The miR-125a/HK2 axis regulates cancer cell energy metabolism reprogramming in hepatocellular carcinoma

Jin, Fangfang; Li, Han; Zhu, Yanan; Li, Shan; Liu, Ying; Chen, Cheng; Wang, Xiaohua; Zen, Ke; Liu, Limin

doi:10.1038/s41598-017-03407-3

Cited by 59 publications

(47 citation statements)

References 48 publications

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“…Other evidences also favored that imatinib resistance was associated with overexpression of the MDR1 gene in tumor cells [143,144]. Consistently, miR-125a/HK2 axis was found to regulate the energy metabolism of hepatocellular carcinoma or squamous cell carcinoma [146,147]. Consistently, miR-125a/HK2 axis was found to regulate the energy metabolism of hepatocellular carcinoma or squamous cell carcinoma [146,147].…”

Section: Osteosarcoma and Myeloid Leukemiamentioning

confidence: 69%

“…In addition, UCA1 also conferred the resistance of adriamycin, a chemotherapy drug used for the treatment of AML, by sponging the miR-125a targeting HK2 to promote glycolysis [145]. Consistently, miR-125a/HK2 axis was found to regulate the energy metabolism of hepatocellular carcinoma or squamous cell carcinoma [146,147].…”

Section: Osteosarcoma and Myeloid Leukemiamentioning

confidence: 91%

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Crosstalk between the lncRNA UCA1 and microRNAs in cancer

Xuan

Zhang

et al. 2019

FEBS Letters

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Long non-coding RNAs (lncRNAs) are a major subset of highly conserved non-coding RNAs (ncRNAs) that consist of at least 200 nucleotides and have limited protein-coding potential. Cumulative data have shown that lncRNAs are deregulated in many types of cancer and may control pathophysiological processes of cancer at various levels, including transcription, post-transcription and translation. Recently, lncRNAs have been demonstrated to interact with microRNAs (miRNAs), another major subset of ncRNAs, which regulate physiological and pathological processes by inhibiting target mRNA translation or promoting mRNA degradation. The lncRNA urothelial carcinomaassociated 1 (UCA1) has recently gained much attention as it is overexpressed in many types of cancer and is involved in carcinogenesis. Here, we review the crosstalk between UCA1 and miRNAs during the pathogenesis of cancer, with a focus on cancer-cell proliferation, invasion, drug resistance, and metabolism.

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Section: Osteosarcoma and Myeloid Leukemiamentioning

confidence: 69%

Section: Osteosarcoma and Myeloid Leukemiamentioning

confidence: 91%

Crosstalk between the lncRNA UCA1 and microRNAs in cancer

Xuan

Zhang

et al. 2019

FEBS Letters

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“…49 HK2 has been previously identified as a target of miR-125a in laryngeal squamous cell carcinoma 50 and hepatocellular carcinoma. 51 Rescue experiments demonstrated that UCA1 overexpression overturned miR-125-mediated inhibition on HIF-1α-dependent glycolysis in HL60 and HL60/ADR cells. Collectively, these results demonstrated that knockdown of UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the miR-125a/HK2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of LncRNA‐UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA‐125a/hexokinase 2 pathway

Zhang

Liu

2018

J of Cellular Biochemistry

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Dysregulation of lncRNAs is implicated in chemoresistance in varieties of tumor including acute myeloid leukemia (AML). LncRNA urothelial carcinoma-associated 1 (UCA1) was reported to play an oncogenic role in AML. However, whether UCA1 was involved in chemoresistance in pediatric AML remains unclear. UCA1 expression in AML patients after adriamycin (ADR)-based chemotherapy and ADR-resistant AML cells was examined by qRT-PCR. The effects of UCA1 on the cytotoxicity of ADR and glycolysis were evaluated by MTT assay and measuring the glucose consumption and lactate production in HL60 and HL60/ADR cells, repectively. The protein levels of hypoxia-inducible factor 1α (HIF-1α) and hexokinase 2 (HK2) were determined by Western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the relationships between UCA1, HK2, and miR-125a. We found that UCA1 expression was upregulated following ADR-based chemotherapy. Knockdown of UCA1 increased the cytotoxic effect of ADR and inhibited HIF-1α-dependent glycolysis in ADR-resistant AML cells. Additionally, UCA1 functioned as a ceRNA of miR-125a by directly binding to miR-125a. HK2, a target of miR-125a, was positively regulated by UCA1 in HL60 and HL60/ADR cells. More notably, UCA1 overexpression overturned miR-125-mediated inhibition on HIF-1α-dependent glycolysis in HL60 and HL60/ADR cells. Furthermore, 2-deoxy-glucose (2-DG) exposure inhibited HIF-1α-dependent glycolysis, and attenuated UCA1-induced increase of chemoresistance in HL60 and HL60/ADR cells. We conclude that knockdown of UCA1 plays a positive role in overcoming the chemoresistance of pediatric AML, through suppressing glycolysis by the miR-125a/HK2 pathway, contributing to a better understanding of the molecular mechanism of chemoresistance in AML.

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“…Finally, miR‐125‐a, known to be involved in macrophage differential activation through downregulation of TNF‐α‐induced protein 3 (TNFAIP3) (Graff, Dickson, Clay, McCaffrey, & Wilson, ) and of the inflammatory transcription factor Kruppel‐like factor 13 (KLF13) (Banerjee, Cui, et al, ), has been recently found to be upregulated in reactive microglia and in extracellular vesicles (EVs) thereof (Prada et al, ). Few glycolytic enzymes, including enolase‐1 (ENO‐1), HK2 (F. Jin et al, ; C. M. Sun, Wu, Zhang, Shi, & Chen, ) and phosphofructokinase (PFK1) are miR‐125‐a validated targets (Table 1). Consistently, miR‐125‐a decreases the uptake of glucose and the production of lactate, and the levels of ATP and ROS in other cell types (F. Jin et al, ).…”

Section: Micrornas Promoting Pro‐regenerative Microglia Phenotype Andmentioning

confidence: 99%

“…Few glycolytic enzymes, including enolase‐1 (ENO‐1), HK2 (F. Jin et al, ; C. M. Sun, Wu, Zhang, Shi, & Chen, ) and phosphofructokinase (PFK1) are miR‐125‐a validated targets (Table 1). Consistently, miR‐125‐a decreases the uptake of glucose and the production of lactate, and the levels of ATP and ROS in other cell types (F. Jin et al, ). Whether the miRNA suppresses glycolysis in microglia remains to be proven.…”

Section: Micrornas Promoting Pro‐regenerative Microglia Phenotype Andmentioning

confidence: 99%

How to reprogram microglia toward beneficial functions

Fumagalli

Lombardi

Gressèns

et al. 2018

Glia

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Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

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The miR-125a/HK2 axis regulates cancer cell energy metabolism reprogramming in hepatocellular carcinoma

Cited by 59 publications

References 48 publications

Crosstalk between the lncRNA UCA1 and microRNAs in cancer

Crosstalk between the lncRNA UCA1 and microRNAs in cancer

Knockdown of LncRNA‐UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA‐125a/hexokinase 2 pathway

How to reprogram microglia toward beneficial functions

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