AR-p62介导的自噬在内皮细胞促进去势抵抗性前列腺癌转移中的作用机制研究

Castration-resistant prostate cancer (CRPC) is one of the difficulties in the treatment of prostate cancer. CRPC speed up the progression of this disease. The prognosis is poor, no effective treatment recently. The tumor microenvironment especially endothelial cells play a key role in the progression of CRPC. Applicants found that endothelial cells can enhance tumor invasiveness via influencing androgen receptor (AR) level in CRPC cell. It reveals the important role of endothelial cells in AR mediated promotion to CRPC progression. Another study found that, knockdown AR in CRPC cells can reduce the expression of p62, then induce autophagy. P62 participates in the regulation of multiple stress pathways, such as autophagy. Many studies have shown the close relationship between autophagy and tumor metastasis. Thus, we hypothesize that AR-p62 mediated autophagy may play an important role in promoting CRPC metastasis by endothelial cells. This project aims to investigate and verify whether endothelial cells induce autophagic response of CRPC cells and related stress pathways, promote tumor invasiveness and metastasis, by influencing the AR-p62 expression of CRPC cells in vitro and in a orthotopic tumor nude mice model. This research has the important value in clarifying the survival mechanism of CRPC in the tumor microenvironment, and exploring the new strategy for prostate cancer treatment.

去势抵抗性前列腺癌（CRPC）是目前前列腺癌（PCa）治疗的一大难点。CRPC进展快，预后差，目前无有效治疗。肿瘤微环境特别是内皮细胞在CRPC进展中起关键作用。申请者研究发现，内皮细胞能通过影响CRPC细胞雄激素受体（AR）水平，增强肿瘤侵袭力，揭示了内皮细胞在AR介导下促进CRPC进展的重要作用。研究还发现，敲低CRPC细胞AR的表达会下调p62表达，诱发自噬。p62参与调节自噬等多种应激通路。多项研究显示自噬与肿瘤转移密切相关。由此我们推测AR-p62介导的自噬可能在内皮细胞促CRPC转移中发挥重要作用。本课题拟在体外环境及裸鼠原位瘤模型中探讨验证内皮细胞是否通过影响CRPC细胞AR-p62的表达，诱导CRPC细胞的自噬及相关应激通路，促进肿瘤侵袭转移。本课题对阐明CRPC在肿瘤微环境中的生存机制，以及探索PCa新的治疗策略，都具有重要价值。

去势抵抗性前列腺癌（CRPC）是目前前列腺癌（PCa）治疗的一大难点。CRPC进展快，预后差，目前无有效治疗。肿瘤微环境特别是内皮细胞在CRPC进展中起关键作用。申请者研究发现，内皮细胞能通过影响CRPC细胞雄激素受体（AR）水平，增强肿瘤侵袭力，揭示了内皮细胞在AR介导下促进CRPC进展的重要作用。研究还发现，敲低CRPC细胞AR的表达会下调p62表达，诱发自噬。p62参与调节自噬等多种应激通路。多项研究显示自噬与肿瘤转移密切相关。我们进一步验证了AR-p62介导的自噬在内皮细胞促CRPC转移中发挥了重要作用。本课题在体外环境及裸鼠原位瘤模型中探讨验证了内皮细胞通过分泌CCL5影响CRPC细胞AR-p62的表达，诱导CRPC细胞的自噬及相关应激通路，促进肿瘤侵袭转移。本课题对阐明CRPC在肿瘤微环境中的生存机制，以及探索PCa新的治疗策略，都提供了重要价值。