miR-138-1* regulates aflatoxin B1-induced malignant transformation of BEAS-2B cells by targeting PDK1

Wang, Yun; Zhang, Zhan; Wang, Huanqiang; Zhang, Yudong; Ji, Minghui; Xu, Hengsen; Wang, Chao; Sun, Zhenzhen; Gao, Weimin; Wang, Shoulin

doi:10.1007/s00204-015-1551-4

Cited by 36 publications

(23 citation statements)

References 44 publications

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“…Transwell assay was performed using cell culture inserts of 6.5 mm diameter (Corning incorporated, New York, USA) as described previously (Wang et al , 2016). Briefly, the 8-μm pore size filters were coated with 100 μL of 1 mg/mL Matrigel (BD Biosciences, San Jose, CA) at 4 °C and the Matrigel layers were solidified at 37 °C for 1 hr.…”

Section: Methodsmentioning

confidence: 99%

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Liu

Gao

2017

Toxicology and Applied Pharmacology

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has demonstrated dramatic clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of acquired drug resistance. The aim of this study was to explore the potential utility of chromosome region maintenance 1 (CRM1) inhibitor leptomycin B (LMB) in combination with gefitinib to overcome primary and acquired gefitinib resistance in NSCLC cells. The combinative effects of gefitinib and LMB were evaluated by MTT and its underlining mechanism was assessed by flow cytometry and Western blot. LMB displayed a synergistic effect on gefitinib- induced cytotoxicity in A549 (IC50: 25.0±2.1 μM of gefitinib+LMB vs. 32.0±2.5 μM of gefitinib alone, p<0.05). Gefitinib+LMB caused a significantly different cell cycle distribution and signaling pathways involving in EGFR/survivin/p21 compared with gefitinib. A549 cells then were treated with progressively increasing concentrations of gefitinib (A549GR) or in combination with LMB (A549GLR) over 10 months to generate gefitinib resistance. IC50 of gefitinib in A549GLR (37.0±2.8 μM) was significantly lower than that in A549GR (53.0±3.0 μM, p<0.05), which indicates that LMB could reverse gefitinib-induced resistance in A549. Further mechanism investigation revealed that the expression patterns of EGFR pathway and epithelial- mesenchymal transition (EMT) markers in A549, A549GR, and A549GLR were significantly different. In conclusion, LMB at a very low concentration combined with gefitinib showed synergistic therapeutic effects and ameliorated the development of gefitinib- induced resistance in lung cancer cells.

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Section: Methodsmentioning

confidence: 99%

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Liu

Gao

2017

Toxicology and Applied Pharmacology

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“…Zhu et al found that upregulation of miR-34a might suppress the Wnt/βcatenin signaling pathway in HepG2 cells anticipated by AFB1 [110]. Another functional studies revealed that miR-138-1* inhibited proliferation, colony formation, migration, and invasion of P50 B-2A13 cells and might affect AFB1-induced malignant transformation through targeting PDK1 [111].…”

