Retinol Dehydrogenase 10 Promotes Metastasis of Glioma Cells via the Transforming Growth Factor-β/SMAD Signaling Pathway
Glioma is the most common primary malignant tumor in the central nervous system, accounting for approximately 70% of primary malignant brain tumors. With an incidence rate of about 5 per 100,000, it particularly affects individuals older than 65 years. Despite advances in treatment, the prognosis for glioma patients remains poor, with a 5-year survival rate of less than 5%. The aggressive nature of glioma, characterized by high proliferation and invasion, along with its resistance to chemoradiotherapy, contributes to the dismal outcomes. Current treatment strategies, including surgery combined with chemoradiotherapy, have not significantly improved survival rates. For glioblastoma, the most malignant form of glioma, the median survival time is only 12 to 15 months. Therefore, understanding the molecular mechanisms underlying glioma cell proliferation and invasion is crucial for developing new therapeutic targets and improving patient outcomes.
Retinol dehydrogenase 10 (RDH10) is a member of the short-chain dehydrogenase/reductase family, initially identified in retinal pigment epithelial cells. It plays a vital role in the retinoid A visual cycle by mediating the oxidation of retinol (vitamin A) into retinal, an essential precursor for retinoic acid synthesis. RDH10 has been implicated in various physiological development processes and is highly expressed during the differentiation of forelimbs and hindlimbs. Studies have shown that RDH10 is involved in the initiation and development of several cancers, including liver cancer and prostate cancer. Our previous research demonstrated that RDH10 promotes the proliferation of glioma cells both in vitro and in vivo. However, the role of RDH10 in glioma cell metastasis and invasion remains largely unexplored.
This study aimed to investigate the effect of RDH10 on the migration and invasion of glioma cells and to explore the potential mechanisms involved. We found that RDH10 is highly expressed in glioma cells compared to normal human astrocytes (NHA). Using lentivirus-mediated RNA interference, we successfully knocked down RDH10 expression in human glioma cell lines U87 and U251. The knockdown efficiency was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Specifically, RDH10 mRNA expression was reduced by 86.2% in U87 cells and 69.2% in U251 cells. Protein levels of RDH10 were also significantly downregulated in both cell lines.
To assess the impact of RDH10 knockdown on glioma cell migration, we performed scratch assays. The results showed that downregulation of RDH10 significantly inhibited the migration of both U87 and U251 cells. The inhibition rate of migration area was approximately two-fold higher in RDH10 knockdown cells compared to control cells. Similarly, transwell assays demonstrated that RDH10 knockdown significantly reduced the invasive capacity of glioma cells. The number of invading cells was drastically lower in RDH10 knockdown groups compared to control groups, with U87 cells showing a reduction from 97.30 ± 7.01 to 13.70 ± 0.58 and U251 cells from 96.20 ± 7.10 to 18.30 ± 2.08.
Given the critical role of the transforming growth factor-β (TGF-β)/SMAD signaling pathway in tumor metastasis, we examined whether RDH10 knockdown affects this pathway. Western blotting revealed that downregulation of RDH10 significantly inhibited the expression of TGF-β, phosphorylated SMAD2, and phosphorylated SMAD3. Specifically, TGF-β expression was reduced by 47%, phosphorylated SMAD2 by 58%, and phosphorylated SMAD3 by 59%. These findings suggest that RDH10 promotes glioma cell metastasis via the TGF-β/SMAD signaling pathway.
The TGF-β/SMAD signaling pathway is known to play a pivotal role in the epithelial-mesenchymal transition (EMT), a process critical for tumor metastasis. TGF-β is a multifunctional cytokine that promotes epithelial differentiation and inhibits cell proliferation. However, in cancer, aberrant TGF-β signaling can promote tumor progression, invasion, and metastasis. In glioma, the TGF-β/SMAD pathway is highly activated, contributing to the aggressive behavior of the tumor. TGF-β supports glioma invasion by promoting the expression of matrix metallopeptidase 2 (MMP-2) and inducing the expression of platelet-derived growth factor subunit B (PDGF-B). Additionally, TGF-β-induced microRNA (miRNA)-10a/miRNA-10b expression has been shown to promote glioma cell invasion by targeting phosphatase and tensin homolog (PTEN) expression.
Our findings indicate that RDH10 knockdown inhibits glioma cell migration and invasion by downregulating the TGF-β/SMAD signaling pathway. This suggests that RDH10 may serve as a potential therapeutic target for glioma. By targeting RDH10, it may be possible to inhibit the metastatic potential of glioma cells, thereby improving patient outcomes. Further studies are needed to elucidate the detailed mechanisms by which RDH10 regulates TGF-β/SMAD signaling and to explore the therapeutic potential of targeting RDH10 in glioma treatment.
In conclusion, glioma remains a significant challenge in oncology due to its aggressive nature and resistance to conventional therapies. The identification of RDH10 as a regulator of glioma cell metastasis via the TGF-β/SMAD signaling pathway provides new insights into the molecular mechanisms underlying glioma progression. Targeting RDH10 may offer a novel therapeutic strategy to inhibit glioma metastasis and improve patient survival. Future research should focus on validating these findings in preclinical models and exploring the clinical potential of RDH10-targeted therapies.
doi.org/10.1097/CM9.0000000000000478
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