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MFN2 suppresses clear cell renal cell carcinoma progression by modulating mitochondria-dependent dephosphorylation of
Li Luo1, Denghui Wei1, Yihui Pan2
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.
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.
Insights
Mitofusin-2 (MFN2) suppresses clear cell renal cell carcinoma (ccRCC) progression by inhibiting the epidermal growth factor receptor (EGFR) pathway. Loss of MFN2 activates EGFR signaling, promoting ccRCC tumorigenesis and metastasis.
Area of Science:
- Oncology
- Cell Biology
- Molecular Mechanisms
Background:
- Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer with poor prognosis.
- Molecular drivers of ccRCC progression and metastasis are not fully understood.
- Identifying novel therapeutic targets is crucial for improving ccRCC patient outcomes.
Purpose of the Study:
- Investigate the role of mitofusin-2 (MFN2) in ccRCC tumorigenesis and metastasis.
- Elucidate the molecular mechanisms by which MFN2 influences ccRCC progression.
- Determine the clinical significance of MFN2 in ccRCC patients.
Main Methods:
- Analysis of MFN2 expression in ccRCC using The Cancer Genome Atlas and patient cohorts.
- In vitro and in vivo experiments (cell proliferation, xenograft, transgenic models) to assess MFN2's role.
- Molecular analyses including RNA-sequencing, mass spectrometry, co-immunoprecipitation, and immunofluorescence.
Main Results:
- MFN2 is downregulated in ccRCC and correlates with favorable prognosis.
- MFN2 suppresses ccRCC tumor growth and metastasis by inhibiting the EGFR signaling pathway.
- Loss of MFN2 in a mouse model activates EGFR signaling, leading to kidney lesions.
Conclusions:
- MFN2 acts as a tumor suppressor in ccRCC through a mitochondria-dependent pathway.
- The Rab21-MFN2-PTPRJ axis regulates EGFR signaling, impacting ccRCC development.
- This pathway represents a potential therapeutic target for ccRCC treatment.
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