Transforming growth factor-β (TGFβ) is enriched in the bone matrix and serves as a key factor in promoting bone metastasis in cancer. In addition, TGFβ signaling activates mammalian target of rapamycin (mTOR) functions, which is important for the malignant progression. Here, we demonstrate that TGFβ regulates the level of microRNA-96 (miR-96) through Smad-dependent transcription and that miR-96 promotes the bone metastasis in prostate cancer. The enhanced effects in cellular growth and invasiveness suggest that miR-96 functions as an oncomir/and metastamir. Supporting this idea, we identified a downstream target of the TGFβ-miR-96 signaling pathway to be AKT1S1 mRNA, whose translated protein is a negative regulator of mTOR kinase. Our findings provide a novel mechanism accounting for the TGFβ signaling and bone metastasis.

Current therapeutic regimens for prostate cancer focus on targeting androgen receptor (AR) signaling. However, the AR is a key factor in luminal epithelium differentiation and was shown to have a role as a tumor suppressor. Thus, its inhibition may activate oncogenic pathways that contribute to metastatic castration-resistant prostate cancer (CRPC). Herein, we report a novel tumor promoter, ZBTB46, which is negatively regulated by AR signaling via microRNA (miR)-1-mediated downregulation. ZBTB46 is associated with malignant prostate cancer and is essential for metastasis. Its overexpression can overcome the antitumor effects of miR-1 and promote androgen-independent proliferation. We demonstrated that ZBTB46 can transcriptionally regulate SNAI1, a key epithelial-to-mesenchymal transition (EMT) driver, which could contribute to induction of the EMT after androgen-deprivation therapy and metastasis. Our findings are supportive of the model that disruption of AR's function may predispose prostate cancer to progress to metastatic CRPC.

We demonstrated that the AR-miR-1 axis negatively regulates the novel oncogenic factor, TCF7. Dysregulation of TCF7 promoted a survival advantage and resistance to androgen deprivation, suggesting its therapeutic potential for castration-resistant prostate cancer.

ABSTRACT. The aim of this meta-analysis was to investigate the overall diagnostic and prognostic values of CTHRC1 expression in human cancer development. Based on the inclusion and exclusion criteria, 8 cohort studies were included in the meta-analysis. The data were extracted, and analyses were performed using a random-effects model. Summary odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs) were calculated to assess the strength of the associations. A total of 1065 cancer patients from the 8 studies were included in the meta-analysis. The results revealed a positive correlation of CTHRC1 protein expression in tumors with tumor-node-metastasis (TNM) stage and with lymph node (LN) metastasis (TNM: OR = 2.98, 95%CI = 1.48-6.00, P = 0.002; LN: OR = 4.26, 95%CI = 1.88-9.67, P = 0.001). CTHRC1 expression was higher in tumors with sizes ≥5 cm than in tumors with sizes <5 cm (OR = 2.39, 95%CI = 1.12-5.09, P = 0.024). Patients with higher CTHRC1 expression had decreased overall survival (OS) (ES = 1.78, 95%CI = 1.23-2.33, P < 0.001) and poorer disease-free survival (DFS) (ES = 1.71, 95%CI = 1.11-2.31, P < 0.001). Disease-stratified analyses yielded significantly different estimates of CTHRC1 levels in the majority of the subgroups (all P < 0.05). In conclusion, increased CTHRC1 expression is associated with advanced TNM stage, increased LN metastasis and tumor size, and decreased OS and DFS, indicating that CTHRC1 may be a biomarker for prognosis of cancer patients.