Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P.R. China.
Department of Pathology, West China Second Hospital, Sichuan University, Chengdu, P.R. China.
Cancer Res. 2017 Mar 15;77(6):1369-1382. doi: 10.1158/0008-5472.CAN-16-1615. Epub 2017 Jan 13.
The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs and were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14-high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. .
大多数上皮性卵巢癌患者在存在腹膜转移时被诊断为晚期；然而，对于这种疾病的转移过程知之甚少。在这项研究中，我们报告了长非编码 RNA LINC00092 作为由癌症相关成纤维细胞 (CAF) 介导的转移进展的节点驱动因子的鉴定。发现 CAFs 和 的促转移特性与趋化因子 CXCL14 的表达升高有关。在临床标本中，CAFs 中 CXCL14 的高水平也与预后不良相关。值得注意的是，CXCL14 高的 CAFs 介导了卵巢癌细胞中 LINC00092 的上调，其水平也与患者的预后不良相关。机制研究表明，LINC00092 结合了一种糖酵解酶，即果糖-2,6-二磷酸酶 PFKFB2，从而通过改变糖酵解和维持 CAFs 的局部支持功能来促进转移。总的来说，我们的研究揭示了 CXCL14 阳性 CAFs 和卵巢癌细胞代谢中的正反馈环，这对于转移进展至关重要。
