Upregulation of SDHA inhibited proliferation, migration, and invasion of clear cell renal cell carcinoma cells via inactivation of the Wnt/ß-catenin pathway.

Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy with high mortality. Recent findings suggest that the succinate dehydrogenase complex subunit A (SDHA) is lowly expressed in many types of cancers and involved in tumorigenesis. However, the potential regulatory roles and molecular mechanisms by which SDHA affects the development and progression of ccRCC remain largely unknown. In this study, our results showed that there was significant downregulation of SDHA in ccRCC tissue relative to corresponding non-cancerous tissue, and low expression of SDHA was associated with Fuhrman pathological grade, tumor size, TNM stage, metastasis, and poor prognosis in ccRCC patients. Moreover, overexpression of SDHA inhibited the proliferation, invasion, and migration capacities of ccRCC cells. Mechanistically, SDHA impeded the proliferation and metastasis of ccRCC cells by inactivation of the Wnt/ß-catenin pathway. In vivo experiments, SDHA suppressed ccRCC growth in a nude mouse model. In conclusion, our study results indicated that SDHA may act as a new molecular marker for judging the occurrence and development of ccRCC and serve as a therapeutic target for the treatment of human ccRCC.

Quantitative Global Proteome and Lysine Succinylome Analyses Reveal the Effects of Energy Metabolism in Renal Cell Carcinoma.

In light of the increasing incidence of renal cell carcinoma (RCC), its molecular mechanisms have been comprehensively explored in numerous recent studies. However, few studies focus on the influence of multi-factor interactions during the occurrence and development of RCC. This study aims to investigate the quantitative global proteome and the changes in lysine succinylation in related proteins, seeking to facilitate a better understanding of the molecular mechanisms underlying RCC. LC-MS/MS combined with bioinformatics analysis are used to quantitatively detect the perspectives at the global protein level. IP and WB analysis were conducted to further verify the alternations of related proteins and lysine succinylation. A total of 3,217 proteins and 1,238 lysine succinylation sites are quantified in RCC tissues, and 668 differentially expressed proteins and 161 differentially expressed lysine succinylation sites are identified. Besides, expressions of PGK1 and PKM2 at protein and lysine, succinylation levels are significantly altered in RCC tissues. Bioinformatics analysis indicates that the glycolysis pathway is a potential mechanism of RCC progression and lysine succinylation may plays a potential role in energy metabolism. These results can provide a new direction for exploring the molecular mechanism of RCC tumorigenesis.

TGF-ß1 induced fascin1 expression facilitates the migration and invasion of kidney carcinoma cells through ERK and JNK signaling pathways.

Transforming growth factor-ß1 (TGF-ß1) plays a crucial role in the signaling network that controls cellular invasion and motility capability during tumor development. To investigate whether fascin1 plays a crucial role in TGF-ß1-facilitated invasion and migration of kidney cancer cells (KCC), real-time PCR and western blotting were used to test the fascin1 expression after TGF-ß1 treatment (10 ng/ml) in 769-P and OSRC cells. Fascin1 was silenced using the small interfering RNA (siRNA) technique. Cytoskeleton staining was used to test the change of Cytoskeleton. Cell migration and invasion changes were measured by wound-healing and Transwell assay. The results indicate that mRNA and protein levels of fascin1 were dramatically increased after treatment with 10 ng/ml TGF-ß1 in 769-P and OSRC cells. TGF-ß1 promoted the occurrence of EMT (Epithelial-Mesenchymal Transition) and the invasive and migratory capabilities of the two cell lines after treatment with 10 ng/ml TGF-ß1. In addition, fascin1 siRNA dramatically attenuated the invasiveness and migration induced by TGF-ß1. Furthermore, we identified that specific inhibitors of ERK and JNK signaling pathways, FR180204 and SP600125, can suppress TGF-ß1-induced fascin1 expression. In conclusion, these results reveal that fascin1 is an important mediator of TGF-ß1-induced invasion and migration of KCC through ERK and JNK signal pathways.

Long non-coding RNA ZEB1-AS1 regulates miR-200b/FSCN1 signaling and enhances migration and invasion induced by TGF-ß1 in bladder cancer cells.

BACKGROUND: The effect of competing endogenous RNA (ceRNA) can regulate gene expression by competitively binding microRNAs. Fascin-1 (FSCN1) plays an important role in the regulation of cellular migration and invasion during tumor progression, but how its regulatory mechanism works through the ceRNA effect is still unclear in bladder cancer (BLCA). METHODS: The role of fascin-1, miR-200b, and ZEB1-AS1 in BLCA was investigated in vitro and in vivo. The interaction between fascin-1, miR-200b, and ZEB1-AS1 was identified using bioinformatics analysis, luciferase activity assays, RNA-binding protein immunoprecipitation (RIP), quantitative PCR, and western blotting. Loss (or gain)-of-function experiments were performed to investigate the biological roles of miR-200b and ZEB1-AS1 on migration, invasion, proliferation, cell apoptosis, and cell cycle. RESULTS: ZEB1-AS1 functions as a competing endogenous RNA in BLCA to regulate the expression of fascin-1 through miR-200b. Moreover, the oncogenic long non-coding RNA ZEB1-AS1 was highly expressed in BLCA and positively correlated with high tumor grade, high TNM stage, and reduced survival of patients with BLCA. Moreover, ZEB1-AS1 downregulated the expression of miR-200b, promoted migration, invasion, and proliferation, and inhibited apoptosis in BLCA. Furthermore, we found TGF-ß1 induced migration and invasion in BLCA by regulating the ZEB1-AS1/miR-200b/FSCN1 axis. CONCLUSION: The observations in this study identify an important regulatory mechanism of fascin-1 in BLCA, and the TGF-ß1/ZEB1-AS1/miR-200b/FSCN1 axis may serve as a potential target for cancer therapeutic purposes.