NOX1 mediates chemoresistance via HIF1α/MDR1 pathway in gallbladder cancer

Zhan, Ming; Wang, Hui; Chen, Tao; Chen, Wei; Yang, Linhua; He, Min; Xu, Sunwang; Wang, Jian

doi:10.1016/j.bbrc.2015.10.161

Cited by 29 publications

(32 citation statements)

References 24 publications

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“…4, 5, 6 Several studies have implicated PKC family in regulating several chemotherapeutic-resistant protein such as P-gp and BCRP. In order to find out whether miR-218-5p is also capable of modulating these proteins, MDR1 , MRP1 , BCRP mRNA, and protein expression were analyzed in NOZ and GBC-SD cells transfected with miR-218-5p mimic or antisense by Q-PCR and western blot.…”

Section: Resultsmentioning

confidence: 99%

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miR-218-5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer

Wang

Zhan

et al. 2017

Cell Death Dis

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Gallbladder cancer (GBC) is one of the most common malignancy of the biliary tract characterized by its high chemoresistant tendency. Although great progresses have been made in recent decades for treating many cancers with anticancer drugs, effective therapeutics methods for anti-GBC are still lacking. Therefore, investigations into identifying the mechanisms underlying the drug resistance of GBC are greatly needed. In this study, we show that miR-218-5p plays a critical role in gemcitabine resistance of GBC. miR-218-5p levels were significantly lower in GBC than adjacent non-cancer tissues, and which were also associated with patient prognosis. While miR-218-5p overexpression abrogated gemcitabine resistance of GBC cells, silencing of which exhibited the opposite effects. Via six microRNA targets prediction algorithms, we found that PRKCE is a potential target of miR-218-5p. Moreover, miR-218-5p overexpression repressed the luciferase activity of reporter constructs containing 3′-UTR of PRKCE and also reduced PRKCE expression. Further studies revealed that miR-218-5p promotes sensitivity of gemcitabine by abolishing PRKCE-induced upregulation of MDR1/P-gp. Taken together, our results imply that an intimate correlation between miR-218-5p and PRKCE/MDR1 axis abnormal expression is a key determinant of gemcitabine tolerance, and suggest a novel miR-218-5p-based clinical intervention target for GBC patients.

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Section: Resultsmentioning

confidence: 99%

“…3 Although several potential targets and signaling pathways underlying GBC chemoresistance have been revealed, the precise mechanisms are still elusive. 4, 5, 6 Thus deeper unraveling the molecular mechanisms of drug resistance is of vital importance and urgently needed.…”

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confidence: 99%

miR-218-5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer

Wang

Zhan

et al. 2017

Cell Death Dis

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“…In essence, a particular tumour can be clinically recognized as MDR through the identification of a unique spectrum of dysregulated expression patterns of multiple mRNA biomarkers [29,30,31,32,33]. However, the discovery of the miRNA and long non-coding RNA (lncRNA) families have created additional layers of genomic regulatory functions [2,34,35,36,37,38,39].…”

Section: Cancer Chemoresistance Manifestations and Development Mecmentioning

confidence: 99%

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

Ayers

Vandesompele

2017

Genes

101

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Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology.

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“…This effect may be mediated by ROS, as NADPH oxidase I (NOX1), a generator of ROS, was found to be upregulated in cisplatin-resistant cell lines. Knockdown and overexpression of NOX1 caused subsequent decreases and increases in MDR-1 expression, respectively, and this effect was mediated through HIF-1 signaling [152]. In addition, a separate study by Syu et al suggests that Nrf2 is involved in drug transporter-mediated chemoresistance in hypoxia.…”

Section: Hypoxia and The Oxidative Stress Responsementioning

confidence: 99%

Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia

Toth

Warfel

2017

Antioxidants

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The importance of the tumor microenvironment for cancer progression and therapeutic resistance is an emerging focus of cancer biology. Hypoxia, or low oxygen, is a hallmark of solid tumors that promotes metastasis and represents a significant obstacle to successful cancer therapy. In response to hypoxia, cancer cells activate a transcriptional program that allows them to survive and thrive in this harsh microenvironment. Hypoxia-inducible factor 1 (HIF-1) is considered the main effector of the cellular response to hypoxia, stimulating the transcription of genes involved in promoting angiogenesis and altering cellular metabolism. However, growing evidence suggests that the cellular response to hypoxia is much more complex, involving coordinated signaling through stress response pathways. One key signaling molecule that is activated in response to hypoxia is nuclear factor, erythroid 2 like-2 (Nrf2). Nrf2 is a transcription factor that controls the expression of antioxidant-response genes, allowing the cell to regulate reactive oxygen species. Nrf2 is also activated in various cancer types due to genetic and epigenetic alterations, and is associated with poor survival and resistance to therapy. Emerging evidence suggests that coordinated signaling through Nrf2 and HIF-1 is critical for tumor survival and progression. In this review, we discuss the distinct and overlapping roles of HIF-1 and Nrf2 in the cellular response to hypoxia, with a focus on how targeting Nrf2 could provide novel chemotherapeutic modalities for treating solid tumors.

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NOX1 mediates chemoresistance via HIF1α/MDR1 pathway in gallbladder cancer

Cited by 29 publications

References 24 publications

miR-218-5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer

miR-218-5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia

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