Non-coding RNAs and ferroptosis: potential implications for cancer therapy
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Abstract Ferroptosis is a recently defined form of regulated cell death, which is biochemically and morphologically distinct from traditional forms of programmed cell death such as apoptosis or necrosis. It is driven by iron, reactive oxygen species, and phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage and breakdown of membrane integrity. Numerous cellular signaling pathways and molecules are involved in the regulation of ferroptosis, including enzymes that control the cellular redox status. Alterations in the ferroptosis-regulating network can contribute to the development of various diseases, including cancer. Evidence suggests that ferroptosis is commonly suppressed in cancer cells, allowing them to survive and progress. However, cancer cells which are resistant to common chemotherapeutic drugs seem to be highly susceptible to ferroptosis inducers, highlighting the great potential of pharmacologic modulation of ferroptosis for cancer treatment. Non-coding RNAs (ncRNAs) are considered master regulators of various cellular processes, particularly in cancer where they have been implicated in all hallmarks of cancer. Recent work also demonstrated their involvement in the molecular control of ferroptosis. Hence, ncRNA-based therapeutics represent an exciting alternative to modulate ferroptosis for cancer therapy. This review summarizes the ncRNAs implicated in the regulation of ferroptosis in cancer and highlights their underlying molecular mechanisms in the light of potential therapeutic applications.Keywords:
Cancer Therapy
Evidence is emerging that long noncoding RNAs (lncRNAs) play vital roles in tumorigenesis. LncRNA gastric cancer-associated transcript 3 (GACAT3) is reported to participate in the development of breast cancer, colorectal cancer, nonsmall cell lung cancer, and gastric cancer. However, whether it is implicated in glioma has not been elucidated. Here, we found that GACAT3 level was aberrantly elevated in glioma tissues and cell lines. Higher GACAT3 expression predicted lower survival rate. Knockdown of GACAT3 suppressed the proliferation, colony formation, migration, and invasion but promoting apoptosis in glioma cells. Next, we determined that GACAT3 contributes to glioma progression through inhibiting microRNA (miR)-3127-5p. Subsequently, ELAVL1 was identified as a direct target of miR-3127-5p by bioinformatics analysis and luciferase reporter assay. Moreover, we confirmed that GACAT3 promoted ELAVL1 expression through sponging miR-3127-5p, leading to glioma progression. Taken together, our study elucidated that GACAT3/miR-3127-5p/ELAVL1 signaling regulates glioma development and might be a promising therapeutic target.
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Hepatocellular carcinoma (HCC) as one of the most refractory cancers leads to high mortality worldwide. Long noncoding RNAs have been widely acknowledged as important biomarkers and therapeutic targets in HCC. In this study, we investigated the effects of long noncoding RNA FGFR3-AS1 on tumor growth and metastasis in HCC. First, we found that the expression of FGFR3-AS1 was upregulated about threefold in HCC samples and cell lines. We knocked down FGFR3-AS1 in Huh7 and Hep3B cells and found that FGFR3-AS1 knockdown significantly inhibited cell proliferation but induced apoptosis. Moreover, FGFR3-AS1 knockdown led to more HCC cells arrested in the G 0 stage. FGFR3-AS1 knockdown significantly inhibited cell migration and invasion. Additionally, we found that FGFR3-AS1 silencing dramatically delayed tumor growth in vivo. We found that, mechanistically, FGFR3-AS1 silencing decreased the activation of the PI3K/AKT signaling pathway. Taken together, our data demonstrated the pro-oncogenic role of FGFR3-AS1 in HCC and suggested that FGFR3-AS1 may serve as a novel biomarker for the diagnosis and therapeutic target for HCC treatment.
