Stromal-epithelial lactate shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma.
Stromal-epithelial lactate shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma.
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肿瘤衍生的白细胞介素1β诱导的基质-上皮乳酸穿梭促进口腔鳞状细胞癌的细胞增殖。
DOI：
10.3892/ijmm.2017.3267
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发表时间：
2018-03
影响因子：
5.4
通讯作者：
Xia J
中科院分区：
文献类型：
--
作者：
Wu J;Hong Y;Wu T;Wang J;Chen X;Wang Z;Cheng B;Xia J
基质-上皮乳酸穿梭是支持肿瘤细胞快速生长的重要过程，但其机制尚不清楚。白细胞介素-1 β（IL-1β）是口腔鳞状细胞癌（OSCC）间质细胞和上皮细胞中的关键节点基因，可能参与了这种代谢重编程。在本研究中，评估了癌症相关成纤维细胞（CAFs）的无氧糖酵解，并确定了IL-1β在调节基质-上皮乳酸穿梭中的作用。建立了原代成纤维细胞和OSCC细胞系（CAL 27，UM 1或SCC 25）的共培养系统，以研究基质-上皮相互作用。检测成纤维细胞α-平滑肌肌动蛋白（α-SMA）的表达、口腔鳞癌细胞IL-1β的表达和细胞增殖，以及一系列糖酵解相关基因的表达。重组IL-1β处理和IL-1β在UM 1细胞中的敲低也用于评估IL-1β的作用。α-SMA、葡萄糖转运蛋白1、己糖激酶2、乳酸脱氢酶和单羧酸转运蛋白（MCT）4在活化的成纤维细胞中显著过表达，而IL-1β和MCT 1在OSCC细胞中上调，表明肿瘤基质细胞中糖酵解增强，乳酸穿梭至肿瘤细胞。此外，外源性IL-1β诱导成纤维细胞呈现与共培养系统中相似的表达谱。IL-1β的沉默显著消除了UM 1细胞对基质糖酵解的调节作用。此外，羧基荧光素琥珀酰亚胺酯细胞示踪表明，OSCC细胞增殖加速与成纤维细胞共培养。这些结果表明，肿瘤来源的IL-1β增强了基质糖酵解，并诱导了从肿瘤间质到转化上皮的单向乳酸流动，这促进了OSCC增殖。
Stromal-epithelial lactate shuttle is an essential process to support fast-growing tumor cells, however, the underlying mechanism remains ambiguous. Interleukin-1β (IL-1β), which is a key node gene in both stromal and epithelial cells of oral squamous cell carcinoma (OSCC), may participate in this metabolic reprogramming. In the present study, anaerobic glycolysis of cancer-associated fibroblasts (CAFs) was evaluated and the role of IL-1β in regulating stromal-epithelial lactate shuttle was determined. A co-culture system of primary fibroblasts and OSCC cell lines (CAL27, UM1 or SCC25) was created to investigate the stromal-epithelial interaction. α-smooth muscle actin (α-SMA) expression of fibroblasts, IL-1β expression and cell proliferation of OSCC cells, and a series of glycolytic genes were measured. Recombinant IL-1β treatment and IL-1β knockdown in UM1 cells were also used to evaluate the effect of IL-1β. Expression of α-SMA, glucose transporter 1, hexokinase 2, lactic dehydrogenase and mono-carboxylate transporter (MCT) 4 were significantly overexpressed in activated fibroblasts, while IL-1β and MCT1 were upregulated in OSCC cells, indicating enhanced glycolysis in cells of the tumor stroma and a lactate shuttle to the tumor cells. Furthermore, exogenous IL-1β induced fibroblasts to present similar expression profiles as that in the co-culture system. Silencing of IL-1β significantly abrogated the regulatory effect of UM1 cells on stromal glycolysis. Additionally, carboxy-fluorescein succinimidyl ester cell tracing indicated that OSCC cell proliferation was accelerated during co-cultivation with fibroblasts. These results indicate that tumor-derived IL-1β enhanced stromal glycolysis and induced one-way lactate flow from the tumor mesenchyme to transformed epithelium, which promotes OSCC proliferation.
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