A novel stromal lncRNA signature reprograms fibroblasts to promote the growth of oral squamous cell carcinoma via LncRNA-CAF/interleukin-33
A novel stromal lncRNA signature reprograms fibroblasts to promote the growth of oral squamous cell carcinoma via LncRNA-CAF/interleukin-33
复制标题
一种新型基质 lncRNA 特征通过 LncRNA-CAF/interleukin-33 重新编程成纤维细胞以促进口腔鳞状细胞癌的生长
DOI：
10.1093/carcin/bgy006
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发表时间：
2018-03-01
期刊：
影响因子：
4.7
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
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作者：
Ding, Liang;Ren, Jing;Hou, Yayi
间质癌相关成纤维细胞(CAF)是肿瘤微环境(TME)中主要的非免疫细胞。CAF与癌细胞相互作用，促进肿瘤增殖。长非编码RNA(Long Non-Coding RNAs，LncRNAs)调控肿瘤细胞的生长、凋亡和转移，但其在间质细胞中的作用尚不清楚。通过RNA测序，我们鉴定了口腔鳞状细胞癌(OSCC)中正常成纤维细胞(Nf)的CAF转化过程中的间质LncRNA特征。我们发现了一个未鉴定的lncRNA，Flj22447，它在CAF中显著上调，以下称为lncRNA-CAF(LNC-CAF)。IL-33主要定位于间质，并与LNC-CAF阳性共表达，上调成纤维细胞中CAF标志物(α-SMA、Vimentin和N-钙粘素)的表达。在共培养系统中，IL-33基因敲除会削弱LNC-CAF介导的间质成纤维细胞的激活，导致肿瘤细胞增殖减少。在机制上，LNC-CAF上调IL-33水平，并阻止依赖p62的自噬-溶酶体降解IL-33，这不依赖于lncRNA-蛋白支架的作用。自噬诱导剂雷帕霉素通过促进IL-33的降解而削弱LNC-CAF/IL-33的增殖作用。反过来，肿瘤细胞通过胞外体LNC-CAF进一步增加间质成纤维细胞中LNC-CAF的水平。在口腔鳞癌患者中，LNC-CAF/IL-33高表达与高TNM分期相关(n=140)。此外，LNC-CAF高表达预示预后不良。在体内，LNC-CAF基因敲除抑制了肿瘤的生长，并与Ki-67表达和α-SMA+CAF在间质中的表达降低有关。综上所述，我们发现了一个基质LncRNA信号，它通过LNC-CAF/IL-33将NFs重新编程为CAF，并促进OSCC的发展。
Stromal carcinoma-related fibroblasts (CAFs) are the main type of non-immune cells in the tumor microenvironment (TME). CAFs interact with cancer cells to promote tumor proliferation. Long non-coding RNAs (lncRNAs) are known to regulate cell growth, apoptosis and metastasis of cancer cells, but their role in stromal cells is unclear. Using RNA sequencing, we identified a stromal lncRNA signature during the transformation of CAFs from normal fibroblasts (NFs) in oral squamous cell carcinoma (OSCC). We uncovered an uncharacterized lncRNA, FLJ22447, which was remarkably up-regulated in CAFs, referred to LncRNA-CAF (Lnc-CAF) hereafter. Interleukin-33 (IL-33) was mainly located in the stroma and positively co-expressed with Lnc-CAF to elevate the expression of CAF markers (α-SMA, vimentin and N-cadherin) in fibroblasts. In a co-culture system, IL-33 knockdown impaired Lnc-CAF-mediated stromal fibroblast activation, leading to decreased proliferation of tumor cells. Mechanistically, Lnc-CAF up-regulated IL-33 levels and prevented p62-dependent autophagy-lysosome degradation of IL-33, which was independent of LncRNA-protein scaffold effects. Treatment with the autophagy inducer, rapamycin, impaired the proliferative effect of Lnc-CAF/IL-33 by promoting IL-33 degradation. In turn, tumor cells further increased Lnc-CAF levels in stromal fibroblasts via exosomal Lnc-CAF. In patients with OSCC, high Lnc-CAF/IL-33 expression correlated with high TNM stage (n = 140). Moreover, high Lnc-CAF expression predicted poor prognosis. In vivo, Lnc-CAF knockdown restricted tumor growth and was associated with decreased Ki-67 expression and α-SMA+ CAF in the stroma. In conclusion, we identified a stromal lncRNA signature, which reprograms NFs to CAFs via Lnc-CAF/IL-33 and promotes OSCC development.