Abstract
BackgroundCholangiocarcinoma represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades. Cholangiocarcinoma silent nature limits early diagnosis and prevents efficient treatment.MethodsImmunoblotting and immunohistochemistry were used to assess the expression profiling of USP9X and EGLN3 in cholangiocarcinoma patients. ShRNA was used to silence gene expression. Cell apoptosis, cell cycle, CCK8, clone formation, shRNA interference and xenograft mouse model were used to explore biological function of USP9X and EGLN3. The underlying molecular mechanism of USP9X in cholangiocarcinoma was determined by immunoblotting, co-immunoprecipitation and quantitative real time PCR (qPCR).ResultsHere we demonstrated that USP9X is downregulated in cholangiocarcinoma which contributes to tumorigenesis. The expression of USP9X in cholangiocarcinoma inhibited cell proliferation and colony formation in vitro as well as xenograft tumorigenicity in vivo. Clinical data demonstrated that expression levels of USP9X were positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that USP9X was involved in the deubiquitination of EGLN3, a member of 2-oxoglutarate and iron-dependent dioxygenases. USP9X elicited tumor suppressor role by preventing degradation of EGLN3. Importantly, knockdown of EGLN3 impaired USP9X-mediated suppression of proliferation. USP9X positively regulated the expression level of apoptosis pathway genes de through EGLN3 thus involved in apoptosis of cholangiocarcinoma.ConclusionThese findings help to understand that USP9X alleviates the malignant potential of cholangiocarcinoma through upregulation of EGLN3. Consequently, we provide novel insight into that USP9X is a potential biomarker or serves as a therapeutic or diagnostic target for cholangiocarcinoma.
Highlights
Cholangiocarcinoma represents the second most common primary liver malignancy
We investigated the effect of Ubiquitin-specific peptidase 9X (USP9X) expression on postoperative survival in cholangiocarcinoma patients by immunohistochemistry
The results demonstrated that high expression levels of USP9X are associated with better prognosis of patients with cholangiocarcinoma in overall survival (OS) (Fig. 1B)
Summary
Cholangiocarcinoma represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades. Cholangiocarcinoma silent nature limits early diagnosis and prevents efficient treatment. Cholangiocarcinoma (CC) is a heterogeneous disease for a complex interaction between host-specific genetic background and multiple risk factors [1]. The incidence rates of cholangiocarcinoma reveal geographical variation in globally, which possess much higher incidence. Most patients are diagnosed at an advanced, nonsurgical stage and only about 1 in 5 cases are surgically resectable [6, 7]. The outcome of advanced cholangiocarcinoma is poor with an overall survival of maximum 15 months with chemotherapy [8]. Development of strategies for early diagnosis and effective treatments of cholangiocarcinoma are extremely essential
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