BackgroundThe long noncoding RNA (lncRNA) OTUD6B antisense RNA 1 (OTUD6B-AS1) is oriented in an antisense direction to the protein-coding gene OTUD6B on the opposite DNA strand. TCGA database data show that the expression of the lncRNA OTUD6B-AS1 is downregulated and that OTUD6B-AS1 acts as an antioncogene in a variety of tumors. However, the expression and biological functions of the lncRNA OTUD6B-AS1 are still unknown in tumors, including clear cell renal cell carcinoma (ccRCC).MethodsThe expression level of OTUD6B-AS1 was measured in 75 paired human ccRCC tissue and corresponding adjacent normal renal tissue samples. The correlations between the OTUD6B-AS1 expression level and clinicopathological features were evaluated using the chi-square test. The effects of OTUD6B-AS1 on ccRCC cells were determined via MTT assay, clone formation assay, transwell assay, and flow cytometry. Furthermore, the impact of OTUD6B-AS1 overexpression on the activation of the Wnt/β-catenin signaling pathway was investigated. Finally, ACHN cells with OTUD6B-AS1 overexpression were subcutaneously injected into nude mice to evaluate the influence of OTUD6B-AS1 on tumor growth in vivo.ResultsIn this study, we found that the expression of the lncRNA OTUD6B-AS1 was downregulated in ccRCC tissue samples and that patients with low OTUD6B-AS1 expression had shorter overall survival than patients with high OTUD6B-AS1 expression, which showed that the different expression level of OTUD6B-AS1 indirectly correlated with survival of patients. Lentivirus-mediated OTUD6B-AS1 overexpression significantly decreased the proliferation of ccRCC cells and promoted the apoptosis of the cells. Furthermore, OTUD6B-AS1 overexpression partly inhibited cell migration and invasion. The overexpression of OTUD6B-AS1 decreased the activity of the Wnt/β-catenin pathway and suppressed the expression of epithelial-to-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and Snail) in ccRCC cells. In addition, compared with the parental ACHN cells, OTUD6B-AS1-overexpressing ACHN cells injected into nude mice exhibited decreased tumor growth in vivo.ConclusionsTaken together, our findings present a road map for targeting the newly identified lncRNA OTUD6B-AS1 to suppress ccRCC progression in cell lines, and these results elucidate a novel potential therapeutic target for ccRCC treatment.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0942-1) contains supplementary material, which is available to authorized users.
Cancer Science. 2020;111:1555-1566. | 1555 wileyonlinelibrary.com/journal/cas | INTRODUC TI ONRenal cell carcinoma is a highly malignant tumor that is common in the urinary system. It has the characteristics of radiotherapy and chemotherapy tolerance. 1,2 Regarding the pathological types of RCC, approximately 75%-80% of cases are clear cell renal cell carcinoma (ccRCC). Although surgical treatment is available, the recurrence rate after radical nephrectomy is still as high as 20%-40%, and the 5-year survival rate of ccRCC after surgical resection is only approximately 20%. 3 Therefore, revealing the molecular mechanism of renal cancer radiotherapy and chemotherapy tolerance is critical. 4The bone morphogenetic protein (BMP) ligand family plays an important role in embryonic development, morphogenesis, differentiation, proliferation and apoptosis of various types of cells throughout the body. BMP are found to be members of the transforming growth factor-beta (TGF-β) family, including activin in This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractThere is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK-8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As 2 O 3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1-mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP-qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As 2 O 3 . Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC. K E Y W O R D S As 2 O 3 , BMP8A, Nrf2, TRIM24, Wnt pathway
Background: This study investigated the biological function of the gene MAN1C1 α-mannosidase in renal cell carcinoma. It has been reported that MAN1C1 is probably a potential tumor suppressor gene in Wilms. However, the role of MAN1C1 in human clear cell renal cell carcinoma (ccRCC) has not been reported.Methods: In this study, MAN1C1 gene over-expression was used to transfect human renal cancer cell lines 786-O and OS-RC-2 to study apoptosis and the underlying mechanisms which influence epithelial-mesenchymal transition.Results: MAN1C1 was down-regulated in ccRCC and related to the clinicopathological factors and prognosis of ccRCC. We revealed that over-expression MAN1C1 showed anti-tumor effect by inducing apoptosis, as determined by Cell Counting Kit-8 (CCK-8) assay, cell cycle analysis, and western blot analysis. What's more, MAN1C1 over-expression remarkably increased the ratio of Bax/Bcl-2 and inhibited epithelial-mesenchymal transition by increasing the expression of E-CA. In addition, the ratio of Bax/Bcl-2 and E-CA were also increased in MAN1C1 gene over-expression renal cancer cells compared with the control cells.Conclusion: We find that re-expression of silenced MAN1C1 in ccRCC cell lines inhibited cell viability, colony formation, induced apoptosis, suppressed cell invasion and migration. In conclusion, MAN1C1 is a novel functional tumor suppressor in renal carcinogenesis. This is the first time that the function of MAN1C1 gene has been verified in the renal tumor tissue so far.
Bladder cancer (BCa) is the most costly solid tumor owing to its high recurrence. Relapsed cancer is known to acquire chemoresistant features after standard intravesical chemotherapy. This cancer state is vulnerable to ferroptosis, which occurs when lipid peroxides generated by iron metabolism accumulate to lethal levels. Increasing the labile iron pool (LIP) by iron oxide nanoparticles (IONPs) promises to inhibit chemoresistant BCa (CRBCa), but systemically administered IONPs do not sufficiently accumulate at the tumor site. Therefore, their efficacy is weakened. Here, we present a three-tier delivery strategy through a mucoadhesive hydrogel platform conveying hyaluronic acid-coated IONPs (IONP−HA). When instilled, the hydrogel platform first adhered to the interface of the tumor surface, sustainably releasing IONP−HA. Subsequently, the tumor stiffness and interstitial fluid pressure were reduced by photothermal therapy, promoting IONP−HA diffusion into the deep cancer tissue. As CRBCa expressed high levels of CD44, the last delivery tier was achieved through antibody-mediated endocytosis to increase the LIP, ultimately inducing ferroptosis. This three-tiered strategy delivered the IONPs stepwise from anatomical to cellular levels and increased the iron content by up to 50-fold from that of systematic administration, which presents a potential regimen for CRBCa.
Maintaining good friction performance of highway pavement is important for road safety. The friction is affected by many factors, and the present study investigates the effect of the compactness on the texture and friction of asphalt concrete during the polishing process. Two three-dimensional (3D) texture parameters and the mean texture depth (MTD) were used to characterize the surface texture of AC-13 asphalt concrete. The differences of surface texture are then being analyzed among the pavement in the field, rutting slabs with 97% compactness (RS-97), rutting slabs with 100% compactness (RS-100), and rutting slabs with 103% (RS-103). The rutting slabs were polished by a circular vehicle simulator (CVS). The 3D surface topography, British pendulum number (BPN), and MTD were obtained during the polishing process. Test results show that the surface of the rutting slab can be smoother as the compactness increased from 97% to 103%. During the whole polishing process, the rutting slab with smaller compactness had higher value of the MTD. The impact of compactness on the BPN is insignificant during the polishing process, but rutting slabs with smaller compactness had better friction at high speed as the result of the higher MTD.
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