肿瘤分泌的外泌体对癌细胞的生长、转移和药物抵抗具有广泛的影响。然而，调节外泌体分泌的分子机制是否以及如何影响肿瘤进展仍然知之甚少。已经报道了Klotho-beta（KLB）在前列腺癌中的异常调节，但其功能仍未知。在本研究中，我们首先确定了KLB在前列腺癌中的上调，并且其表达水平与前列腺癌的恶性表型在体外和体内均呈正相关。有趣的是，KLB的过表达会损害前列腺癌细胞的外泌体释放，并导致多囊体在细胞内积累。机制上，KLB通过Rab8a依赖途径减弱了外泌体的分泌。在KLB过表达的细胞中，Rab8a被下调，而Rab8a的过表达可以拯救受损的外泌体释放，并在体外和体内减弱KLB导致的前列腺癌恶性表型。综上所述，本研究揭示了KLB通过Rab8a依赖机制对外泌体分泌的调控在肿瘤促进中的作用。这些研究结果可为前列腺癌的新型治疗和诊断靶点的开发提供有力支持。©2023. 本文作者独家授权Springer Nature Limited使用。

Tumor-secreted exosomes have a wide range of effects on the growth, metastasis, and drug resistance of cancer cells. However, whether and how the molecular mechanisms that regulate the secretion of exosomes could affect tumor progression remains poorly understood. Klotho beta (KLB) has been reported dysregulated in prostate cancer, but its function remains unknown. Herein, we first determined that KLB was upregulated in prostate cancer and its expression level was positively correlated with prostate cancer malignant phenotype both in vitro and in vivo. Intriguingly, KLB overexpression could impair the release of exosomes and cause the intracellular accumulation of multivesicular bodies (MVBs) in prostate cancer cells. Mechanistically, KLB attenuated exosomes secretion through a Rab8a-dependent pathway. Rab8a was downregulated in KLB overexpressing cells whereas overexpression of Rab8a could rescue the impaired release of exosomes and attenuate the KLB-induced malignant phenotype of prostate cancer both in vitro and in vivo. Taken together, this study has unveiled the tumor-promoting role of KLB mediated by its regulation on exosomes secretion through a Rab8a-dependent mechanism. These findings could be exploited to develop novel theranostic targets for prostate cancer.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.