Hypoxia decreases macrophage glycolysis and M1 percentage by targeting microRNA‐30c and mTOR in human gastric cancer

Abstract

Macrophages are essential inflammatory cells which regulate the features of immune reactions within tumors. Many studies have reported their regulatory roles in immunity through cytokines and cell signaling. However, relatively few studies have focused on their metabolic features and mechanisms. We aimed to determine the signaling pathway regulating cell metabolism and the mechanism related to the regulation of human tumor‐associated macrophages (TAMs) in gastric cancer (GC). Tumor‐infiltrated macrophages were isolated from human GC tissues using magnetic beads, gene transcription was determined by real‐time PCR, protein expression was monitored using western blots, metabolites were determined using HPLC, and transcriptional regulation was analyzed by the luciferase‐based reporter gene system. A significant decrease in microRNA (miR)‐30c and an increase in regulated in development and DNA damage responses 1 (REDD1) were detected in human GC TAMs, the transcription of miR‐30c was negatively correlated with REDD1. MicroRNA‐30c expression was suppressed by hypoxia‐inducible factor‐1α activation and related to decreased mTOR activity as well as glycolysis in human GC TAMs. Hypoxia‐regulated miR‐30c downregulated REDD‐1 expression by targeting its 3′UTR. Overexpression of miR‐30c or restored mTOR activity in macrophages with miR‐30cLow expression promoted M1 macrophage differentiation and function in TAMs. Therefore, hypoxia in the human GC microenvironment suppressed the expression of miR‐30c, and decreased mTOR activity as well as glycolysis in GC TAMs, thus inhibiting M1 differentiation and function. These results provide a novel metabolic strategy for tumor microenvironment‐based therapy.

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

“…M1-type macrophages can kill tumor cells in multiple ways, while M2-type macrophages promote the occurrence, invasion, and metastasis of the tumors. Zhihua et al [34] reported that the expression of microRNA (miRNA)-30c was significantly reduced in GC. Further studies showed that hypoxia-inducible factor-1α (HIF-1α) inhibited miRNA-30c expression.…”

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

“…To alleviate hypoxia, hyaluronic acid NPs targeted towards TAMs have been designed to increase O 2 production in the TME, showing inhibition of tumor growth and metastasis in 4T1 tumors [ 183 , 184 ]. Inactivation of HIF-1α by restoring miR-30c expression in macrophages showed antitumoral efficacy in gastric cancer [ 185 ]. In other reports, tumor oxygenation was improved by normalizing the tumor vasculature, through inhibition of VEGF or REDD1 in TAMs [ 186 ].…”

Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer

“…Animal and experimental studies have supported that TAM can provide a favorable microenvironment to promote tumor progression and metastasis 5,9 . In response to various microenvironment signals, macrophages can shift: M1‐like and M2‐like macrophages have distinct functional phenotypes, and while M1‐like macrophage is involved in the pro–inflammatory response, the M2‐like macrophage promotes the anti–inflammatory response 10‐12 . It is generally accepted that TAM display the M2‐polarized phenotype and are a critical player in the tumor microenvironment 5,13,14 …”