CircNOP14 increases the radiosensitivity of hepatocellular carcinoma via inhibition of Ku70-dependent DNA damage repair.

Circular RNAs (circRNAs) are profoundly affected in hepatocellular carcinoma (HCC) through various pathways. However, the role of circRNAs in the radiosensitivity of HCC cells is yet to be explored. In this study, we identified a circRNA-hsa_circ_0006737 (circNOP14) involved in the radiosensitivity of HCC. We found that circNOP14 increased the radiosensitivity of HCC cells both in vitro and in vivo. Notably, using a circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified Ku70 as a novel and robust interacting protein of circNOP14. Mechanistically, circNOP14 interacts with Ku70 and prevents its nuclear translocation, thereby increasing irradiation-induced DNA damage. Therefore, our findings may provide a predictive indicator and intervention option for 125I brachytherapy or external radiotherapy in HCC.

Circular RNA circEYA3 promotes the radiation resistance of hepatocellular carcinoma via the IGF2BP2/DTX3L axis.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high incidence and mortality rate despite various treatment options, including 125I seed implantation. However, recurrence and radiation resistance remain challenging issues. Hsa_circ_0007895 (circEYA3)-derived from exons 2-6 of EYA3-facilitates the proliferation and progression of pancreatic ductal adenocarcinoma. However, the role of circEYA3 in HCC 125I radiation resistance remains unclear. Thus, we aimed to investigate the functions and underlying molecular mechanisms of circEYA3 in HCC under 125I and X-ray irradiation conditions. METHODS: CircEYA3 was identified by RNA-seq in patients with HCC before and after 125I seed implantation treatment, followed by fluorescence in situ hybridization and RNase R assays. The radiosensitivity of HCC cell lines irradiated with 125I seeds or external irradiation were evaluated using the Cell Counting Kit 8, flow cytometry, γH2A.X immunofluorescence and comet assays. RNA pull-down and RNA immunoprecipitation assays were performed to explore the interactions between circEYA3 and IGF2BP2. DTX3L mRNA was identified by RNA-seq in PLC/PRF/5 cells with overexpressed circEYA3. The corresponding in vitro results were verified using a mouse xenograft model. RESULTS: CircEYA3 decreased the radiosensitivity of HCC cells both in vitro and in vivo. Notably, using a circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified IGF2BP2 as a novel and robust interacting protein of circEYA3. Mechanistically, circEYA3 binds to IGF2BP2 and enhances its ability to stabilize DTX3L mRNA, thereby specifically alleviating radiation-induced DNA damage in HCC cells. CONCLUSIONS: Our findings demonstrate that circEYA3 increases the radioresistance of HCC to 125I seeds and external irradiation via the IGF2BP2/DTX3L axis. Thus, circEYA3 might be a predictive indicator and intervention option for 125I brachytherapy or external radiotherapy in HCC.

Learning and Investigation of the Role of Angiotensin-Converting Enzyme in Radiotherapy for Nasopharyngeal Carcinoma.

Ionizing radiation (IR) is an important treatment for nasopharyngeal carcinoma (NPC) that mainly kills tumor cells by producing large amounts of reactive oxygen species (ROS). Intracellular ROS levels affect the sensitivity of tumor cells to IR. Recently, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-converting enzyme (ACE) have been found to affect the intracellular levels of ROS. Therefore, we performed a health informatics assessment of ACE in the TCGA database. We explored the effect of ACE in NPC cells. We found that either knockdown of ACE or inhibition of ACE by enalaprilat could decrease ROS levels in NPC cells. Furthermore, knockdown of ACE or inhibition of ACE by enalaprilat could reduce IR-induced ROS levels. ACE knockdown or inhibition reduced IR-induced DNA damage and apoptosis. ACE overexpression increased the level of ROS in NPC cells and further increased sensitivity to IR. These findings indicate that ACE influences the effect of IR by regulating the level of ROS in NPC cells.

Clinical efficacy of CT-guided 125I brachytherapy in patients with local residual or recurrent hepatocellular carcinoma after thermal ablation.

OBJECTIVES: Treatment methods of local residual or recurrent hepatocellular carcinoma (HCC) after thermal ablation are limited. Therefore, our study aimed to explore the efficacy and prognostic factors of 125I brachytherapy for local residual or recurrent lesion after thermal ablation. METHODS: A total of 114 patients with 212 local residual or recurrent HCC tumors after thermal ablation underwent 125I brachytherapy. Local progression-free survival (LPFS) and prognostic factors were analyzed by Kaplan-Meier curves and the Cox model. RESULTS: After a 6-month follow-up, the percentage of patients who achieved complete response (CR), partial response (PR), and stable disease (SD) was 57%, 13.2%, and 5.2%, respectively. The 1-, 2-, and 3-year LPFS rates were 58.7%, 50.0%, and 41.2%, respectively. Portal vein tumor thrombus (PVTT) (p = 0.03), the number of intrahepatic tumors (p = 0.01), and AFP level (p = 0.02) were independent risk factors for local tumor progression (LTP). The median LPFS in patients without PVTT (22 months) was much longer compared to those with PVTT (10 months). The median LPFS in patients with less than three intrahepatic lesions improved from 17 to 24 months. The median LPFS was only 5 months in the high AFP group, but was prolonged with a decrease in AFP level (24 months). No severe complications were recorded. All complications were controllable and treatable. CONCLUSIONS: CT-guided 125I brachytherapy was a safe and effective treatment for patients with local residual or recurrent HCC after thermal ablation to improve local control rate.

High Levels of DEAH-Box Helicases Relate to Poor Prognosis and Reduction of DHX9 Improves Radiosensitivity of Hepatocellular Carcinoma.

Background: Liver hepatocellular carcinoma (LIHC), one of the most common primary malignancies, exhibits high levels of molecular and clinical heterogeneity. Increasing evidence has confirmed the important roles of some RNA helicase families in tumor development, but the function of the DEAH-box RNA helicase family in LIHC therapeutic strategies has not yet been clarified. Methods: The LIHC dataset was downloaded from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to group the patients. Least absolute shrinkage and selection operator Cox regression and univariate and multivariate Cox regression were used to develop and validate a prognostic risk model. The Tumor Immune Estimation Resource and Tumor Immune Single Cell Hub databases were used to explore the role of DEAH-box RNA helicases in LIHC immunotherapy. In vitro experiments were performed to investigate the role of DHX9 in LIHC radiosensitivity. Results: Twelve survival-related DEAH-box RNA helicases were identified. High helicase expression levels were associated with a poor prognosis and clinical features. A prognostic model comprising six DEAH-box RNA helicases (DHX8, DHX9, DHX34, DHX35, DHX38, and DHX57) was constructed. The risk score of this model was found to be an independent prognostic indicator, and LIHC patients with different prognosis were distinguished by the model in the training and test cohorts. DNA damage repair pathways were also enriched in patients with high-risk scores. The six DEAH-box RNA helicases in the risk model were substantially related to innate immune cell infiltration and immune inhibitors. In vitro experiments showed that DHX9 knockdown improved radiosensitivity by increasing DNA damage. Conclusion: The DEAH-box RNA helicase signature can be used as a reliable prognostic biomarker for LIHC. In addition, DHX9 may be a definitive indicator and therapeutic target in radiotherapy and immunotherapy for LIHC.