Lin28b/Myc Loop Regulates Aerobic Glycolysis And Tumor Acidic Microenvironment To Promote Cancer Stemness And Cancer Progression

Abstract Substantial evidences have proven that targeting cancer addictive metabolism could suppress tumor progression. Tumor microenvironment (TME) supports the development of metabolic reprograming of tumor cells. The function of cancer stem cells (CSCs) closely related with its own metabolic alteration. However, the relationship between CSCs’ metabolic reprograming and their supportive TME, as well as underlying mechanism remains largely unknown. In this study, we have demonstrated a novel mechanism that the LIN28B/MYC positive regulation loop could promote the aerobic glycolysis of cancer cells and glycolysis-derived lactate and further enhance the cancer stemness to facilitate tumor progression. 1) Metabolic analysis revealed that glycolysis (ECAR) was suppressed after LIN28B was knocked down in MDA-MB-231 or H1299 cancer cells respectively. Consistently, both the glucose-uptake and lactate-secretion were attenuated in shLIN28B cancer cells. Importantly, either the glucose accumulation in cancer tissues or lactate secretion in serum was reduced in mouse injected with shLIN28B cancer cells. 2) Metabolic analysis revealed that CSCs possessed higher ECAR and higher level of LIN28B, MYC and HIF1a. Furthermore, glycolysis-derived lactate not only increase the proportion of ALDH+ cells, but also enhance the tumorsphere forming ability and mobility of cancer cells. 3) MicroRNAs screening analysis revealed that 6 miRNAs were up-regulated above 2 folds after LIN28B was knocked down in MDA-MB-231 cells. Metabolic analysis revealed that miR-34a-5p could suppress the aerobic glycolysis (ECAR) in MDA-MB-231 cells. 4) LIN28B inhibitor could reduce the expression of LIN28B and MYC in vitro and then suppressed tumor growth and metastasis in vivo. Taken together, our study demonstrated that LIN28B/MYC loop could sustain the aerobic glycolysis of cancer cells and then enhance the function of CSCs via regulating the tumor acid microenvironment, thus, established the LIN28B/MYC as a central node in connecting tumor metabolism and tumor microenvironment, and could serve as a therapeutical target. Citation Format: Chong Chen, Lipeng Bai, Fengqi Cao, shengnan wang, Yan Liu, Jian Guo, Qin Si, Rong Xiang, Yunping Luo. LIN28B/MYC loop regulates aerobic glycolysis and tumor acidic microenvironment to promote cancer stemness and cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3546. doi:10.1158/1538-7445.AM2017-3546