COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma.

BACKGROUND & AIMS: Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC). METHODS: The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models. RESULTS: We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop. CONCLUSIONS: COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC. LAY SUMMARY: Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.

Image-guided, intensity-modulated radiotherapy for the treatment of diffuse-type tenosynovial giant cell tumor of the knee: Case report and review of the literature.

RATIONALE: Tenosynovial giant cell tumor (TGCT) is a neoplastic, inflammatory disease with a benign but aggressive course that often presents as localized (TGCT-L) and diffuse (TGCT-D) forms based on the growth pattern and clinical behavior. For TGCT-L, simple excision of the diseased synovial tissue is the preferred treatment option, while for TGCT-D, adequate synovectomy is usually tricky but is essential. However, approximately 44% of TGCT-D cases will relapse after surgery alone. Thus, the optimal treatment strategy in patients with TGCT-D is evolving, and standalone surgical resection can no longer be regarded as the only treatment. The previous studies have shown that postoperative adjuvant radiotherapy can reduce recurrence in TGCT, especially in patients with incomplete synovectomy. PATIENT CONCERNS: In the first case, a 54-year-old male presented with recurrent pain and swelling of the right knee with a protracted disease course (≥10 years). The other patient is a 64-year-old male who developed swelling, pain, abnormal bending, and limited movement of the left knee without obvious inducement. DIAGNOSES: Clinical and imaging examinations can provide a definitive diagnosis, and pathology is the gold standard. TGCT-D was confirmed by postoperative pathology. After the operation, the patients underwent an MRI re-examination and showed that the lesions of the knee were not completely resected. INTERVENTIONS: Arthroscopic synovectomy was performed on the patients, and postoperative pathology was confirmed as TGCT-D. Because of incomplete synovectomy, the 2 cases received image-guided, intensity-modulated radiotherapy (IG-IMRT) after the operation. OUTCOMES: The follow-up time was 1 year, no evidence of disease progression was found in MRI. No obvious adverse effects associated with radiotherapy were detected during the follow-up period. LESSONS: These cases and reviews illustrate the necessity of radiotherapy for TGCT-D and that IG-IMRT is a safe and effective method for treating TGCT-D of the knee.

ΔCT Value of Amplified Refractory Mutation System Predicts Efficacy of EGFR-TKIs in Advanced Non-Small-Cell Lung Cancer: A Multi-Center Retrospective Study.

Purpose: This multi-center retrospective study determines whether the ΔCT value of the Amplified Refractory Mutation System (ARMS) predicts the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients who harbored an exon 19 deletion (19Del) or L858R mutation detected by the ARMS and previously received treatment of EGFR-TKIs as a monotherapy were enrolled. A total of 108 NSCLC patients in four hospitals were enrolled. We divided the patients into a high ΔCT group (Group H) and a low ΔCT group (Group L) by the Martingale residuals analysis and log-rank test. The primary outcome was progression-free survival (PFS). Univariate analysis and multivariable regression were applied to compare the PFS between the groups. Result: The Martingale residuals analysis and log-rank test were applied to find the cutoff ΔCT value (0.8). In the 108 patients we enrolled, 59 were in group L and 49 were in group H. Patients' demographics and clinical characteristics, including age, sex, smoking history, pathology, mutation sites, TNM stage, and line of TKIs therapy, were not significantly different between group L and group H. The median PFS was 11.1 months in group L and 6.9 months in group H, and the difference showed statistical significance (p < 0.001). Moreover, the objective response rates (ORRs) in group L was significantly higher than in group H (61.0 vs 34.7%, p = 0.002). The median OS was 25.0 months in group L and 20.0 months in group H (p = 0.046). Conclusion: The ΔCT value of ARMS could be an efficacy predictor for EGFR-TKI treatment in advanced EGFR-mutant NSCLC.

COMMD10 inhibits tumor progression and induces apoptosis by blocking NF-κB signal and values up BCLC staging in predicting overall survival in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Currently, there is limited knowledge of dysregulation of cellular proliferation and apoptosis that contribute to the malignant phenotype in HCC. Copper metabolism gene MURR1 domain 10 (COMMD10) is initially identified as a suppressor gene in the pathogenesis of HCC in our observations. Here we aimed to explore its function and prognostic value in the progression of HCC. METHODS: Functional experiments were performed to explore the role of COMMD10 in HCC. The molecular mechanisms of COMMD10 were determined by luciferase assay, immunofluorescence, and immunoprecipitation. The nomogram was based on a retrospective and multicenter study of 516 patients who were pathologically diagnosed with HCC from three Chinese hospitals. The predictive accuracy and discriminative ability of the nomogram were determined by a C-index and calibration curve and were compared with COMMD10 and the Barcelona Clinic Liver Cancer (BCLC) staging system. The primary endpoint was overall survival (OS). RESULTS: COMMD10 expression was significantly lower in HCC than that in normal liver tissues. In vitro and in vivo experiments revealed that COMMD10 suppressed cell proliferation and induced apoptosis in HCC. Mechanistically, COMMD10 inhibits TNFα mediated ubiquitination of IκBα and p65 nuclear translocation through the combination of COMMD10-N terminal to the Rel homology domain of p65, which inhibited NF-κB activity and increased expression of cleaved caspase9/3 in HCC. Clinically, COMMD10 stratifies early-stage HCC patients into two risk groups with significantly different OS. Additionally, the nomogram based on COMMD10 and BCLC stage yielded more accuracy than BCLC stage alone for predicting OS of HCC patients in three cohorts. CONCLUSIONS: COMMD10 suppresses proliferation and promotes apoptosis by inhibiting NF-κB signaling and values up BCLC staging in predicting OS, which provides evidence for the identification of potential therapeutic targets and the accurate prediction of prognosis for patients with HCC.

