Renal cell carcinoma (RCC) is the most common type of kidney cancer, about one third of the cases are diagnosed at advanced stages with metastases and effective treatments for metastatic RCC are lacking. The molecular events supporting RCC progression remain poorly understood. SPOP, an E3 ubiquitin ligase component, was recently showed to sufficiently promote RCC tumorigenesis, however, other potential functions of SPOP in RCC have not been studied. In the present investigation, by assessing the immunohistochemical staining of SPOP in urological tumors, we found the protein was highly expressed in RCC, in particular, it was specifically expressed in clear cell RCC. cDNA microarray data showed that SPOP mRNA level was significantly increased in clear cell RCC compared to normal kidney tissues, which might be the result of the abnormal DNA copy number of this gene. More interestingly, SPOP was positive in tumors with local invasion or metastasis, and it was associated with tumor recurrence-free survival of clear cell RCC patients. Further in vitro assays demonstrated that SPOP drove RCC epithelial-mesenchymal transition (EMT) and promoted cell invasion. Mechanistically, SPOP enhanced β-catenin protein expression as well as its nuclear translocation, and elevated TCF4 expression. Both β-catenin and TCF4 upregulated the critical EMT-inducing transcription factor ZEB1, which functioned as an effector of β-catenin/TCF4 signaling in RCC invasion. These data identified SPOP as a new marker and prognostic factor for clear cell RCC, and its functions provide new insight into the molecular mechanisms of RCC progression, in which SPOP appears to be an EMT activator.

No abstract

Because bladder cancer (BCa) is the 9th most common malignant tumor and 13th leading cause of death due to cancer, therapeutic approaches have attracted a great deal of attention from both clinicians and BCa patients. Although the development of surgery and targeted drugs has brought new challenges for the traditional concept of BCa therapy, various types of chemotherapy remain the final treatment method for many BCa patients. However, chemoresistance inevitably appears, leading to the failure of chemotherapy. Silibinin, a polyphenolic flavonoid component isolated from the fruits or seeds of milk thistle, has been reported to play important roles in inhibiting tumor chemoresistance in breast cancer and head and neck squamous cell carcinomas. Our previous study indicated that silibinin inhibited BCa progression in some mechanisms but with no conclusion of chemoresistance inhibition. Therefore, in the present study, we dissected the role of silibinin in BCa progression and chemoresistance. Our results revealed that in BCa, chemodrug-induced chemoresistance was reversed in the presence of silibinin. Further mechanistic study indicated that silibinin suppressed chemoresistance and BCa malignancy in an NF-κB-dependent and -independent manner. In addition, all of the inhibitory effects were dose‑dependent. Thus, our results provide a potential use for silibinin in BCa therapeutics.