MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells

Li, Zhimin; Hu, Sha; Wang, Jing; Cai, Jing; Xiao, Lan; Yu, Lili; Wang, Zehua

doi:10.1016/j.ygyno.2010.06.004

Cited by 171 publications

(120 citation statements)

References 33 publications

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“…33 Interestingly, bioinformatics software (mirWalk) 23 indicated HIPK2 to be a validated target of miR-27a as well as of miR-181a. Recent studies have demonstrated the capacity of miR-27a to modulate MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells, 18 highlighting a new player in hypoxia-mediated chemoresistance. HIPK2 is a tumor suppressor gene involved in the activation of p53 proapoptotic function, but it also acts as a co-repressor for many transcription factors, such as HIF1a.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15][16][17] We selected some miRNAs that recent literature and bioinformatics tools have highlighted to be involved in MDR1, HIF1A and HIPK2 gene modulation. Several studies have suggested the ability of miR-27a to modulate MDR1/P-gp expression [18][19][20] and the association of miR-181a deregulation with the modulation of HIPK2. 21 Moreover, emerging evidence documented miR-20b as a direct regulator of HIF1a expression.…”

Section: Introductionmentioning

confidence: 99%

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Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

Danza

Silvestris

Simone

et al. 2016

Cancer Biology & Therapy

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Despite the search for new therapeutic strategies for gastric cancer (GC), there is much evidence of progression due to resistance to chemotherapy. Multidrug resistance (MDR) is the ability of cancer cells to survive after exposure to chemotherapeutic agents. The involvement of miRNAs in the development of MDR has been well described but miRNAs able to modulate the sensitivity to chemotherapy by regulating hypoxia signaling pathways have not yet been fully addressed in GC. Our aim was to analyze miR-20b, miR-27a and miR-181a expression with respect to (epirubicin/oxaliplatin/capecitabine (EOX)) chemotherapy regimen in a set of GC patients, in order to investigate whether miRNAs deregulation may influence GC MDR also via hypoxia signaling modulation. Cancer biopsy were obtained from 21 untreated HER2 negative advanced GC patients, retrospectively analyzed. All patients received a first-line chemotherapy (EOX) regimen. MirWalk database was used to identify miR-27a, miR-181a and miR-20b target genes. The expression of miRNAs and of HIPK2, HIF1A and MDR1 genes were detected by real-time PCR. HIPK2 localization was assessed by immunohistochemistry. Our data showed the down-regulation of miR-20b, miR-27a, miR-181a concomitantly to higher levels of MDR1, HIF1A and HIPK2 genes in GC patients with a progressive disease respect to those with a disease control rate. Moreover, immunohistochemistry assay highlighted a higher cytoplasmic HIPK2 staining, suggesting a different role for it. We showed that aberrant expression of miR-20b, miR27a and miR-181a was associated with chemotherapeutic response in GC through HIF1A, MDR1 and HIPK2 genes modulation, suggesting a possible novel therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

Danza

Silvestris

Simone

et al. 2016

Cancer Biology & Therapy

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“…For instance, the expression levels of miR-27a were found to be increased in paclitaxel-resistant ovarian cancer cell line A2780/taxol when compared with its parental line A2780. Transfection of A2780/ taxol cells with inhibitors of miR-27a enhanced the sensitivity of A2780/taxol cells to paclitaxel and increased paclitaxelinduced apoptosis, which suggest that the deregulation of miR-27a may be involved in the development of drug resistance in ovarian cancer (67). miRNA expression profiles revealed that miR-27b is downregulated in most drug-resistant Ehrlich ascites tumor cells, suggesting this miRNA may be involved in drug resistance (68), even though no further results have been reported.…”

Section: Functional Prediction and Analysis Based On Protein/ Gene-prmentioning

confidence: 93%

Upregulation of NEK2 is associated with drug resistance in ovarian cancer

et al. 2013

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Abstract. NEK2 [NIMA (never in mitosis gene A)-related expressed kinase 2] is associated with various biological behaviors in the development of cancer, while research concerning its association with drug resistance is limited. The association of NEK2 with drug resistance in ovarian cancer has not yet been reported. In the present study, on the basis of microarray results from Oncomine and the GEO Profiles online database, we revealed that NEK2 mRNA expression in ovarian cancer tissues is upregulated. In addition, its expression in drugresistant ovarian cancer cells was upregulated when compared with expression with their sensitive or parental counterparts. Finally, we performed a comprehensive bioinformatic analysis consisting of protein/gene-protein/gene interaction network, annotation of biological processes and microRNA-mRNA interaction analysis. We observed that NEK2 directly or indirectly interacts with a number of genes, proteins, microRNAs and biological processes associated with drug resistance in ovarian and other types of cancer. These results indicate that NEK2 contributes to drug resistance in ovarian cancer and it may be an important therapeutic target.

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“…For example, it has been shown that miR-451 and miR-27a upregulation was P-gp dependent in cell lines representing ovarian cancer, leukemia and hepatocellular carcinoma [112,114,115] . In contrast, deregulation rather than upregulation of certain miRNAs, such as miR27a and miR 331-5p, can also cause drug resistance reversal and decreased P-gp expression, as seen in doxorubicin resistant leukemia cell lines K562 and HL60 [131][132][133] . Furthermore one study found a possible prognostic value for miR-296, whose expression can distinguish long-term survivors from short-term survivors, while its downregulation sensitized cells to known P-gp and BCRP substrates [134] .…”

Section: The Role Of Micrornas In P-gp Modulationmentioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells

Cited by 171 publications

References 33 publications

Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

Upregulation of NEK2 is associated with drug resistance in ovarian cancer

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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