Department of Oral Medicine, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China.
Int J Mol Med. 2018 Feb;41(2):687-696. doi: 10.3892/ijmm.2017.3267. Epub 2017 Nov 17.
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.
间质-上皮细胞乳酸穿梭是支持快速生长的肿瘤细胞的必要过程，然而，其潜在机制尚不清楚。白细胞介素-1β（IL-1β）是口腔鳞状细胞癌（OSCC）间质和上皮细胞中的关键节点基因，可能参与这种代谢重编程。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在调节间质-上皮细胞乳酸穿梭中的作用。创建了原代成纤维细胞和 OSCC 细胞系（CAL27、UM1 或 SCC25）的共培养系统，以研究间质-上皮细胞的相互作用。测量了成纤维细胞的α-平滑肌肌动蛋白（α-SMA）表达、OSCC 细胞的 IL-1β表达和细胞增殖以及一系列糖酵解基因。还使用重组 IL-1β处理和 UM1 细胞中的 IL-1β敲低来评估 IL-1β的作用。在激活的成纤维细胞中，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 的表达显著过表达，而 OSCC 细胞中 IL-1β和 MCT1 上调，表明肿瘤基质细胞中的糖酵解增强和乳酸穿梭到肿瘤细胞。此外，外源性 IL-1β诱导成纤维细胞呈现与共培养系统相似的表达谱。IL-1β 沉默显著削弱了 UM1 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，在与成纤维细胞共培养期间，OSCC 细胞增殖加速。这些结果表明，肿瘤衍生的 IL-1β增强了基质糖酵解，并诱导单向乳酸从肿瘤间质流向转化的上皮细胞，从而促进 OSCC 增殖。
