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ALDH1L2 orchestrates redox-growth coupling in renal carcinoma: pan-cancer evidence and mechanistic validation of the
Chao Jiang1, Songsong Liu1, Liwen Zhang1
1Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Background:
Aldehyde dehydrogenase family 1 member L2 (ALDH1L2) has been relatively understudied in cancer. We aimed to systematically characterize its expression patterns, clinical significance, and potential functions across cancers and to validate its biological roles in urologic tumors.
Methods:
Leveraging The Cancer Genome Atlas pan-cancer resource, we profiled ALDH1L2 across tumor types with respect to expression patterns, clinical outcomes, genomic features, immune contexture, epigenetic associations, and indices of stemness and heterogeneity. Protein-level differences were examined by immunohistochemistry in bladder cancer (BLCA), prostate adenocarcinoma (PRAD), and kidney renal clear cell carcinoma (KIRC) tissues. To functionally interrogate ALDH1L2, we performed siRNA-mediated knockdown in relevant cell models and evaluated proliferation and motility-related phenotypes using wound-healing, Transwell, and EdU incorporation assays. In KIRC, Western blotting together with reactive oxygen species (ROS) detection was conducted to probe potential mechanistic links.
Results:
ALDH1L2 was differentially expressed in multiple cancers and significantly associated with overall and disease-specific survival in KIRC. IHC showed higher ALDH1L2 expression in KIRC tissues than in adjacent normal tissues, but lower expression in BLCA and PRAD. Functionally, ALDH1L2 knockdown suppressed proliferation and migration in KIRC cells, while promoting these processes in BLCA and PRAD cells. In KIRC, ALDH1L2 silencing increased ROS levels and reduced Akt/mTOR/S6K phosphorylation, consistent with decreased EdU incorporation.
Conclusion:
This study is the first to systematically untangle the divergent roles of ALDH1L2 in KIRC, BLCA, and PRAD from a pan-cancer perspective combined with ex vivo experiments, suggesting that ALDH1L2 may serve as an important molecule influencing tumor progression and the immune microenvironment, thereby providing a new potential target for the diagnosis and treatment of related cancers.
Insights
Aldehyde dehydrogenase family 1 member L2 (ALDH1L2) plays divergent roles in different cancers. It suppresses proliferation in kidney cancer but promotes it in bladder and prostate cancers, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Aldehyde dehydrogenase family 1 member L2 (ALDH1L2) is understudied in cancer.
- Characterizing ALDH1L2 expression, clinical significance, and function is crucial, especially in urologic tumors.
Purpose of the Study:
- To systematically analyze ALDH1L2 expression patterns and clinical significance across various cancers.
- To investigate the functional roles of ALDH1L2 in urologic tumors, including bladder cancer (BLCA), prostate adenocarcinoma (PRAD), and kidney renal clear cell carcinoma (KIRC).
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) for pan-cancer analysis of ALDH1L2 expression, clinical outcomes, and genomic features.
- Performed immunohistochemistry (IHC) for protein-level analysis in BLCA, PRAD, and KIRC tissues.
- Conducted siRNA-mediated knockdown experiments to assess ALDH1L2's functional impact on cell proliferation and motility, including wound-healing, Transwell, and EdU assays. Investigated mechanistic links in KIRC using Western blotting and reactive oxygen species (ROS) detection.
Main Results:
- ALDH1L2 exhibited differential expression across cancers and was linked to survival in KIRC.
- IHC revealed higher ALDH1L2 in KIRC but lower levels in BLCA and PRAD compared to normal tissues.
- ALDH1L2 knockdown inhibited proliferation and migration in KIRC cells, while promoting these in BLCA and PRAD cells. In KIRC, ALDH1L2 silencing increased ROS and reduced Akt/mTOR/S6K phosphorylation.
Conclusions:
- This study provides the first systematic analysis of ALDH1L2's divergent roles in KIRC, BLCA, and PRAD.
- ALDH1L2 influences tumor progression and the immune microenvironment, suggesting its potential as a diagnostic and therapeutic target.
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