Abstract
Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, may play important roles to modulate the metabolic diseases and prostate tumorigenesis. Here we found TR4 could increase prostate cancer (PCa) cell invasion. Mechanism dissection revealed that TR4 might increase PCa cell invasion via decreasing the miR-373-3p expression that resulted in the activation of the TGFβR2/p-Smad3 signals. The in vivo mouse model using orthotopically xenografted CWR22Rv1 cell line transfected with luciferase-reporter confirmed in vitro cell line studies showing TR4 increased PCa metastasis via decreasing the miR-373-3p expression. Together, these data suggest that TR4 may increase PCa metastasis via a newly identified signal and targeting these TR4/miR-473-3p/TGFβR2/p-Smad3 signals using TR4 antagonist or TR4-siRNA or miR-373-3p may allow us to develop a new potential therapeutic approach to better suppress PCa metastasis.
Highlights
Prostate cancer (PCa) has the second highest mortality in men [1]
Using matrigel coated transwell invasion assays with Testicular nuclear receptor 4 (TR4)-shRNA to knock down TR4 in PC3 cells, we found that reduced TR4 decreased prostate cancer (PCa) cell invasion (Figure 1C)
We applied an opposite approach with addition of functional TR4-cDNA into CWR22Rv1 cells, and results revealed that increased TR4 significantly increased PCa cell invasion (Figure 1E)
Summary
Most patients eventually relapse with recurrent metastatic PCa that has become castration resistant after androgen deprivation therapy (ADT) [2,3,4]. Identifying molecules and signals linked to enhanced PCa metastasis and development of new therapies to suppress the metastatic PCa may help us to better inhibit the PCa at the later castration resistant stage. In vivo mouse studies suggested that TR4 might play important roles to modulate the progression of several diseases including metabolic disorders and various tumors [9,10,11]. Studies revealed that TR4 might play a protective role to inhibit the prostate tumorigenesis and knocking-out TR4 in a mouse model (TR4KO) might increase PIN and/or prostatic carcinoma formation [12]. The role of TR4 in PCa metastasis, especially involving the regulation of microRNAs (miRNAs), remains to be further elucidated
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