Lin Tsung-Chieh, Yeh Yuan-Ming, Fan Wen-Lang, Chang Yu-Chan, Lin Wei-Ming, Yang Tse-Yen, Hsiao Michael
Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou 33305, Taiwan.
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Cancers (Basel). 2019 Mar 4;11(3):303. doi: 10.3390/cancers11030303.
Ghrelin is a peptide hormone, originally identified from the stomach, that functions as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) and promotes growth hormone (GH) release and food intake. Increasing reports point out ghrelin's role in cancer progression. We previously characterized ghrelin's prognostic significance in the clear cell subtype of renal cell carcinoma (ccRCC), and its pro-metastatic ability via Snail-dependent cell migration. However, ghrelin's activity in promoting cell invasion remains obscure. In this study, an Ingenuity Pathway Analysis (IPA)-based investigation of differentially expressed genes in Cancer Cell Line Encyclopedia (CCLE) dataset indicated the potential association of Aurora A with ghrelin in ccRCC metastasis. In addition, a significant correlation between ghrelin and Aurora A expression level in 15 ccRCC cell line was confirmed by variant probes. ccRCC patients with high ghrelin and Aurora A status were clinically associated with poor outcome. We further observed that ghrelin upregulated Aurora A at the protein and RNA levels and that ghrelin-induced ccRCC in vitro invasion and in vivo metastasis occurred in an Aurora A-dependent manner. Furthermore, MMP1, 2, 9 and 10 expressions are associated with poor outcome. In particular, MMP10 is significantly upregulated and required for the ghrelin-Aurora A axis to promote ccRCC invasion. The results of this study indicated a novel signaling mechanism in ccRCC metastasis.
胃饥饿素是一种最初从胃中发现的肽类激素，它作为生长激素促分泌素受体（GHSR）的内源性配体，促进生长激素（GH）释放和食物摄入。越来越多的报道指出胃饥饿素在癌症进展中的作用。我们之前已阐述了胃饥饿素在肾透明细胞癌（ccRCC）中的预后意义，以及其通过Snail依赖的细胞迁移促进转移的能力。然而，胃饥饿素在促进细胞侵袭方面的活性仍不清楚。在本研究中，基于 Ingenuity 通路分析（IPA）对癌细胞系百科全书（CCLE）数据集中差异表达基因的研究表明，在ccRCC转移中，极光激酶A（Aurora A）与胃饥饿素之间存在潜在关联。此外，通过不同探针证实了15种ccRCC细胞系中胃饥饿素与Aurora A表达水平之间存在显著相关性。胃饥饿素和Aurora A水平高的ccRCC患者在临床上与不良预后相关。我们进一步观察到，胃饥饿素在蛋白质和RNA水平上上调Aurora A，并且胃饥饿素诱导的ccRCC体外侵袭和体内转移以Aurora A依赖的方式发生。此外，基质金属蛋白酶1、2、9和10的表达与不良预后相关。特别是，基质金属蛋白酶10显著上调，并且是胃饥饿素 - Aurora A轴促进ccRCC侵袭所必需的。本研究结果表明了ccRCC转移中的一种新的信号传导机制。
