A novel miR-155/miR-143 cascade controls glycolysis by regulatinghexokinase 2in breast cancer cells

Abstract

Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is an anomalous characteristic of glucose metabolism in cancer cells. Chronic inflammation is a key promoting factor of tumourigenesis. It remains, however, largely unexplored whether and how pro-tumourigenic inflammation regulates glucose metabolism in cancer cells. Here, we show that pro-inflammatory cytokines promote glycolysis in breast cancer cells, and that the inflammation-induced miR-155 functions as an important mediator in this process. We further show that miR-155 acts to upregulate hexokinase 2 (hk2), through two distinct mechanisms. First, miR-155 promotes hk2 transcription by activation of signal transducer and activator of transcription 3 (STAT3), a transcriptional activator for hk2. Second, via targeting C/EBPb (a transcriptional activator for mir-143), miR-155 represses mir-143, a negative regulator of hk2, thus resulting in upregulation of hk2 expression at the post-transcriptional level. The miR-155-mediated hk2 upregulation also appears to operate in other types of cancer cells examined. We suggest that the miR-155/miR-143/HK2 axis may represent a common mechanism linking inflammation to the altered metabolism in cancer cells.

Coordinated regulation of synthesis and stability of RNA during the acute TNF-induced proinflammatory response

“…23 A and B) after a 1-h TNF treatment. miR155 and miR146 have been shown to be induced by NFkB during inflammation (27,28), and miR155 has been shown to suppress miR143 (29).…”

MicroRNA-155 broadly orchestrates inflammation-induced changes of microRNA expression in breast cancer

“…Given our previous finding that IL-6 and miR-155 repress mir-143 via targeting its transcriptional activator C/EBPβ in MDA-MB-231 cells [6], which also occurred in MCF-7 cells ( Figure 1A and Supplementary information, Figure S3A), we hypothesized that targeting C/EBPβ might be responsible for the miR-155-mediated repression of the other 4 miRNAs. To test this hypothesis, we searched the human P mir-376a , P mir-198 , P mir-98 and P mir-205 and found that, similar to P mir-143 , these 4 promot- Figure 1 miR-155 regulates miRNA expression in breast cancer cells by targeting ETS-1 and C/EBPβ.…”

“…miRNA-155 (miR-155) has been documented as one of the most prominent miRNAs linking inflammation to cancer [4]. On one hand, mir-155 is ubiquitously induced by inflammation stimuli [3]; on the other hand, miR-155 leads to the constitutive activation of pro-tumorigenic inflammatory STAT3 signaling by targeting socs1 [5] and conveys the inflammatory signals to the Warburg effect by upregulating hexokinase-2 [6]. We previously observed that pro-inflammatory cytokine interleukin-6 (IL-6)-induced miR-155 represses a specific miRNA gene mir-143 through targeting a transcription factor [6]; however, it is unclear how generally this mechanism might be utilized in the regulation of miRNAs by inflammation.…”

“…Given that miR-155 plays a well-evident role in linking inflammation and cancer [4], we asked whether miR-155, induced by IL-6 via NF-κB pathway in breast cancer cells [6], is involved in the regulation of miRNAs by IL-6. To this end, we used anti-miR-155 to inhibit miR-155 function in IL-6-treated MCF-7 cells (Supplementary information, Figure S1A).…”

“…On one hand, mir-155 is ubiquitously induced by inflammation stimuli [3]; on the other hand, miR-155 leads to the constitutive activation of pro-tumorigenic inflammatory STAT3 signaling by targeting socs1 [5] and conveys the inflammatory signals to the Warburg effect by upregulating hexokinase-2 [6]. We previously observed that pro-inflammatory cytokine interleukin-6 (IL-6)-induced miR-155 represses a specific miRNA gene mir-143 through targeting a transcription factor [6]; however, it is unclear how generally this mechanism might be utilized in the regulation of miRNAs by inflammation. In the present study, we show that miR-155 acts as a key regulating node linking inflammation to expression control of a number of cancer-related miRNAs, revealing a novel mechanism for the regulation of miRNAs by inflammation.…”