Knocking down AR promotes osteoblasts to recruit prostate cancer cells by altering exosomal circ-DHPS/miR-214-3p/CCL5 pathway.

ABSTRACT: Tumor-derived exosomes have been shown to play a key role in organ-specific metastasis, and the androgen receptor regulates prostate cancer (PCa) progression. It is unclear whether the androgen receptor regulates the recruitment of prostate cancer cells to the bone microenvironment, even bone metastases, through exosomes. Here, we found that exosomes isolated from PCa cells after knocking down androgen receptor (AR) or enzalutamide treatment can facilitate the migration of prostate cancer cells to osteoblasts. In addition, AR silencing or treatment with the AR antagonist enzalutamide may increase the expression of circular RNA-deoxyhypusine synthase (circ-DHPS) in PCa cells, which can be transported to osteoblasts by exosomes. Circ-DHPS acts as a competitive endogenous RNA (ceRNA) against endogenous miR-214-3p to promote C-C chemokine ligand 5 (CCL5) levels in osteoblasts. Increasing the level of CCL5 in osteoblasts could recruit more PCa cells into the bone microenvironment. Thus, blocking the circ-DHPS/miR-214-3p/CCL5 signal may decrease exosome-mediated migration of prostate cancer cells to osteoblasts.

Multimodal recurrence scoring system for prediction of clear cell renal cell carcinoma outcome: a discovery and validation study.

BACKGROUND: Improved markers for predicting recurrence are needed to stratify patients with localised (stage I-III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel assay integrating three modalities-clinical, genomic, and histopathological-to improve the predictive accuracy for localised renal cell carcinoma recurrence. METHODS: In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI). FINDINGS: The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825-0·876 vs 0·608-0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio [HR] 4·57, 95% CI 2·49-8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19-6·59; p<0·0001). INTERPRETATION: Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy. FUNDING: National Natural Science Foundation of China, and National Key Research and Development Program of China.

HOTAIR and androgen receptor synergistically increase GLI2 transcription to promote tumor angiogenesis and cancer stemness in renal cell carcinoma.

Tumor angiogenesis is a major characteristic of renal cell carcinoma (RCC). Herein, we report a novel mechanism of how lncRNA and androgen receptor (AR) drive the Hedgehog pathway to promote tumor angiogenesis in RCC. We found that the high expression of lncRNA HOTAIR in RCC is associated with poor prognosis. Moreover, HOTAIR and AR form a feedback loop to promote the expression of each other. Interestingly, we also found that in RCC, HOTAIR is associated with the Hedgehog pathway, especially GLI2, via bioinformatics analysis. Furthermore, HOTAIR promotes GLI2 expression in the presence of AR. Mechanistically, HOTAIR interacts with AR and they cooperatively bind to GLI2 promoter and increase its transcription activity. We further confirmed how HOTAIR-AR axis regulates GLI2 expression by analyzing its function in RCC cells and found that HOTAIR and AR synergistically enhanced the expression of GLI2 downstream genes, such as VEGFA, PDGFA, and cancer stem cell transcription factors, and promoted tumor angiogenesis and cancer stemness in RCC cells both in vitro and in tumor xenografts. Overall, these findings suggest that HOTAIR and GLI2 could be novel therapeutic targets against RCC.