Background/Aims: MiR-30a-5p, a member of the microRNA-30 family (miR-30), is known to function as a tumor suppressor in several different cancers. However, the expression levels, biological function, and underlying mechanisms of miR-30a-5p in renal cell carcinoma (RCC) remain unclear. Glucose-regulated protein78 (GRP78) is a common cancer biomarker and promotes the growth and survival of cancer cells. The expression of GRP78 has been reported to be modulated by miR-30a in neurons. In this study, the expression profile of miR-30a-5p in clear cell renal cell carcinoma (ccRCC) and its effect on ccRCC through regulating GRP78 expression was investigated. Methods: MiR-30a-5p expression was analyzed using bioinformatic software on open microarray datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and confirmed by quantitative RT-PCR (qRT-PCR) in ccRCC cell lines. Cell proliferation was investigated using CCK-8 and cell count assays. Western blotting, immunohistochemistry, luciferase reporter assays, and flow cytometry were employed to investigate the mechanisms of the effect of miR-30a-5p on ccRCC Results: MiR-30a-5p was down-regulated in ccRCC and related to the clinicopathological factors and prognosis of ccRCC. MiR-30a-5p was found to both suppress the growth of ccRCC cells and promote apoptosis of ccRCC cells in vitro. GRP78 was the direct target gene of miR-30a-5p, and the GRP78 expression was inversely correlated with the expression of miR-30a-5p in vivo and in vitro. The functional studies of GRP78 overexpression or knockdown demonstrated that GRP78 promoted proliferation and anti-apoptosis of ccRCC cells, and the oncogenic activity of GRP78 resulting in by miR-30a-5p overexpression. Conclusion: MiR-30a-5p is a bona fide negative regulator of GRP78 expression, and the anti-tumor activity of miR-30a-5p in ccRCC is due at least in part to down-regulating GRP78 expression and modulating the unfolded protein response (UPR) pathway. Thus, miR-30-GRP78 interaction provides a novel therapeutic candidate target in ccRCC treatment.

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

Nucleobindin 2 (NUCB-2) is a multifunctional protein that contains several functional domains and is associated with a wide variety of biological processes, such as food intake and energy homeostasis. NUCB-2 has been demonstrated to be associated with worse malignant outcomes and cell migration in breast and prostate cancer. However, to the best of our knowledge, its clinical and biological significance in renal cell carcinoma remains unknown. In the present study, tissue specimens from 68 patients with renal cell carcinoma and 10 normal controls were collected for NUCB-2 mRNA and protein assays. The NUCB-2 level in the patients with renal cell cancer was significantly increased compared with the normal control patients. NUCB-2-knockout in the renal cancer cell line SK-RC-52 inhibited migration and invasion. In addition, the expression levels of molecules associated with epithelial-mesenchymal transition (EMT), including E-cadherin, β-catenin, Slug and Twist, were affected by NUCB-2 suppression and the zinc finger E-box binding to homeobox 1 (ZEB1)-dependent pathway. The AMP-dependent protein kinase (AMPK)/target of rapamycin complex (mTORC) 1 signaling pathway participates in the regulation of NUCB-2-mediated metastasis and EMT. Suppression of NUCB-2 also inhibited tumor nodule formation in a murine renal cell carcinoma tumor model. In summary, NUCB-2 increased migration, invasion and EMT in renal cell carcinoma cells through the AMPK/TORC1/ZEB1 pathway in vitro and in vivo.

To investigate the diagnostic value of urothelial carcinoma-associated 1 as a urine biomarker in urinary bladder cancer patients by performing a comprehensive meta-analysis. A comprehensive literature search was conducted by the databases PubMed, Embase, Cochrane Library, China Knowledge Resource Integrated, and Web of Science. The quality of eligible studies was scored with the Quality Assessment of Diagnostic Accuracy Studies. The bivariate meta-analysis model was used to pool the sensitivity, specificity, likelihood ratio, and diagnostic odds ratio. Receiver operating characteristic curves and hierarchical summary receiver operating characteristic models were employed to check the overall test performance in this meta-analysis. Seven publications involving 678 patients and 563 controls were included in this meta-analysis. The pooled sensitivity was 0.84 (95% confidence interval: 0.80-0.88), specificity was 0.87 (95% confidence interval: 0.75-0.94), positive likelihood ratio was 6.5 (95% confidence interval: 3.10-13.62), negative likelihood ratio was 0.18 (95% confidence interval: 0.13-0.25), and diagnostic odds ratio was 36 (95% confidence interval: 13-99). The area under the summary receiver operating characteristic curve was 0.89 (95% confidence interval: 0.86-0.91). Our results indicated that urothelial carcinoma-associated 1 was a potential diagnostic biomarker with good specificity and sensitivity in urinary bladder cancer. Further prospective studies with larger cohorts are necessary to evaluate the diagnostic accuracy of urothelial carcinoma-associated 1 for urinary bladder cancer.

Renal cell carcinomas (RCCs) account for about 90% of renal tumors, and their major histological subtype is ccRCC (clear cell RCC). Increasing evidence has indicated that the tumor microenvironment plays a significant role in the occurrence and development of ccRCC. In this study, we used ESTIMATE and CIBERSORT computational methods to calculate the proportion of immune and stromal components and the rate of TICs (tumor‐infiltrating immune cells) in 539 ccRCC samples from The Cancer Genome Atlas database. By examining the intersection of the differentially expressed genes obtained by the protein–protein interaction network and Cox regression analysis, we identified only one overlapping gene: IGLL5 (immunoglobulin lambda‐like polypeptide 5). We report that IGLL5 expression is correlated with TICs. Furthermore, our immunoinfiltration analyses revealed that three types of TIC are positively correlated with IGLL5 expression. IGLL5 may have potential as a prognostic biomarker of ccRCC.