Abstract
BackgroundWilms’ tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation. The regulation of cell cycle is mainly dependent on cyclins and cyclin-dependent protein kinases (CDKs). Recent studies have shown that CDKs are closely related to the tumor diagnosis, progression and response to treatment. However, their specific biological roles and related mechanism in renal cell carcinoma (RCC) remain unknown.MethodsQuantitative real-time PCR, western blotting and immunohistochemistry were used to detect the expression of WTAP and CDK2. The survival analysis was adopted to explore the association between WTAP expression and the prognosis of RCC. Cells were stably transfected with lentivirus approach and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of WTAP in RCC. RNA immunoprecipitation, Luciferase reporter assay and siRNA were employed to identify the direct binding sites of WTAP with CDK2 transcript. Colony formation assay was conducted to confirm the function of CDK2 in WTAP-induced growth promoting.ResultsIn RCC cell lines and tissues, WTAP was significantly over-expressed. Compared with patients with low expression of WTAP, patients with high expression of WTAP had lower overall survival rate. Additionally, cell function test indicated that cell proliferation abilities in WTAP over-expressed group were enhanced, while WTAP knockdown showed the opposite results. Subcutaneous xenograft tumor model displayed that knockdown of WTAP could impede tumorigenesis in vivo. Mechanism study exhibited that CDK2 expression was positively associated with the expression of WTAP. Moreover, WTAP stabilized CDK2 transcript to enhance CDK2 expression via binding to 3′-UTR of CDK2 transcript. Additionally, specific inhibitors of CDK2 activity and small interfering RNA (siRNA) of CDK2 expression inhibited WTAP-mediated promotion of proliferation.ConclusionsThese findings suggest that WTAP may have an oncogenic role in RCC through physically binding to CDK2 transcript and enhancing its transcript stability which might provide new insights into RCC therapy.
Highlights
Wilms’ tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation
WTAP is significantly upregulated in renal cell carcinoma (RCC) tissues and related to RCC patient prognosis To explore the potential role of WTAP in RCC, we first examined the mRNA and protein expression of WTAP in tumor tissues and paired adjacent tissues by qRT-PCR and western blot
We found that WTAP was significantly up-regulated in RCC tissues compared with the adjacent tissues (Fig. 1a)
Summary
Wilms’ tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation. Recent studies have shown that CDKs are closely related to the tumor diagnosis, progression and response to treatment. Their specific biological roles and related mechanism in renal cell carcinoma (RCC) remain unknown. Approximately 30% of patients have locally advanced or developed metastases at the time of diagnosis and about 30–50% of patients will develop metastatic RCC following surgical resection of the primary tumor [4] These patients with metastatic RCC are inoperable and the long-term prognosis remains poor though recent therapeutic developments, such as molecular targeted therapy, have improved the overall survival [5].
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