Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells

Babar, Imran; Czochor, Jennifer R.; Steinmetz, Allison; Weidhaas, Joanne B.; Glazer, Peter M.; Slack, Frank J.

doi:10.4161/cbt.12.10.17681

Cited by 107 publications

(87 citation statements)

References 29 publications

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“…A recent piece of evidence suggests that the FoxO family is also regulated by microRNA. mir155, mir96 and mir21 are thought to directly regulate FoxO3a, while mir205 regulates FoxO3a via its upstream target PTEN [39][40][41][42][43] . FoxO3a is also known to be regulated by a transcription factor.…”

Section: Ubiquitin Proteasome Degradationmentioning

confidence: 99%

FoxO3a and disease progression

Nho

Hergert

2014

WJBC

139

108

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highlighted as a critical protein that regulates numerous cell functions from proliferation/apoptosis to stressresistance and aging. FoxO3a has been found to be deregulated in several diseases and FoxO3a targeting approaches are currently underway to treat various types of cancers. This review will describe the current concept of FoxO3a's pathological role in various diseases and elucidate the regulatory mechanisms involved. It will also provide the clinical significance and strategies to target FoxO3a to limit the progression of human diseases. INTRODUCTIONForkhead box O (FoxO) transcription factors are the human homologues of the C. elegans transcription factor DAF-16 and share a highly conserved 110-amino acid DNA binding domain, forkhead box or winged-helix domain [1,2] . Forkhead box proteins comprise more than 100 members in humans, classified from FOXA to FOXR [3][4][5] . Members of class O share the characteristic of being regulated by the insulin/PI3K/Akt signaling pathway [4] . Four principal members of the mammalian FoxO subfamily, FoxO1, FoxO3a, FoxO4 and FoxO6 have been previously described [3] . Although they seem to bind a common set of DNA sites, FoxO6 is mainly specific to neurons, while the other 3 FoxO family members are expressed in most tissues. These FoxO members are linked to cell survival, cellular proliferation and DNA damage repair response [5,6] . Among them, FoxO3a has recently been studied extensively as a crucial protein that is involved in the regulation of several essential cellular functions (see page 349). Prior studies have shown that FoxO3a functions as a tumor suppressor by regulating expression of genes in- AbstractThe Forkhead box O (FoxO) family has recently been highlighted as an important transcriptional regulator of crucial proteins associated with the many diverse functions of cells. So far, FoxO1, FoxO3a, FoxO4 and FoxO6 proteins have been identified in humans. Although each FoxO family member has its own role, unlike the other FoxO families, FoxO3a has been extensively studied because of its rather unique and pivotal regulation of cell proliferation, apoptosis, metabolism, stress management and longevity. FoxO3a alteration is closely linked to the progression of several types of cancers, fibrosis and other types of diseases. In this review, we will examine the function of FoxO3a in disease progression and also explore FoxO3a's regulatory mechanisms. We will also discuss FoxO3a as a potential target for the treatment of several types of disease.

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Section: Ubiquitin Proteasome Degradationmentioning

confidence: 99%

FoxO3a and disease progression

Nho

Hergert

2014

WJBC

139

108

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“…Therefore, the development of novel approaches is urgently required, in order to overcome the radioresistance of NSCLC and improve the survival rate of patients. A previous study reported that under hypoxic conditions, miR-155 expression was induced, leading to increased resistance of NSCLC cells to irradiation (14).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of microRNA-155 sensitizes lung cancer cells to irradiation via suppression of HK2-modulated glucose metabolism

Zhang

et al. 2016

Molecular Medicine Reports

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Abstract. MicroRNAs (miRNAs) are small non-coding regulatory RNAs, which are involved in the post-transcriptional regulation of gene expression. miRNA (miR)-155, which has previously been reported to be overexpressed in lung cancer, is correlated with poor patient prognosis. The present study aimed to investigate the effects of miR-155 on the radiosensitivity of human non-small cell lung cancer (NSCLC) cells. To explore the roles of miRNAs in the regulation of irradiation sensitivity of human lung cancer cells, the expressions of miR-155 in response to irradiation, have been studied by RT-qPCR, and the putative direct target of miR-155 was identified by western blot and luciferase assays. The results of the present study revealed that the expression of miR-155 was induced by irradiation, thus suggesting a positive correlation between miR-155 and radiosensitivity. Furthermore, overexpression of miR-155 rendered lung cancer cells resistant to irradiation. In addition, hexokinase 2 (HK2) was identified as an indirect target of miR-155; exogenous overexpression of miR-155 upregulated the expression of HK2, whereas inhibition of miR-155 by antisense miRNA suppressed HK2 expression. In addition, HK2-modulated glucose metabolism was significantly upregulated by overexpression of miR-155. Notably, inhibition of miR-155 sensitized lung cancer cells to irradiation via suppression of glucose metabolism. In conclusion, the present study reported a novel function for miR-155 in the regulation of NSCLC cell radiosensitivity, thus suggesting that miR-155 may be considered a therapeutic target for the development of anticancer drugs.

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“…10 In addition, hypoxic conditions induced miR-155 expression in lung cancer cells, and the inhibition of miR-155 by anti-miR-155 molecules enhanced cellular sensitivity to radiation therapy. 11 Therefore, there is evidence that miR-155 functions as an oncogenic microRNA in lung cancers, but information about the molecular mechanisms is still limited.…”

Section: Introductionmentioning

confidence: 99%

MiR-155 inhibits the sensitivity of lung cancer cells to cisplatin via negative regulation of Apaf-1 expression

Fang

et al. 2012

Cancer Gene Ther

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MicroRNA-155 (miR-155) overexpression is often found in malignancies including lung cancer. The objective of this study is to verify the hypothesis, based on the results of bioinformatics analysis, that miR-155 modulates cellular apoptosis and DNA damage through the regulation of Apaf-1 and is thus involved in the development and progression of lung cancer. First, we measured the expression of miR-155 and the Apaf-1 protein in lung cancer tissues. The results showed that expression of miR-155 was significantly higher in lung cancer tissues than in paracancerous and normal tissues; whereas Apaf-1 expression was lower in the lung cancerous tissues. We then established miR-155-silenced and Apaf-1-overexpressed A549 cell lines by transfection with pMAGic2.0-BIC-siRNA and pcDNA3.1-Apaf-1, respectively. These cell lines were then treated with cisplatin, and apoptosis and DNA damage were assessed, with non-transfected A549 cells used as negative controls. The results showed that, relative to controls, the silencing of miR-155 resulted in elevated expression of the Apaf-1 protein, whereas Apaf-1 mRNA levels remained unchanged. Both the silencing of miR-155 and the overexpression Apaf-1 greatly increased the sensitivity of A549 cells to cisplatin treatment, as evidenced by elevated rates of apoptosis and DNA damage. Furthermore, dual-transfection of A549 cells with miR-155 siRNA and Apaf-1 siRNA resulted in the attenuation of apoptosis and DNA damage. In conclusion, the inhibition of miR-155 can enhance the sensitivity of A549 cells to cisplatin treatment by modulation of cellular apoptosis and DNA damage through an Apaf-1-mediated pathway.

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Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells

Cited by 107 publications

References 29 publications

FoxO3a and disease progression

FoxO3a and disease progression

Inhibition of microRNA-155 sensitizes lung cancer cells to irradiation via suppression of HK2-modulated glucose metabolism

MiR-155 inhibits the sensitivity of lung cancer cells to cisplatin via negative regulation of Apaf-1 expression

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