lincRNA-ARR募集hnRNPK下调雄激素受体抑制前列腺癌去势抵抗的机制研究

Castration resistance is the main reason of metastasis and death in advanced prostate cancer patients. Androgen receptor signaling persist in CRPC and plays pivotal role in the progression of the disease, but the mechanism is not fully understood. Emerging evidence reveals that RNA(lincRNAs) may play an important regulatory role in cancer by acting as oncogenes or tumor suppressors. However, the roles of lincRNAs in CRPC remain elusive. Our previous study found that the expression of lincRNA-ARR is decreased in castration resistant prostate cancer cell sublines, leading to an enhanced Androgen Receptor signaling and castration resistance. Furthermore, we identified that lincRNA-ARR binds to hnRNP K by RNA Pull-down and Mass Spectrometry. Therefore, we propose a new mechanism that lincRNA-ARR inhibits AR translation by recruiting hnRNP K to AR mRNA to inhibit the castration resistance of prostate cancer. To gain the proof of lincRNA-ARR regulating castration resistance of prostate cancer by hnRNP K, we will perform in vitro and vivo experiments, RNA Pull-down and next generation sequencing analysis. This study aims to elucidate the function and mechanism of lincRNA-ARR in prostate cancer and how they modulate castration resistance by binding hnRNP K. To identify the new targets for castration resistant prostate cancer cell targeting therapy and the clinical significance of lincRNA-ARR in prostate cancer castration resistance and prognosis.

去势抵抗是晚期前列腺癌转移和患者死亡的主要原因，雄激素受体AR信号通路异常是去势抵抗前列腺癌(CRPC)发生的关键，但机制未完全阐明。长链基因间非编码RNA(lincRNA)对肿瘤发生、发展起关键调控作用，但是否调控CRPC及其机制未明。我们预实验发现linc-ARR 在CRPC细胞株和癌组织中低表达，它能抑制前列腺癌细胞的去势抵抗和雄激素受体(AR)的表达，免疫共沉淀实验证实linc-ARR能与hnRNPK结合，由此我们提出调控CRPC新机制:linc-ARR募集hnRNPK到AR的mRNA上，抑制AR的蛋白翻译及其信号通路激活，从而抑制前列腺癌细胞去势抵抗的发生和发展。本研究拟进一步采用体内外实验，免疫共沉淀和高通量测序等技术，获得linc-ARR通过hnRNPK调控CRPC的可靠证据，确定它在前列腺癌去势抵抗转化和预后中的意义，为发现CRPC的新标记物和治疗靶点提供科学依据。

对前列腺癌（PCa）患者来说，进展到去势抵抗状态是PCa患者死亡的主要原因。雄激素受体（AR）信号在去势耐受性前列腺癌（CRPC）的进展中发挥关键作用，因此了解低雄激素状态下AR激活的机制，对于研发治疗CRPC的新方法至关重要。在本研究中，我们发现lincRNA-ARR在CRPC细胞系和组织中的低表达。lincRNA-ARR下调与PCa患者较高的Gleason评分、T分期和不良预后相关。在雄激素去除或AR阻断条件下，我们发现在前列腺癌细胞中过表达或敲低lincRNA ARR后，PCa细胞的去势抵抗分别得到抑制或增强。此外，在雄激素缺乏的情况下，敲除lincRNA-ARR显著提高AR蛋白的翻译，从而激活AR信号通路。在机制上，lincRNA-ARR通过与hnRNPK和AR的mRNA形成复合物来抑制AR翻译效率。综上所述，lincRNA- ARR作为一种新型AR翻译调节因子发挥作用，通过与hnRNPK相互作用抑制前列腺癌的去势抵抗。这为lncRNA介导的AR激活从而调节CRPC的机制提供了新的思路，同时lincRNA-ARR-hnRNPK-AR轴也可以作为CRPC的治疗的新方向。