The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
1] Discipline of Pathology, School of Medicine and Molecular Medicine Research Group, University of Western Sydney, Sydney, New South Wales, Australia [2] Department of Anatomical Pathology, Liverpool Hospital, Sydney, New South Wales, Australia.
Oncogene. 2014 Jul 3;33(27):3561-70. doi: 10.1038/onc.2013.315. Epub 2013 Aug 12.
Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF; polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of α-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co-expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets.
窖蛋白-1 在前列腺癌中具有复杂的作用，并被认为是一种潜在的生物标志物和治疗靶点。由于成熟的窖蛋白-1 存在于质膜的凹陷脂质筏域——小窝中，因此小窝已被认为是前列腺癌中的促肿瘤信号平台。然而，小窝的形成需要窖蛋白-1 和 cavin-1（也称为 PTRF；聚合酶 I 和转录释放因子）。在这里，我们使用包括正常、非恶性和恶性前列腺组织的组织微阵列检查了窖蛋白-1 在前列腺上皮和基质中的表达。我们发现，在晚期前列腺癌中，窖蛋白-1 在没有 cavin-1 的情况下被诱导，这种表达模式在 PC-3 细胞系中得到了反映。相比之下，正常的前列腺上皮既不表达窖蛋白-1 也不表达 cavin-1，而前列腺基质则高度表达窖蛋白-1 和 cavin-1。利用 PC-3 细胞作为窖蛋白-1 阳性的晚期前列腺癌的合适模型，我们发现 PC-3 细胞中的 cavin-1 表达抑制了非锚定依赖性生长，并减少了在前列腺癌异种移植小鼠模型中的体内肿瘤生长和转移。在携带 PC-3-cavin-1 肿瘤细胞的小鼠肿瘤中，基质中α-平滑肌肌动蛋白的表达以及癌细胞中的白细胞介素-6（IL-6）的表达也降低了。为了确定 cavin-1 是否通过中和窖蛋白-1 起作用，我们在窖蛋白-1 阴性的前列腺癌细胞 LNCaP 和 22Rv1 中表达了 cavin-1。窖蛋白-1 的表达增加了 LNCaP 和 22Rv1 细胞的非锚定依赖性生长。在窖蛋白-1 阳性的 LNCaP 细胞中，cavin-1 的共表达逆转了窖蛋白-1 的作用。总之，这些结果表明，由于缺乏 cavin-1 的表达，晚期前列腺癌中的窖蛋白-1 存在于小窝之外。cavin-1 的表达部分通过降低 IL-6 微环境功能来减弱非小窝窖蛋白-1 微区的作用。由于循环窖蛋白-1 是晚期前列腺癌的潜在生物标志物，确定受 cavin-1 影响的分子途径可能为提供新的治疗靶点。
