clear cell renal cell carcinoma (ccRCC) is the most lethal renal cancer. An overwhelming increase of patients experience tumor progression and unfavorable prognosis. However, the molecular events underlying ccRCC tumorigenesis and metastasis remain unclear. Therefore, uncovering the underlying mechanisms will pave the way for developing novel therapeutic targets for ccRCC. In this study, we sought to investigate the role of mitofusin-2 (MFN2) in supressing ccRCC tumorigenesis and metastasis.
Methods
The expression pattern and clinical significance of MFN2 in ccRCC were analyzed by using the Cancer Genome Atlas datasets and samples from our independent ccRCC cohort. Both in vitro and in vivo experiments, including cell proliferation, xenograft mouse models and transgenic mouse model, were used to determine the role of MFN2 in regulating the malignant behaviors of ccRCC. RNA-sequencing, mass spectrum analysis, co-immunoprecipitation, bio-layer interferometry and immunofluorescence were employed to elucidate the molecular mechanisms for the tumor-supressing role of MFN2.
Results
we reported a tumor-suppressing pathway in ccRCC, characterized by mitochondria-dependent inactivation of epidermal growth factor receptor (EGFR) signaling. This process was mediated by the outer mitochondrial membrane (OMM) protein MFN2. MFN2 was down-regulated in ccRCC and associated with favorable prognosis of ccRCC patients. in vivo and in vitro assays demonstrated that MFN2 inhibited ccRCC tumor growth and metastasis by suppressing the EGFR signaling pathway. In a kidney-specific knockout mouse model, loss of MFN2 led to EGFR pathway activation and malignant lesions in kidney. Mechanistically, MFN2 preferably binded small GTPase Rab21 in its GTP-loading form, which was colocalized with endocytosed EGFR in ccRCC cells. Through this EGFR-Rab21-MFN2 interaction, endocytosed EGFR was docked to mitochondria and subsequently dephosphorylated by the OMM-residing tyrosine-protein phosphatase receptor type J (PTPRJ).
Conclusions
Our findings uncover an important non-canonical mitochondria-dependent pathway regulating EGFR signaling by the Rab21-MFN2-PTPRJ axis, which contributes to the development of novel therapeutic strategies for ccRCC.
CONFLICTS OF INTEREST STATEMENT
The authors declare that they have no competing interests.
Open Research
DATA AVAILABILITY STATEMENT
The raw RNA sequencing data are available at the Genome Sequence Archive (GSA) database (accession number HRA002229). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE33 partner repository with the dataset identifiers PXD033112 for the interactome of MFN2, PXD033104 for the interactome of Rab21, and PXD033099 for the mitochondrial proteome of 786-O cells. The key raw data have been deposited into the Research Data Deposit (www.researchdata.org.cn), with the approval number of 2302230001.
Supporting Information
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| cac212428-sup-0001-FigureS1.tif21 MB | Supporting Information |
| cac212428-sup-0002-FigureS2.tif24.5 MB | Supporting Information |
| cac212428-sup-0003-FigureS3.tif13.7 MB | Supporting Information |
| cac212428-sup-0004-FigureS4.tif20.9 MB | Supporting Information |
| cac212428-sup-0005-FigureS5.tif26.5 MB | Supporting Information |
| cac212428-sup-0006-FigureS6.tif16.1 MB | Supporting Information |
| cac212428-sup-0007-FigureS7.tif13.4 MB | Supporting Information |
| cac212428-sup-0008-FigureS8.tif25.3 MB | Supporting Information |
| cac212428-sup-0009-FigureS9.tif25.7 MB | Supporting Information |
| cac212428-sup-0010-FigureS10.tif23.2 MB | Supporting Information |
| cac212428-sup-0011-FiguresCaption.docx45 KB | Supporting Information |
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