High expression of TARS is associated with poor prognosis of endometrial cancer.

INTRODUCTION: Endometrial cancer is the second largest and most common cancer in the world. It is urgent to explore novel biomarkers. METHODS: Data were obtained from The Cancer Genome Atlas (TCGA) database. The receiver operating characteristic (ROC) curves, Kaplan-Meier curves and Cox analysis, nomograms, gene set enrichment analysis (GSEA) were conducted. Cell proliferation experiments were performed in Ishikawa cell. RESULTS: TARS was significantly highly expressed in serous type, G3 grade, and deceased status. Significant association was between high TARS expression with poor overall survival (P = 0.0012) and poor disease specific survival (P = 0.0034). Significant differences were observed in advanced stage, G3 and G4, and old. The stage, diabetes, histologic grade, and TARS expression showed independent prognostic value for overall survival of endometrial cancer. The stage, histologic grade, and TARS expression showed independent prognostic value for disease specific survival of endometrial cancer. Activated CD4+ T cell, effector memory CD4+ T cell, memory B cell and type 2 T helper cell may participate in the high TARS expression related immune response in endometrial cancer. The CCK-8 results showed significantly inhibited cell proliferation in si-TARS (P < 0.05) and promoted cell proliferation in O-TARS (P < 0.05), confirmed by the colony formation and live/dead staining. CONCLUSION: High TARS expression was found in endometrial cancer with prognostic and predictive value. This study will provide new biomarker TARS for diagnosis and prognosis of endometrial cancer.

Radioprotective countermeasures for radiation injury (Review).

A series of physiological and pathological changes occur after radiotherapy and accidental exposure to ionizing radiation (IR). These changes cause serious damage to human tissues and can lead to death. Radioprotective countermeasures are radioprotective agents that prevent and reduce IR injury or have therapeutic effects. Based on a good understanding of radiobiology, a number of protective agents have achieved positive results in early clinical trials. The present review grouped known radioprotective agents according to biochemical categories and potential clinical use, and reviewed radiation countermeasures, i.e., radioprotectors, radiation mitigators and radiotherapeutic agents, with an emphasis on their current status and research progress. The aim of the present review is to facilitate the selection and application of suitable radioprotectors for clinicians and researchers, to prevent or reduce IR injury.

AdipoR1 Regulates Ionizing Radiation-Induced Ferroptosis in HCC cells through Nrf2/xCT Pathway.

Radiotherapy has been used for decades in the treatment of liver cancer. We previously found that adiponectin receptor (AdipoR1) is a prognostic biomarker for hepatoma carcinoma (HCC) after stereotactic body radiation therapy (SBRT) and blocking AdipoR1 enhances radiation sensitivity in hepatoma carcinoma cells. In the current study, we aimed to elucidate the roles of AdipoR1 in ionizing radiation- (IR-) induced radiosensitivity by activating ferroptosis pathway in HCC cells. We found that IR upregulated the expression of AdipoR1 and furthermore promoted the protein stability of transcription factor Nrf2, Nrf2 binded to the xCT promoter and increased xCT transcription and expression, and this directly contributed to the protective function in the early stage of radiation in HCC cells. AdipoR1 knockdown significantly inhibited expression of Nrf2 and xCT and, furthermore, increased both IR- and erastin-induced ferroptosis, which could be abolished by the rescue of Nrf2 and xCT. For the first time, we found that radiation-induced ferroptosis was mediated by AdipoR1-Nrf2-xCT pathway in HCC cells. These results provide new insights to the development and application of novel therapeutic strategies for hepatoma carcinoma.

Molecular pathways associated with oxidative stress and their potential applications in radiotherapy (Review).

Radiotherapy is an essential and effective treatment modality for cancer. Excessive levels of reactive oxygen species (ROS) induced by ionizing radiation disrupt the redox homeostasis and lead to oxidative stress that may result in cell death. However, the tumor cell microenvironment is dynamic and responds to radiotherapy by activating numerous cellular signaling pathways. By scavenging excess ROS, the activity levels of the endogenous antioxidant enzymes result in radioresistance and worsen the clinical outcomes. To assess the full potential of radiotherapy, it is essential to explore the underlying mechanisms of oxidative stress in radiotherapy for potential target identification. The present review article summarized recent data demonstrating nuclear factor­erythroid factor 2­related factor 2 (Nrf2) as a powerful transcription factor and one of the major cellular defense mechanisms that protect against oxidative stress in response to radiotherapy; the glutathione (GSH) and thioredoxin (Trx) systems complement each other and are effective antioxidant mechanisms associated with the protection of cancer cells from radiation damage. In addition, it is suggested that dual targeting to inhibit GSH and Trx enzymes may be a potential strategy for the development of radiosensitive and radioprotective drugs.

