Stromal-epithelial lactate shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma

Wu,Jie; Hong,Yun; Wu,Tong; Wang,Juan; Chen,Xiaobing; Wang,Zhi; Cheng,Bin; Xia,Juan

doi:10.3892/ijmm.2017.3267

Stromal-epithelial lactate shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma

Authors:
- Jie Wu
- Yun Hong
- Tong Wu
- Juan Wang
- Xiaobing Chen
- Zhi Wang
- Bin Cheng
- Juan Xia
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Affiliations: Department of Oral Medicine, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
Published online on: November 17, 2017 https://doi.org/10.3892/ijmm.2017.3267
Pages: 687-696
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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