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SLC39A8/Zinc Suppresses the Progression of Clear Cell Renal Cell Carcinoma.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most frequent and lethal subtype, which has high risk of metastasis or recurrence, accounting for 75-83% of renal cell carcinoma (RCC). Zrt- and Irt-like proteins (ZIP) family members (SLC39A1-14) function to pass zinc into the cytoplasm for many critical biological processes when cellular zinc is depleted. However, the functional analysis of individual ZIP family genes in ccRCC is not clarified. This study aimed to investigate whether ZIP family genes are related to the clinicopathological features and survival of ccRCC patients, and to identify the function of key gene of ZIP family in ccRCC in vitro. Through bioinformatics analysis of tumor databases, SLC39A8 was identified as a key gene of ZIP family in ccRCC, which could be used as an effective indicator for diagnosing ccRCC and judging its prognosis. With the progression of tumor, the expression of SLC39A8 decreased progressively. The prognosis of patients with low expression of SLC39A8 is significantly worse. Furthermore, we found that overexpression of SLC39A8 or treatment with low concentration of zinc chloride could effectively inhibit the proliferation, migration and invasion of ccRCC cells. Moreover, the inhibition effect of SLC39A8 overexpression could be enhanced by low concentration zinc supplement. Therefore, this study provides a novel understanding for the role of SLC39A8/zinc in the regulation of ccRCC progression. These findings provide a new direction and target for progressive ccRCC drug development and combination therapy strategies.

SUBMITTER: Liu L

PROVIDER: S-EPMC8045709 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundClear 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.MethodsThe 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.Resultswe 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).ConclusionsOur 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.

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SLC39A8/Zinc Suppresses the Progression of Clear Cell Renal Cell Carcinoma.

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