Zhu Hengcheng, Wang Min, Du Yang, Liu Xiuheng, Weng Xiaodong, Li Chenglong
Department of Urology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road 238, Wuhan 430060, Hubei, PR China.
J Cancer. 2019 Jun 2;10(11):2464-2471. doi: 10.7150/jca.29648. eCollection 2019.
4-1BB ligand (4-1BBL) was a transmembrane glycoprotein belonging to the tumor necrosis factor family. It was expressed on activated T lymphocytes and function as a co-stimulatory molecule via cross-linking with 4-1BB (a.k.a, CD137). In addition to its role in immune regulation, 4-1BBL transmitted signals into the cells on which it was expressed (reverse signaling). 4-1BBL represented a promising target for enhancing antitumor immune responses. Recent studies indicated that 4-1BBL also expressed in non-immune cells and possessed different functions in various types of cells. Here, we reported that 4-1BBL didn't express in normal prostate tissues and benign prostatic hyperplasia tissues, but it expressed in prostate cancer (PCa) tissues at moderate level. Expression of 4-1BBL was up-regulated during the transition from PCa to castration resistant prostate cancer (CRPC). Increasing expression of 4-1BBL not only promoted expression of androgen receptor (AR), but also augmented proliferation and invasion ability of prostate cancer cells in androgen deprivation environment. These results were further verified by xenograft tumor experiments. Meanwhile, inhibiting AR signal pathway by chemical antagonist was able to significantly reduce 4-1BBL mediated proliferation and invasion of PCa cells. These novel findings indicated that 4-1BBL might mediate prostate cancer progression to castration-resistant prostate cancer via enhancing expression and function of AR.
4-1BB配体（4-1BBL）是一种属于肿瘤坏死因子家族的跨膜糖蛋白。它在活化的T淋巴细胞上表达，并通过与4-1BB（又名CD137）交联发挥共刺激分子的作用。除了在免疫调节中的作用外，4-1BBL还向其表达的细胞传递信号（反向信号传导）。4-1BBL是增强抗肿瘤免疫反应的一个有前景的靶点。最近的研究表明，4-1BBL也在非免疫细胞中表达，并且在各种类型的细胞中具有不同的功能。在此，我们报道4-1BBL在正常前列腺组织和良性前列腺增生组织中不表达，但在前列腺癌（PCa）组织中呈中等水平表达。在从PCa向去势抵抗性前列腺癌（CRPC）转变的过程中，4-1BBL的表达上调。4-1BBL表达的增加不仅促进雄激素受体（AR）的表达，还增强了雄激素剥夺环境中前列腺癌细胞的增殖和侵袭能力。这些结果通过异种移植肿瘤实验得到进一步验证。同时，用化学拮抗剂抑制AR信号通路能够显著降低4-1BBL介导的PCa细胞增殖和侵袭。这些新发现表明，4-1BBL可能通过增强AR的表达和功能介导前列腺癌进展为去势抵抗性前列腺癌。
