MIG-6 is essential for promoting glucose metabolic reprogramming and tumor growth in triple-negative breast cancer.

Treatment of triple-negative breast cancer (TNBC) remains challenging due to a lack of effective targeted therapies. Dysregulated glucose uptake and metabolism are essential for TNBC growth. Identifying the molecular drivers and mechanisms underlying the metabolic vulnerability of TNBC is key to exploiting dysregulated cancer metabolism for therapeutic applications. Mitogen-inducible gene-6 (MIG-6) has long been thought of as a feedback inhibitor that targets activated EGFR and suppresses the growth of tumors driven by constitutive activated mutant EGFR. Here, our bioinformatics and histological analyses uncover that MIG-6 is upregulated in TNBC and that MIG-6 upregulation is positively correlated with poorer clinical outcomes in TNBC. Metabolic arrays and functional assays reveal that MIG-6 drives glucose metabolism reprogramming toward glycolysis. Mechanistically, MIG-6 recruits HAUSP deubiquitinase for stabilizing HIF1α protein expression and the subsequent upregulation of GLUT1 and other HIF1α-regulated glycolytic genes, substantiating the comprehensive regulation of MIG-6 in glucose metabolism. Moreover, our mouse studies demonstrate that MIG-6 regulates GLUT1 expression in tumors and subsequent tumor growth in vivo. Collectively, this work reveals that MIG-6 is a novel prognosis biomarker, metabolism regulator, and molecular driver of TNBC.

The ubiquitin ligase RNF8 regulates Rho GTPases and promotes cytoskeletal changes and motility in triple-negative breast cancer cells.

The ubiquitin ligase RNF8 is known to induce epithelial-to-mesenchymal (EMT) transition and metastasis in triple-negative breast cancer (TNBC). Besides EMT, Rho GTPases have been shown as key regulators in metastasis. In this study, we investigated the role of RNF8 in regulating Rho GTPases and cell motility. We find that RNF8 knockdown in TNBC cells attenuates the protein and mRNA levels of Ras homolog family member A (RHOA) and cell division cycle 42 (CDC42). We show that the formation of filopodia, focal adhesions, and the association of focal adhesions to stress fibers is impaired upon RNF8 knockdown. Cell migration is significantly inhibited by RNF8 knockdown. Our study suggests a potential novel role for RNF8 in mediating cell migration in TNBC through regulation of the Rho GTPases RHOA and CDC42.

Analysis of the Safety and Efficacy of the Endovascular Treatment for Acute Limb Ischemia with Percutaneous Pharmacomechanical Thrombectomy Compared with Catheter-Directed Thrombolysis.

BACKGROUND: To evaluate the rates of limb salvage, survival, and perioperative mortality in patients with acute limb ischemia (ALI) submitted to endovascular revascularization with pharmacomechanical thrombectomy (PMT) and catheter-directed thrombolysis (CDT). METHODS: This was a retrospective consecutive cohort study of patients with ALI who were submitted to endovascular treatment with PMT or fibrinolysis at the Division of Vascular and Endovascular Surgery, Hospital do Servidor Público Estadual (São Paulo, Brazil), between July 2015 and December 2018. The limb salvage rate and survival rate at 720 days were analyzed in both the PMT (group 1) and CDT treatment (group 2), as well as the perioperative mortality rate (PMR) at 30 days after surgery. RESULTS: One hundred twelve patients were admitted to the emergency department with ALI between July 2015 and December 2018. Seventeen patients diagnosed with Rutherford III irreversible ALI and 46 patients submitted to open surgery were excluded. Thus, 49 patients were submitted to endovascular surgery; 18 (36.7%) were classified into group 1, and 31 (63.3%) were classified into group 2. The clinical data were equal between the 2 groups, but there was a higher prevalence of thrombophilia in group 1 (3 cases; P < 0.001). The limb salvage rate and the overall survival rate at 720 days were similar between groups 1 and 2 (87.8% vs. 89.7%, P = 0.78 and 84.7% vs. 69.2%, P = 0.82, respectively). There was no statistical difference regarding secondary patency rates at 720 days between groups 1 and 2 (group 1, 81.9% and group 2, 78.8%; P = 0.66). The PMR was 16.7% (8 patients) within the first 30 days. Group 2 had a higher overall mortality rate (OMR) (6 patients, 19.3%, P = 0.03). Regarding the PMT group, there was a higher rate of complications such as myoglobinuria, hematuria, acute renal failure, and death in the subgroup of patients in whom there were performed more than 150 cycles/sec during the surgery (P < 0.001). CONCLUSIONS: In the present study, the PMT and CDT endovascular procedures had similar limb salvage, overall survival, and secondary patency rates. However, the OMR was higher in the CDT group. Another important finding was related to the number of cycles/sec performed in the PMT group, in whom patients with more than 150 cycles/sec have presented with higher rates of hematuria, myoglobinuria, acute renal failure, and death.

Analysis of the results of endovascular and open surgical treatment of acute limb ischemia.

OBJECTIVE: The objective of this study was to evaluate the long-term estimates of limb salvage and survival in patients with acute limb ischemia (ALI) receiving open surgery or endovascular revascularization. METHODS: This was a retrospective consecutive cohort study of patients with ALI who underwent open surgery or endovascular treatment at the Vascular and Endovascular Surgery Unit, Hospital do Servidor Público Estadual (São Paulo, Brazil), between July 2010 and July 2016. The overall mortality, limb salvage, and survival rates at 720 days were analyzed in both the open surgery (group 1) and endovascular treatment (group 2) groups. RESULTS: A total of 69 patients were admitted for a limb salvage procedure. The mean follow-up period was 822 ± 480.5 days. All of the analyses were performed at 720 days. Of the 69 patients, 46 (66.6%) were in group 1 and 23 (33.4%) in group 2. The clinical characteristics were similar between the groups, except for higher rates of chronic kidney disease (P = .04) and arrhythmia (P = .01) in group 1. Group 1 had a higher postoperative ankle-brachial index (P = .03). Concerning the Rutherford classification, group 1 had a higher prevalence of Rutherford IIB ALI (P = .003). The preoperative creatine kinase level was higher in group 1 than in group 2 (780 [range, 198-6546] mg/dL and 245 [65-78] mg/dL, respectively). A creatine kinase level >200 mg/dL was seen in 65.2% and 47.8% of patients in group 1 and group 2, respectively (P = .028). The limb salvage and overall survival estimates at 720 days were similar between group 1 and group 2 (79.2% vs 90.6% [P = .27] and 53% vs 60.8% [P = .45], respectively). The overall mortality rate was 10.1% (seven patients) within the first 30 days, and it was higher in group 1 (six patients [13.0%]; P = .03). CONCLUSIONS: Both open surgery and endovascular procedures are safe treatments of patients with ALI, with acceptable limb salvage and survival rates. No previous study has suggested the preferred treatment of ALI. However, based on this study and the overall literature, endovascular treatment may be the preferred treatment of patients with Rutherford I and IIA ALI; open surgery may be the best option for ALI due to arterial embolism and for Rutherford IIB acute arterial thrombosis because of a greater urgency to restore blood flow.