Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents

Zeekpudsa, Ponsilp; Kukongviriyapan, Veerapol; Senggunprai, Laddawan; Sripa, Banchob; Prawan, Auemduan

doi:10.1186/1756-9966-33-11

Cited by 49 publications

(53 citation statements)

References 25 publications

(44 reference statements)

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“…NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.5.2), one of the detoxifying enzymes with antioxidant properties, has been proposed to be associated with the chemotherapeutic response of CCA (5,8). NQO1 is generally recognized as a 'cell protector', its induction in response to various noxious stimuli provides protection for cells against oxidative damage and oxidative stress-associated pathological conditions including cancer (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…Upregulation of NQO1 during carcinogenesis may provide cancer cells with a growth advantage and protection against extreme oxidative stress environments (10,11). Considering the function of NQO1, an increased NQO1 expression level may be associated with disappointing outcomes to certain cancer treatment modalities, including chemotherapy and radiotherapy, which induces cancer cell death by the generation of free radicals and oxidative damage (5,8).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of NAD(P)H:quinone oxidoreductase 1 inhibits proliferation, cell cycle and migration of cholangiocarcinoma cells

et al. 2017

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Abstract. We previously reported that upregulation of NAD(P)H:quinone oxidoreductase 1 (NQO1) in cholangiocarcinoma (CCA; a fatal bile duct cancer) was associated with poor prognosis. It was also demonstrated that the suppression of NQO1 was able to enhance the chemosensitivity of CCA cells. In the present study, in order to elucidate the biological role of NQO1 in CCA, the effects of small interfering RNA (siRNA)-mediated knockdown of NQO1 on cell proliferation, cell cycle and migration were determined in KKU-100 CCA cells, which notably expressed NQO1. The cell proliferation ability and cell cycle distribution were identified by clonogenic cell survival assay and flow cytometric analysis, respectively. Wound healing and Transwell migration assays were performed to evaluate cell migration. The molecules involved in cell proliferation and migration were determined by western blot analysis and reverse transcription-quantitative polymerase chain reaction analysis. The results demonstrated that NQO1 siRNA-mediated knockdown effectively impaired colony formation capacity, induced cell cycle arrest at the G 1 phase and suppressed migration of KKU-100 cells. CCA cells transfected with NQO1 siRNA exhibited increased expression levels of p21 and decreased cyclin D1 protein expression levels. Furthermore, the ratio of matrix metalloproteinase 9/tissue inhibitors of metalloproteinases 1 (TIMP1) mRNA expression level was decreased in the NQO1-knockdown cells. Therefore, the present study provided evidence supporting the biological role of NQO1 in the regulation of cell proliferation, cell cycle and migration of CCA cells. Therefore, NQO1 may prove to be a potential molecular target to enhance CCA treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Downregulation of NAD(P)H:quinone oxidoreductase 1 inhibits proliferation, cell cycle and migration of cholangiocarcinoma cells

et al. 2017

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“…Cholangiocarcinoma is highly resistant to chemotherapy and NQO1 protein, NAD(P)H-quinone oxidoreductase 1, has been shown to play a cooperative role in cancer chemoresistance [64]. Recent data by Zeekpudsa et al [65] showed that NQO1 knock-down increased the response of CCA cells to the chemotherapeutic drugs 5-fluorouracil and gemcitabine. Altogether, these findings suggest a potential role for NQO1 in treatment of patients with CCA.…”

Section: Figurementioning

confidence: 99%

Integrative Analysis of Transcriptome and MicroRNome Profiles in Cholangiocarcinoma

Severino¹,

Hasimoto²,

Rodrigues³

et al. 2017

J Cancer Sci Ther

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Aim: To identify deregulated expression of miRNAs and target genes in cholangiocarcinoma (CCA), as well as drug-gene interactions that may be useful for patient treatment. Methods:We analyzed quantitative transcriptome and miRNA deep sequencing expression data from 45 samples, 36 CCA and 9 histologically normal biliary tissues, obtained from the public repository The Cancer Genome Atlas (TCGA). Bioinformatic methods were used to identify and integrate differential expression of miRNA and transcriptome profiles in CCA vs. normal tissues. Deregulated miRNA and corresponding target genes were identified and mapped into miRNA-mRNA networks. Results:Results showed 64 differentially expressed miRNAs (48 over and 16 under-expressed) between CCA and corresponding normal biliary tissues. Additionally, 432 genes (180 over and 252 under-expressed) were identified between CCA and normal samples. We identified individual miRNAs with the largest number of gene targets. Among these, miR-125a was over-expressed and had the highest number of direct interactions with 33 mRNA targets. miRNAs miR-122 and miR-139 were the under-expressed miRNAs with the highest number of interactions (9 targets each). miR-122 was found to modulate the expression of the transcription factor FOXM1, known to be involved in tumorigenesis and the matrix metalloproteinase MMP7, an important mediator of tumor invasion. miR-148 and miR-194 were predicted to modulate NQO1, which is up-regulated in cancer and associated with treatment resistance in cholangiocarcinoma. Conclusion:The novelty of our study is the identification of complex deregulated networks of miRNAs and target genes in CCA. miRNAs with a large number of targets may have a higher functional impact on cell regulation. These findings contribute for a better understanding of CCA biology. Identified miRNAs and target genes are potential candidates for the design of validation strategies towards the characterization of clinically applicable biomarkers; such biomarkers may be useful for the development of molecularly-targeted therapeutics that can benefit patients.

