Cancer genetics · 2026
CRYL1 inhibits tumorigenesis and metastasis in clear cell renal cell carcinoma through upregulation of CASR.
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Xu Yipeng, Li Peng, Liu Xigao, Zhao Guanan, Wu Qi, Zhang Huijiang, You Shengjie, Zhou Qiyin, Wang He, Li Ziyun, Ye Junjie
Аннотация
BACKGROUND: Identifying novel biomarkers and elucidating the underlying molecular mechanisms are crucial for improving the diagnosis and treatment of advanced clear cell renal cell carcinoma (ccRCC). In our previous investigations, crystallin lambda 1 (CRYL1) was preliminarily identified as an emerging tumor suppressor. The present study expands upon this observation by further exploring its tumor-suppressive role and the underlying molecular mechanisms.
METHODS: Seventy patients with ccRCC were selected to validate CRYL1 expression and its clinical significance. In vitro proliferation, migration, and apoptosis assays were performed to assess the effects of CRYL1 overexpression. Transcriptome sequencing combined with bioinformatics analysis identified the calcium-sensing receptor (CASR) as a key downstream target of CRYL1. In vitro functional assays of CASR and further bioinformatics analyses were subsequently conducted. Rescue experiments in vitro and immunohistochemistry (IHC) of tissues validated their regulatory relationship. Subcutaneous xenograft mouse models were used for in vivo validation.
RESULTS: Low CRYL1 expression was significantly associated with advanced clinical stage (p = 0.012), poorer disease-free survival (DFS, p = 0.031), and poorer overall survival (OS, p = 0.049). CRYL1 overexpression potently suppressed proliferation, colony formation, and migration and induced apoptosis in Caki-1 and OSRC-2 cell lines. Integrated transcriptomic and bioinformatic analyses identified CASR as a major downstream effector of CRYL1. CASR expression was significantly reduced in ccRCC tissues and was inversely correlated with advanced T stage, grade, and metastasis. Low CASR expression predicted worse OS and DFS. Functional studies demonstrated that CASR overexpression inhibited ccRCC cell migration. Crucially, CASR knockdown partially reversed the anti-migratory effects of CRYL1 overexpression. Significant positive correlations were observed between CRYL1 and CASR expression in patient samples (r ≈ 0.2) and in xenograft tumors. Furthermore, CRYL1-overexpressing xenografts exhibited significantly reduced tumor growth, upregulated BAX and TIMP3, and downregulated BCL2 and MMP9.
CONCLUSIONS: The results of this study indicate that CRYL1 functions as a tumor suppressor gene in ccRCC, and that its downregulated expression is closely associated with enhanced tumor aggressiveness and poor patient prognosis. CRYL1 may inhibit cell proliferation and migration and promote apoptosis through regulation of CASR. Therefore, the CRYL1/CASR signaling axis may serve as a novel potential therapeutic target for clear cell renal cell carcinoma.
METHODS: Seventy patients with ccRCC were selected to validate CRYL1 expression and its clinical significance. In vitro proliferation, migration, and apoptosis assays were performed to assess the effects of CRYL1 overexpression. Transcriptome sequencing combined with bioinformatics analysis identified the calcium-sensing receptor (CASR) as a key downstream target of CRYL1. In vitro functional assays of CASR and further bioinformatics analyses were subsequently conducted. Rescue experiments in vitro and immunohistochemistry (IHC) of tissues validated their regulatory relationship. Subcutaneous xenograft mouse models were used for in vivo validation.
RESULTS: Low CRYL1 expression was significantly associated with advanced clinical stage (p = 0.012), poorer disease-free survival (DFS, p = 0.031), and poorer overall survival (OS, p = 0.049). CRYL1 overexpression potently suppressed proliferation, colony formation, and migration and induced apoptosis in Caki-1 and OSRC-2 cell lines. Integrated transcriptomic and bioinformatic analyses identified CASR as a major downstream effector of CRYL1. CASR expression was significantly reduced in ccRCC tissues and was inversely correlated with advanced T stage, grade, and metastasis. Low CASR expression predicted worse OS and DFS. Functional studies demonstrated that CASR overexpression inhibited ccRCC cell migration. Crucially, CASR knockdown partially reversed the anti-migratory effects of CRYL1 overexpression. Significant positive correlations were observed between CRYL1 and CASR expression in patient samples (r ≈ 0.2) and in xenograft tumors. Furthermore, CRYL1-overexpressing xenografts exhibited significantly reduced tumor growth, upregulated BAX and TIMP3, and downregulated BCL2 and MMP9.
CONCLUSIONS: The results of this study indicate that CRYL1 functions as a tumor suppressor gene in ccRCC, and that its downregulated expression is closely associated with enhanced tumor aggressiveness and poor patient prognosis. CRYL1 may inhibit cell proliferation and migration and promote apoptosis through regulation of CASR. Therefore, the CRYL1/CASR signaling axis may serve as a novel potential therapeutic target for clear cell renal cell carcinoma.