Correction to: CBFA2T2 is associated with a cancer stem cell state in renal cell carcinoma.

[This corrects the article DOI: 10.1186/s12935-017-0473-z.].

CBFA2T2 is associated with a cancer stem cell state in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80-90% of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment. METHODS: OncoLnc was used as a tool for interactively exploring survival correlations. Gene manipulation and expression analysis were carried out using siRNA, RT-PCR and Western blotting. Wound healing and invasion assays were used for phenotypical characterization. Aldefluor assay and FACS sorting Sphere culture were used to determine the "stemness" of CSCs. Co-Immunoprecipitation (Co-IP) was used to examine the interaction between OCT4 and CBFA2T2. Student's t-test and Chi square test was used to analyze statistical significance. RESULTS: CBFA2T2 expression can significantly predict the survival of RCC patients. Knocking-down of CBFA2T2 can inhibit cell migration and invasion in RCC cells in vitro, and reduce ALDHhigh CSCs populations. CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines. CONCLUSIONS: Our data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of "stemness" through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment.

Correction: Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells.

[This corrects the article DOI: 10.18632/oncotarget.11538.].

Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma.

Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically, THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.

Computational explanation for bioactivation mechanism of targeted anticancer agents mediated by cytochrome P450s: A case of Erlotinib.

EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine-imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate-determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors.

Jarid2 is essential for the maintenance of tumor initiating cells in bladder cancer.

Bladder cancer is the most common urologic malignancy in China, with an increase of the incidence and mortality rates over past decades. Recent studies suggest that bladder tumors are maintained by a rare fraction of cells with stem cell proprieties. Targeting these bladder tumor initiating cell (TICs) population can overcome the drug-resistance of bladder cancer. However, the molecular and genetic mechanisms regulating TICs in bladder cancer remain poorly defined. Jarid2 is implicated in signaling pathways regulating cancer cell epithelial-mesenchymal transition, and stem cell maintenance. The goal of our study was to examine whether Jarid2 plays a role in the regulation of TICs in bladder cancer. We found that knockdown of Jarid2 was able to inhibit the invasive ability and sphere-forming capacity in bladder cancer cells. Moreover, knockdown of Jarid2 reduced the proportion of TICs and impaired the tumorigenicity of bladder cancer TICs in vivo. Conversely, ectopic overexpression of Jarid2 promoted the invasive ability and sphere-forming capacity in bladder cancer cells. Mechanistically, reduced Jarid2 expression led to the upregulation of p16 and H3K27me3 level at p16 promoter region. Collectively, we provided evidence that Jarid2 via modulation of p16 is a putative novel therapeutic target for treating malignant bladder cancer.

Zinc Prevents Abdominal Aortic Aneurysm Formation by Induction of A20-Mediated Suppression of NF-κB Pathway.

Chronic inflammation and degradation of elastin are the main processes in the development of abdominal aortic aneurysm (AAA). Recent studies show that zinc has an anti-inflammatory effect. Based on these, zinc may render effective therapy for the treatment of the AAA. Currently, we want to investigate the effects of zinc on AAA progression and its related molecular mechanism. Rat AAA models were induced by periaortic application of CaCl2. AAA rats were treated by daily intraperitoneal injection of ZnSO4 or vehicle alone. The aorta segments were collected at 4 weeks after surgery. The primary rat aortic vascular smooth muscle cells (VSMCs) were stimulated with TNF-α alone or with ZnSO4 for 3 weeks. The results showed that zinc supplementation significantly suppressed the CaCl2-induced expansion of the abdominal aortic diameter, as well as a preservation of medial elastin fibers in the aortas. Zinc supplementation also obviously attenuated infiltration of the macrophages and lymphocytes in the aortas. In addition, zinc reduced MMP-2 and MMP-9 production in the aortas. Most importantly, zinc treatment significantly induced A20 expression, along with inhibition of the NF-κB canonical signaling pathway in vitro in VSMCs and in vivo in rat AAA. This study demonstrated, for the first time, that zinc supplementation could prevent the development of rat experimental AAA by induction of A20-mediated inhibition of the NF-κB canonical signaling pathway.

Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells.

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and are involving in diverse cellular processes. However, their roles in reprogramming of gene expression profiles during lineage commitment and maturation of mesenchymal stem cells (MSCs) remain poorly understood. In the current study, we characterize the expression of a lncRNA, HoxA-AS3, during the differentiation of MSCs. We showed that HoxA-AS3 is increased upon adipogenic induction of MSCs, while HoxA-AS3 remains unaltered during osteogenic induction. Silencing of HoxA-AS3 in MSCs resulted in decreased adipogenesis and expression of adipogenic markers, PPARG, CEBPA, FABP4 and ADIPOQ. Conversely, knockdown of HoxA-AS3 expression in MSCs exhibited an enhanced osteogenesis and osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP1. Mechanistically, HoxA-AS3 interacts with Enhancer Of Zeste 2 (EZH2) and is required for H3 lysine-27 trimethylation (H3K27me3) of key osteogenic transcription factor Runx2. Our data reveal that HoxA-AS3 acts as an epigenetic switch that determines the lineage specification of MSC.

Curcumin attenuates rat thoracic aortic aneurysm formation by inhibition of the c-Jun N-terminal kinase pathway and apoptosis.

OBJECTIVE: Recent studies have suggested that c-Jun N-terminal kinase (JNK) plays an important role in the formation of abdominal aortic aneurysms, and that direct blockade of JNK by specific inhibitors can effectively prevent the progression of aortic aneurysms. A study has demonstrated that curcumin can suppress the development of experimental abdominal aortic aneurysms by inhibiting inflammation. We sought to investigate whether curcumin could inhibit JNK pathways and apoptosis in thoracic aortic aneurysms. METHODS: We used a rat model of a CaCl2-induced thoracic aortic aneurysm followed by daily oral gavage with curcumin 100 mg/kg or vehicle alone. After treatment for 4 wk, tissue specimens were obtained for histologic assessments, and tissue composition was evaluated using immunohistochemistry, western blotting, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. RESULTS: Curcumin significantly suppressed the CaCl2-induced expansion of the thoracic aortic diameter and the structural preservation of medial elastin fibers. Most importantly, curcumin treatment significantly inhibited the phosphorylation of JNK and c-Jun, accompanied by less cell apoptosis in thoracic aortic aneurysm tissues. Furthermore, the expression levels of caspase-3 and the Bax/Bcl-2 ratio were significantly decreased in the aortic walls of curcumin-treated rats. CONCLUSION: The present study indicates that the beneficial effect of curcumin on degenerative aortic aneurysms is related to the inhibition of JNK and apoptosis in the walls of thoracic aortic aneurysms.