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“…A high expression of this antioxidant/detoxifying enzyme has been found in the aggressive C2 subtype of HB and is associated to significantly reduced survival compared to patients with lower expression of this gene [24]. NQO1 catalyzes the reduction of anthracyclines to less potent semiquinone radicals and it has been demonstrated that enhanced expression of NQO1 confers resistance to doxorubicin and other chemotherapeutic agents in cholangiocarcinoma cell lines [25]. Inactivating mutations have also been found in the thioredoxindomain containing genes TXNDC15 and TXNDC16, also involved in the regulation of mechanism involved in oxidative stress status [23].…”

Section: Mocmentioning

confidence: 99%

Hepatoblastoma Etiopathogenesis

RIR¹,

Armengol²,

JJG³

2016

J Carcinog Mutagene

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EditorialHepatoblastoma (HB) is the predominant form of pediatric liver cancer, usually arising in young children under 3 years of age [1], but it is a rare pediatric cancer with a very low worldwide incidence (<2 cases per million children under 18 years) [2]. Hepatocellular carcinoma (HCC) can also be diagnosed in children but with much lower incidence, usually found in the teenage population in association with predisposing conditions, such as the presence of underlying liver diseases (i.e., tyrosinemia and several cholestatic syndromes). As compared with HB, the prognostic of HCC is often poorer. A third type of primary liver cancer that appears at the late childhood and adolescence was initially called transitional liver cell tumor (TLCT), because it has a mixture of histological patterns characteristic of HB and HCC [3]. This cancer has been recently classified in a new provisional category named hepatocellular neoplasm not otherwise specified [4], awaiting for a better characterization, in an international symposium aiming to develop a consensus classification system for pediatric liver malignancies.Overall survival of patients with HB has notably improved from 30% in the 1970s to 70-80% nowadays thanks to the incorporation to the treatment of adjuvant and neoadjuvant chemotherapy using cisplatin and doxorubicin combined with efficient surgical approaches, including liver transplantation [5]. However, there are very limited treatment options for patients suffering from immature, invasive, and metastatic HB resistant to conventional first-line chemotherapeutic protocols, being the survival of these patients usually less than 3 years. The International Childhood Liver Tumor Strategy Group (SIOPEL) defined a prognostic stratification system of HB patients taking into consideration PRETEXT stage, metastatic disease, serum α-fetoprotein levels, multifocality, age and histology characterized by small undifferentiated cells [6]. Importantly, a recent study of the Children's Hepatic tumors International Collaboration (CHIC) group has confirmed these prognostic risk factors and identified new ones through a large-scale analysis using an extensive database including 1605 HB cases [7]. Patient stratification and treatment taking into account molecular biomarkers are the future challenges facing clinicians. High-throughput molecular studies of aggressive tumors highly refractory to anticancer drugs have the unique potential to provide a rational basis and new tools (biomarkers/molecular targets) for improving patient stratification and defining more specific and molecular-based therapies.Because HB is a rare tumor, most of the few existing studies have been carried out in small groups of patients, and this fact, together with the existence of several histologic subtypes without a clear consensus for their classification, has hindered advances in the characterization of different aspects of this liver cancer. Histologically, HB is usually composed of combinations of epithelial, mesenchymal, undifferentiated and other ...

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Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents

Cited by 49 publications

References 25 publications

Downregulation of NAD(P)H:quinone oxidoreductase 1 inhibits proliferation, cell cycle and migration of cholangiocarcinoma cells

Downregulation of NAD(P)H:quinone oxidoreductase 1 inhibits proliferation, cell cycle and migration of cholangiocarcinoma cells

Integrative Analysis of Transcriptome and MicroRNome Profiles in Cholangiocarcinoma

Hepatoblastoma Etiopathogenesis

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