Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Statistics, Oklahoma State University, Stillwater, Oklahoma.
Cancer Res. 2015 Sep 15;75(18):3832-41. doi: 10.1158/0008-5472.CAN-14-3690. Epub 2015 Jul 21.
Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. In this study, we found that loss of the receptor for activated C-kinase 1 (RACK1) promoted the metastasis of gastric cancer by enhancing the autocrine expression of IL8 in vitro and in vivo. microRNA (miRNA; miR) array identified that RACK1 modulated the expression of a series of miRNAs, including the miR-302 cluster, and RACK1 modulated the IL8 expression and tumor invasion through miRNA-302c. Moreover, upregulation of IL8 in turn decreased the level of miRNA-302c and induced IL8 expression in a feedback manner. Tissue microarray also indicated that RACK1 was correlated with invasion/metastasis phenotype, IL8 expression, as well as 5-year survival in clinical cases of gastric cancer. Together, our results imply that loss of RACK1 in gastric cancer links epigenetics to inflammatory cytokines to promote tumor metastasis.
胃癌仍然是全球癌症相关死亡的第三大主要原因，而胃癌的侵袭和转移是其预后不良的主要原因。在这项研究中，我们发现，激活蛋白激酶 C 受体 1（RACK1）的缺失通过增强白细胞介素 8（IL8）的自分泌表达促进了胃癌的转移，在体外和体内均如此。microRNA（miRNA；miR）阵列鉴定出 RACK1 调节了一系列 miRNA 的表达，包括 miR-302 簇，并且 RACK1 通过 miR-302c 调节 IL8 的表达和肿瘤侵袭。此外，IL8 的上调反过来又降低了 miR-302c 的水平，并以反馈方式诱导 IL8 的表达。组织微阵列还表明，RACK1 与胃癌临床病例的侵袭/转移表型、IL8 表达以及 5 年生存率相关。总之，我们的研究结果表明，胃癌中 RACK1 的缺失将表观遗传学与炎症细胞因子联系起来，从而促进肿瘤转移。