A meta-analysis of weekly cisplatin versus three weekly cisplatin chemotherapy plus concurrent radiotherapy (CRT) for advanced head and neck cancer (HNC).

PURPOSE: This study was performed to compare the efficacies and acute toxicities in weekly- and three weekly- cisplatin based concurrent chemoradiotherapy (CCRT) for advanced HNC patients. RESULTS: 779 patients of 10 studies were eligible. No difference in the 2-, 3-year OS or 1-, 2-year LRFS was observed, whereas patients in three weekly CCRT arm tended to have a better 5-year OS (HR=1.79, 95%C 0.97-3.31, p=0.06). Weekly arm seemed to show less gastrointestinal toxicities (RR=0.59, 95%CI 0.34-1.02, p=0.06), but similar hematologic toxicity compared to three weekly arm. Subgroup analysis displayed more grade ≥3 mucositis (RR=1.72, p=0.01), and more chemotherapy related delay/interrupt (RR=2.68, p<0.0001) in weekly arm for non-nasopharynx carcinoma (non-NPC) HNC. METHODS: We conducted the meta-analysis by searching PubMed, MEDLINE, ScienceDirect, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases. The primary endpoint was overall survival (OS) with secondary endpoints locoregional recurrence-free survival (LRFS) and grade≥3 acute adverse events. RevMan 5.2 was used to perform statistical analyses. CONCLUSIONS: Three weekly cisplatin-based CCRT might achieve a higher long-term OS with no significant difference in a shorter OS and LRFS. Weekly arm was associated with less gastrointestinal toxicities but more grade≥3 mucositis and chemotherapy related delay/interrupt. Large randomized trials were urgent to further define superiority of these two regimens.

A meta-analysis comparing cisplatin-based to carboplatin-based chemotherapy in moderate to advanced squamous cell carcinoma of head and neck (SCCHN).

PURPOSE: This study was performed to compare the efficacies and toxicities of cisplatin (CDDP)- and carboplatin (CBDCA)-based chemotherapy (CT) in patients with SCCHN. METHODS: The search strategy included Pubmed, Science Direct, the Cochrane Library, and the China National Knowledge Internet Web. Statistical analyses were performed using RevMan 5.2. The primary endpoint was overall survival (OS) with secondary endpoints of locoregional control (LRC) and grade ≥ 3 toxicity. RESULTS: Overall, 12 studies and 1165 patients were included. CDDP-based CT significantly improved 5-year OS (HR=0.67, 95% CI, 0.49 to 0.91; P=0.01) compared to the CBDCA group. No difference in the 3-year OS/LRC was observed, but a subgroup analysis showed a better 3-year OS in the CDDP arm for non-nasopharynx carcinoma (non-NPC) SCCHN (HR=0.66, 95% CI, 0.48 to 0.91; P=0.01). The CDDP-based CT was associated with more gastrointestinal toxicities (RR=4.58; P=0.005) and nephrotoxicity (4/110=3.6%) compared to the CBDCA group, but fewer anemia, leukopenia and thrombocytopenia with RRs of 0.27, 0.71, and 0.28 respectively. CONCLUSIONS: Patients with CDDP-based CT can achieve a higher OS, but there is no significant difference in LRC. The CDDP-based CT is associated with fewer hematological toxicities but more gastrointestinal toxicities and nephrotoxicity compared to the CBDCA arm.

EGFR mutations are associated with higher incidence of distant metastases and smaller tumor size in patients with non-small-cell lung cancer based on PET/CT scan.

The study aimed to explore the correlation of epidermal growth factor receptor (EGFR) mutation with tumor node metastasis (TNM) stage in patients with non-small-cell lung cancer (NSCLC) who underwent positron emission tomography/computed tomography (PET/CT) scan. Patients diagnosed with NSCLC who underwent EGFR mutation status testing and PET/CT or PET/CT plus brain magnetic resonance imaging scan at initial diagnosis in Nanfang Hospital between July 2010 and June 2014 were consecutively enrolled. The correlation of EGFR mutation status with TNM stage and distant metastasis organs including brain, bone, liver, pleural, adrenals and contralateral lobe of lung were analyzed. A total of 401 patients were enrolled. Tumor size in EGFR mutation group was significantly smaller than the wild-type group (P < 0.001). Further, patients with EGFR mutations were demonstrated significantly more frequent in patients with distant metastasis than non-metastasis (45.7 vs 32.2 %, P = 0.007). The rates of bone (32.2 vs 22.8 %, P = 0.007) and brain (16.3 vs 9.4 %, P = 0.008) metastasis were significantly higher in EGFR mutation group than the wild-type group. In the subgroup of 199 metastatic NSCLC patients, patients with EGFR mutation were significantly associated with a smaller tumor size (P = 0.013) and earlier N stage (P = 0.033). Of note, compared with the EGFR wild-type group, patients had a higher likelihood of developing brain plus bone metastases at initial diagnosis of EGFR mutation group (20.9 vs 7.5 %, P = 0.018). Taken together, we identify that EGFR mutations might associate with more aggressive tumor progression than the wild types in NSCLC. In addition, patients with tumor having EGFR mutation had a smaller tumor size than without mutation.