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BACKGROUND: Long noncoding RNAs (lncRNAs) participate in diseases, especially tumorigenesis, including gastric cancer (GC). Although lncRNAs in GC tissues have been extensively studied in previous research, the possible significance of circulating lncRNAs in diagnosing GC is still unknown. OBJECTIVE: The present work investigated lncRNAs ZFPM2-AS1 and XIST with high expression in GC tissues proved as potential plasma biomarkers from 20 early GC cases, 100 GC cases, and 90 normal subjects. METHODS: The possible correlation between ZFPM2-AS1 and XIST expression levels was analyzed with general characteristics and clinicopathological features. The performance in diagnosis was assessed according to receiver operating characteristic (ROC) analysis. RESULTS: According to the results, XIST and ZFPM2-AS1 expression remarkably increased within GC plasma relative to normal subjects (P< 0.01); besides, lncRNA XIST expression after surgery had a tendency of downregulation compared with preoperative levels (P< 0.05). Moreover, the area under ROC curve (AUC) values were 0.62 for ZFPM2-AS1 and 0.68 for XIST, while the pooled AUC value of CA-724 and two lncRNAs was 0.751. CONCLUSION: Circulating lncRNAs ZFPM2-AS1 and XIST can serve as the candidate plasma biomarkers used to diagnose GC.
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Long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) has been demonstrated to play an important role in diverse tumorigenesis. However, the biological function of lncRNAs in glioma is still unknown. In this study, we found that lncRNA CCAT2 was overexpressed in glioma tissues and cell lines and associated with tumor grade and size. Furthermore, patients with high levels of lncRNA CCAT2 had poorer survival than those with lower levels of lncRNA CCAT2. Knocking down lncRNA CCAT2 expression significantly suppressed the glioma cell growth, migration, and invasion, as well as induced early apoptosis of glioma cells in vitro. Moreover, lncRNA CCAT2 regulated epithelial‐mesenchymal transition (EMT)-associated gene expression. In conclusion, lncRNA CCAT2 plays an important role in glioma tumorigenesis and progression and may act as a potential biomarker for therapeutic strategy and prognostic prediction.
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Ye-Eun Lee, Jiyeon Lee, Yong Sun Lee, Jiyoung Joan Jang, Hyeonju Woo, Hae In Choi, Young Gyu Chai, Tae-Kyung Kim, TaeSoo Kim, Lark Kyun Kim, and Sun Shim Choi. Mol. Cells 2021;44:658-69. https://doi.org/10.14348/molcells.2021.0173
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Long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) has been demonstrated to play an important role in diverse tumorigenesis. However, the biological function of lncRNAs in glioma is still unknown. In this study, we found that lncRNA CCAT2 was overexpressed in glioma tissues and cell lines and associated with tumor grade and size. Furthermore, patients with high levels of lncRNA CCAT2 had poorer survival than those with lower levels of lncRNA CCAT2. Knocking down lncRNA CCAT2 expression significantly suppressed the glioma cell growth, migration, and invasion, as well as induced early apoptosis of glioma cells in vitro. Moreover, lncRNA CCAT2 regulated epithelialmesenchymal transition (EMT)-associated gene expression. In conclusion, lncRNA CCAT2 plays an important role in glioma tumorigenesis and progression and may act as a potential biomarker for therapeutic strategy and prognostic prediction.
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Melanoma is the most malignant skin cancer, which account for most of skin-cancer-related deaths. Long noncoding RNA (lncRNA) is a class of noncoding RNAs with crucial roles in many cancers. However, the roles of lncRNAs in melanoma have not been well studied. In the present study, using public available data and clinical tissues samples, we found that lncRNA ILF3-AS1 is up-regulated in melanoma tissues and cell lines, and correlated with poor prognosis of melanoma patients. Functional experiments showed that knockdown of ILF3-AS1 inhibits melanoma cell proliferation, migration, and invasion. Mechanistically, we found that ILF3-AS1 interacts with EZH2, promotes the binding of EZH2 to the miR-200b/a/429 promoter, and represses miR-200b/a/429 expression. The expression of ILF3-AS1 is negatively correlated with that of miR-200b/a/429 in melanoma tissues. Moreover, inhibition of miR-200b/a/429 abrogates the biological roles of ILF3-AS1 knockdown on melanoma cell proliferation, migration, and invasion. In conclusion, these results demonstrate that melanoma-upregulated lncRNA ILF3-AS1 promotes cell proliferation, migration, and invasion via negatively regulating miR-200b/a/429, and imply that ILF3-AS1 may be a potential prognostic biomarker and therapeutic target for melanoma.
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