PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.

Background/Aim: The aim of this study was to examine the efficacy and safety of direct oral anticoagulants for cancer-associated venous thromboembolism (VTE) in patients with active cancer. Patients and Methods: This study included patients with advanced unresectable/metastatic upper gastrointestinal (GI) or hepatopancreatobiliary (HPB) cancers with high risks of VTE and bleeding. Results: No significant differences were noted in potential bleeding factors between the rivaroxaban (n=105) and low-molecular-weight heparin (LMWH) (n=69) groups. Rivaroxaban exhibited similar risk of recurrent/aggravated VTE compared with LMWH (p=0.625) but increased risk of major bleeding (17.4% vs. 7.6%; p=0.072), clinically relevant bleeding (31.9% vs. 14.3%; p=0.019), and total bleeding (40.6% vs. 19%; p=0.010). The multivariate analysis regarded rivaroxaban as a significant factor for major bleeding (p=0.043) and clinically relevant bleeding (p=0.043). Conclusion: Rivaroxaban exhibits comparable efficacy but increases bleeding risks compared with LMWH in patients with active unresectable/metastatic upper GI tract or HPB cancers, requiring extra caution of higher major bleeding risks.As cancer-associated venous thromboembolism (VTE) might cause a delay or discontinuation of anticancer treatments (1), optimal management of VTE is essential in patients with cancer. The anticoagulation treatment in cancer-associated VTE is especially challenging in balancing the risks of recurrent VTE and bleeding during anticoagulation (2, 3). Randomized phase III trials have established that long-term low-molecular-weight heparins (LMWHs), such as dalteparin, correlated with better or similar efficacy and safety than vitamin K antagonists (VKAs) maintenance in patients with cancer (4-6). Accordingly, LMWH has been preferred over VKA for the treatment of cancer-associated thrombosis (7-9).Owing to convenience in administration and monitoring, direct oral anticoagulants (DOACs), including factor Xa inhibitors and thrombin inhibitors, have emerged with expectation to replace oral VKAs or LMWHs, as prophylactic and therapeutic anticoagulation options. In two large randomized studies comparing rivaroxaban, an oral factor Xa inhibitor, with enoxaparin followed by VKA maintenance for the treatment of deep-vein thrombosis (DVT) (EINSTEIN-DVT) and pulmonary embolism (EINSTEIN-PE), rivaroxaban demonstrated noninferior efficacy with similar risk for bleeding (10, 11). Other DOACs, including apixaban (12), edoxaban (13), and dabigatran (14), also showed noninferior efficacy and a similar or lower bleeding risk in patients with VTE compared with an oral VKA. However, these studies were not cancer-specific, and only <10% of patients had cancer, including cancer history only. Although a subgroup analysis of EINSTEIN-DVT and EINSTEIN-PE and a meta-analysis comparing DOAC and VKA in patients with cancer exhibited similar efficacy and safety between DOAC and VKA, these studies examined not only patients with cancer during anticoagulation but also patients whose c...