Blocking Adipor1 enhances radiation sensitivity in Hepatoma Carcinoma Cells.

In this study, we aimed to elucidate the roles of Adipor1 in radiation-induced cell death of Hepatocellular carcinoma (HCC). The human HCC cell line MHCC97-H and HepG2 were used to investigate the underlying mechanisms. Western blotting was used to detect protein expression, and flow cytometry was used to detect cell cycle and cell death. Orthotopic allograft HCC models were established in Rats. LV-Adipor1-RNAi virus were injected into the tumor before radiation. Such parameters as tumor diameter, blood indicators, and liver function index were detected.In vitro results indicated that Adipor1 knockdown enhanced radiation-induced cell death and DNA damage, and inhibited cell cycle arrest at the G2/M and autophagy, leading to increased apoptosis. In vivo experiments showed that Adipor1 knockdown increased radiosensitivity and significantly inhibited liver tumor growth, upregulated the number of red blood cell, platelet count and Hemoglobin content, decreased the content of ALT, AST and ALP. To sum up, Adipor1 blockade enhance therapeutic effects of radiation by inhibiting cell cycle arrest and autophagy, and promoting DNA damage and apoptosis in Hepatoma Carcinoma Cells.

Clinicopathological and Prognostic Significance of PRMT5 in Cancers: A System Review and Meta-Analysis.

PURPOSE: Since protein arginine methyltransferase 5 (PRMT5) is abnormally expressed in various tumors, in this study we aim to assess the association between PRMT5 and clinicopathological and prognostic features. METHODS: Electronic databases including PubMed, Web of Science, Scopus, ScienceDirect, and the Cochrane Library were searched until July 25, 2021. The critical appraisal of the eligible studies was performed using the Newcastle-Ottawa Quality Assessment Scale. Pooled hazard ratios (HR) and pooled odds ratios (OR) were calculated to assess the effect. Engauge Digitizer version 12.1, STATA version 15.1, and R version 4.0.5 were used to obtain and analysis the data. RESULTS: A total of 32 original studies covering 15,583 patients were included. In our data, it indicated that high level of PRMT5 was significantly correlated with advanced tumor stage (OR = 2.12, 95% CI: 1.22-3.70, P =.008; I2 = 80.7%) and positively correlated with poor overall survival (HR = 1.59, 95% CI: 1.46-1.73, P < .001; I2 = 50%) and progression-free survival (HR = 1.53, 95% CI: 1.24-1.88, P < .001; I2 = 0%). In addition, sub-group analysis showed that high level of PRMT5 was associated with poor overall survival for such 5 kinds of cancers as hepatocellular carcinoma, pancreatic cancer, breast cancer, gastric cancer, and lung cancer. CONCLUSION: For the first time we found PRMT5 was pan-cancerous as a prognostic biomarker and high level of PRMT5 was associated with poor prognosis for certain cancers.

The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation.

Radiotherapy is one of the most important treatments for breast cancer. Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, whether ionizing radiation (IR) could induce ferroptosis in breast cancer and how it works remain unknown. Bioinformatics analysis were performed to screen ferroptosis-related genes differentially expressed in breast tumor tissue and normal tissue. Then, breast cancer cell lines with different estrogen receptor (ER) phenotypes were used for studies in vitro, including ER-positive (MCF-7 and ZR-75-1) and ER-negative (MDA-MB-231) cells. The dynamic changes of mRNA and protein levels were examined after x-ray of 8 Gy by qRT-PCR and Western blotting, respectively. Immunoprecipitation (IP) was used to explore the interaction between proteins. Luciferase assay was used to analyze the transcriptional regulation effect of ESR1 on SLC7A11. BODIPY C11 and trypan blue dyes were used to determine lipid peroxidation and cell death, respectively. The result showed that the ferroptosis-related gene SLC7A11 was higher in breast cancer tissues compared with normal tissues and associated with poor survival. A positive correlation exists between ESR1 and SLC7A11 expression. ESR1 promoted SLC7A11 expression at the early stage after IR. ESR1/SLC7A11 knockdown significantly enhanced IR-induced ferroptosis in ER-positive cells. At 12 h after IR, the IP data showed the interaction between E3 ubiquitin ligase NEDD4L and SLC7A11 increased, followed by the ubiquitylation and degradation of SLC7A11. Thus, SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, we elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.