Abstract
Testicular nuclear receptor 4 (TR4) is a member of the nuclear hormone receptor family and acts as a ligand-activated transcription factor and functions in many biological processes, such as development, cellular differentiation, and homeostasis. Recent studies have shown that TR4 plays an important role in prostate cancer, renal cell carcinoma, and hepatocellular carcinoma; however, its potential link to bladder cancer (BC) remains unknown. This study found that bladder cancer exhibited a higher expression of TR4 compared to normal tissues. Overexpressed TR4 promoted the bladder cancer cell proliferation, and knocked down TR4 with TR4-siRNA suppressed the bladder cancer cell proliferation. Mechanistic studies reveal that TR4 functions by altering the expression of Bcl-2 to regulate apoptosis in bladder cancer cells. Furthermore, knocking down Bcl-2 reversed the BC proliferation induced by TR4. In vivo, we also confirmed that TR4 knockdown mice (TR4+/−) showed slower bladder cancer growth than wild-type mice (TR4+/+) induced by the carcinogenic chemicals. Moreover, TR4+/− mice showed a lower grade of histopathology than the control group. In conclusion, these results indicate that TR4 plays a key role in bladder cancer proliferation, and targeting TR4 would probably be a potential strategy for bladder cancer treatment.
Highlights
Bladder cancer (BC) is one of the most common cancers globally and brings a great burden on society (Antoni et al, 2017)
We found that Testicular nuclear receptor 4 (TR4) was upregulated in the bladder cancer tissues compared to the normal tissues
We demonstrated that TR4 promotes bladder cancer progression by upregulating the Bcl-2 expression
Summary
Bladder cancer (BC) is one of the most common cancers globally and brings a great burden on society (Antoni et al, 2017). Significant effort has been made to develop an effective treatment method; patients with bladder cancer still have a poor prognosis, reflected in low 5-year survival rates, in advanced stages (46% for stage 3 and 15% for stage 4) (Berdik, 2017). There is an urgent need to explore the key paths of bladder cancer progression and identify promising targets for early diagnosis and treatment. Testicular orphan receptor (TR4, known as NR2C2) is a member of the nuclear receptor family. It was identified in 1994 by (Chang et al, 1994). Studies have indicated that TR4 acts as a transcriptional regulator and plays a significant role in diverse physiological processes, including neuronal and bone development Collins et al (2004), Chen et al (2005), fat metabolism, and fertility
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