Human homolog of mouse double minute 2 (HDM2) is an oncogene frequently overexpressed in cancers with poor prognosis, but mechanisms of controlling its abundance remain elusive. In an unbiased biochemical search, we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCF FBXO22 ) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. In human breast cancer cells, FBXO22 knockdown (KD) increased cell invasiveness, which was driven by elevated levels of HDM2. Moreover, mouse 4T1 breast tumor model studies revealed that FBXO22 KD led to a significant increase of breast tumor cell metastasis to the lung. Finally, low FBXO22 expression is correlated with worse survival and high HDM2 expression in human breast cancer. Altogether, these findings suggest that SCF FBXO22 targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis.HDM2 abundance | E3 SCF-FBXO22 | breast cancer metastasis M ouse double minute 2 (MDM2; human homolog, HDM2) is defined as a RING-type E3 ubiquitin ligase with a prominent role in tumorigenesis, acting both as an oncogene and a tumor suppressor (1). MDM2/HDM2 is best understood for its oncogenic role, which is executed predominantly via a mechanism that utilizes the intrinsic E3 ligase activity to target the p53 tumor suppressor for ubiquitin-dependent degradation (2, 3). However, accumulating evidence suggests p53-independent mechanisms that contribute to MDM2/HDM2's oncogene function as well (4).As noted by a large body of clinical studies, HDM2 amplification and overexpression are common to a variety of cancers that often have a poor prognosis (4-6). Elevated levels of HDM2 are regarded as a significant risk factor in distant metastasis (7). Although, mechanistically, such phenomena can be attributed to the ability of HDM2 to drive p53 degradation (5), emerging studies have revealed additional contributing mechanisms involving previously underappreciated activity by MDM2/ HDM2 to promote tumor cell invasiveness (8). In this regard, MDM2 was shown to act as an E3 ligase to target epithelial marker E-cadherin for ubiquitin-dependent degradation (8). However, a subsequent study suggests that, in renal cell carcinoma, MDM2 can promote cell motility and invasiveness without the function of MDM2 RING finger domain (9). Another mechanism may involve matrix metalloproteinase (MMP) capable of degrading membrane-associated extracellular proteins, a process critically implicated for metastasis (10). Intriguingly, MDM2 overexpression was found to transcriptionally up-regulate the expression of MMP-9 (11), although the precise mechanism remains to be elucidated.The compelling association between HDM2 overexpression and aggressive cancer malignancy argues for a potentially critical importance concerning cellular mechanisms for the contro...

BackgroundPinX1 (PIN2/TRF1-interacting telomerase inhibitor 1) was suggested to be correlated with tumor progression. This study was designed to evaluate the role of PinX1 in human breast cancer.MethodsTo evaluate the function of PinX1 in breast cancer, we used a tissue microarray (TMA) of 405 human breast cancer patients and immunohistochemistry to analyze the correlation between PinX1 expression and clinicopathologic variables and patient survival. We also detected the abilities of cell migration and invasion in breast cancer by performing cell migration and invasion assay, gelatin zymography and western blot analysis. Lastly, we set up the nude mice model by Tail vein assay to exam the functional role of PinX1 in breast cancer metastasis.ResultsWe found that low PinX1 expression was associated with lymph node metastasis (P = 0.002) and histology grade (P = 0.001) in patients, as well as with poorer overall and disease-specific survival (P = 0.010 and P = 0.003, respectively). Moreover, we identified that PinX1 inhibited the migration and invasion of breast cancer by suppressing MMP-9 expression and activity via NF-κB-dependent transcription in vitro. Finally, our mice model confirmed that PinX1 suppressed breast cancer metastasis in vivo.ConclusionsOur data revealed that low PinX1 expression was an independent negative prognostic factor for breast cancer patients. These findings suggested that PinX1 might be function as a tumor metastasis suppressor in the development and progression of breast cancer by regulating the NF-κB/MMP-9 signaling pathway, and might be a prognostic marker as well as a therapeutic target for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0332-2) contains supplementary material, which is available to authorized users.

Peripheral nerve injury (PNI) is a common and incurable disease in the clinic, but the effects of available treatments are still not satisfactory. Therefore, it is necessary to explore new treatment methods. To explore the effect and mechanism of melatonin in peripheral nerve regeneration, we administered melatonin to mice with PNI by intraperitoneal injection. We applied microarray analysis to detect differentially expressed genes of mice with sciatic nerve injury after melatonin application. Then, we conducted gene ontology and protein–protein interactions to screen out the key genes related to peripheral nerve regeneration. Cell biology and molecular biology experiments were performed in Schwann cells in vitro to verify the key genes identified by microarray analysis. Our results showed that a total of 598 differentially expressed genes were detected after melatonin subcutaneously injecting into mice with sciatic nerve injury. Bioinformatics analysis showed that Shh may be the key gene for the promotion of peripheral nerve regeneration by melatonin. In vitro, the proliferation and migration abilities of schwann cells in the melatonin group were significantly higher than those of Schwann cells in the control group; while after treating with both melatonin and luzindole (a Shh signalling pathway inhibitor), the proliferation and migration abilities of Schwann cells decreased compared with the melatonin group. Our study suggests that melatonin might improve the proliferation and migration of Schwann cells via the Shh signalling pathway after PNI, thus promoting peripheral nerve regeneration. Our study provides a new approach and target for the clinical treatment of PNI.

No abstract

Tripartite motif containing-21 (TRIM21), an E3 ubiquitin ligase, was initially found to be involved in antiviral responses and autoimmune diseases. Recently studies have reported that TRIM21 plays a dual role in cancer promoting and suppressing in the occurrence and development of various cancers. Despite the fact that TRIM21 has effects on multiple metabolic processes, inflammatory responses and the efficacy of tumor therapy, there has been no systematic review of these topics. Herein, we discuss the emerging role and function of TRIM21 in cancer metabolism, immunity, especially the immune response to inflammation associated with tumorigenesis, and also the cancer treatment, hoping to shine a light on the great potential of targeting TRIM21 as a therapeutic target.