Section: The Metabolism and Toxic Mechanism Of Afb1mentioning

confidence: 99%

The Toxic Effects of Aflatoxin B1: An Update

Shan¹

2020

Aflatoxin B1 Occurrence, Detection and Toxicological Effects

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Aflatoxin B1 (AFB1) is the most toxic in aflatoxin family. It is well known for its involvement in hepatic carcinogenesis. Other adverse effects include immune weakness, reproduction deficiency, malnutrition, and growth impairment. The key mechanism of AFB1 carcinogenesis is supposed to be epoxidation, which produce the AFB1-8,9-epoxide (AFBO) strongly adductive to DNA molecules. Other metabolites like AFM1, AFH1, and AFL, which retain DNA adductive capability, extend its toxicity. Scientists now found that AFB1 also affected epigenetic regulation, which might shed new light into AFB1 toxicity mechanism researches. The detoxification of AFB1 has always been a hot spot in AFB1-related studies. The major methods can be categorized into physical treatment, biological treatment, chemical treatment, combination strategy, and sorbent additives. None of the methods is 100% perfect, however considering economic factors, simplicity, effectiveness, safety, and preservation of the food nutrition. This review will discuss the toxicity and toxic mechanisms of AFB1. Also, detoxification of AFB1 will be reviewed.2 as in the 1970s, its hepatocarcinogenic property has been testified in animal models [5], and there since, several epidemiological studies from Asia and Africa areas monitored intersection of high HCC incidence and AFB1 contamination, with 4.6-28.2% of HCC cases globally attributed to AFB1 exposure [6]. Moreover, hepatitis B virus (HBV) that cooperates with AFB1 can drastically increase the risk of HCC by 30-fold [7]. Recent researches also find evidences that hepatitis C virus (HCV) also has a synergistic role with AFB1 in hepatocarcinogenesis. Jeannot et al. found that the incidence of tumorous or pretumorous lesions was elevated by 2.5-fold in AFB1-treated HCV transgenic mice compared with wild-type mice [8]. Recently, a 20-year clinical follow-up study in Taiwan investigated HCC risk associated with AFB1 exposure in HCV-positive and HBV-HCV-negative individuals. HCV and AFB1 exposure were both found as independent risk factors for HCC development. Elevated serum AFB1albumin adduct levels were significantly associated with an increased risk of HCC newly developed within 8 years of follow-up in non-HBV-non-HCV participants with habitual alcohol consumption [crude OR (95% CI) for high vs. low/undetectable levels, 4.22 (1.16-15.37)], and HCV-infected participants [3.39 (1.31-8.77)], but not in non-HBV-non-HCV participants without alcohol drinking habit. Therefore, it indicated that AFB1 exposure contributes to the development of HCC in participants with significant risk factors for cirrhosis including alcohol and HCV infection [9]. What's more, AFB1 exposure can induce the increased levels of blood glucose in mice and, also, the high probability to develop liver cancer [10].Liver is not the only target organ of AFB1 toxification. Its impairment on the immune system has been established in both humans and animals. Several studies linked AFB1 exposure with reduced levels or functions of immunological factors, such as de...

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“…Among HCC tumor cells associated with AFB1 exposure, upregulation of several miRNAs, such as miR-429 and miR-24 [86], are associated with larger tumor size [83]. In human bronchial epithelial cells that express CYP2A13 (P50-B-2a13 CELLS), AFB1 exposure induces malignant transformation of immortalized cells [89]. Among transformed cells, one downregulated miRNA was miR-138-1, observed to inhibit proliferation, colony formation, and transformation of P50-B-2a13 CELLS [89].…”

Section: Epigenetic Changes Associated With Afb1-associated Damagementioning

confidence: 99%

Cellular Responses to Aflatoxin-Associated DNA Adducts

Fasullo¹

2019

DNA Repair- An Update

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Aflatoxin B1 (AFB1) is the most potent known hepatocarcinogen. The signature p53 mutation (p53 249 ser) that is found in AFB1-associated liver cancer suggests that AFB1 is a potent genotoxin. AFB1 is not genotoxic per se but is metabolically activated by cytochrome P450 enzymes that convert the promutagen into a highly reactive epoxide, which primarily reacts with the N 7 group of guanine, forming 8,9-dihydro-8-(N 7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N 7-dG). While this primary adduct is unstable, the subsequent trans-8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxy aflatoxin B1 (AFB1-Fapy)derived adducts are stable and are mutagenic. Studies have revealed that nucleotide excision repair (NER), base excision repair (BER), recombinational repair, and DNA replication bypass are all involved in conferring AFB1 resistance. To minimize the genotoxicity of AFB1, pathways function to detoxify the metabolically active intermediate, excise resulting DNA adducts, bypass unrepaired adducts, and repair secondary DNA breaks. How these repair pathways functionally cooperate to minimize AFB1-associated genetic instability phenotypes is not well understood. Insights can be gained from epidemiological research and model organisms. Gene profiling and next-generation sequencing are facilitating how pathways and tissuespecific differences are induced. This review will encompass studies concerning human genetic susceptibility to AFB1 and pathways that repair and tolerate AFB1associated DNA damage.

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miR-138-1* regulates aflatoxin B1-induced malignant transformation of BEAS-2B cells by targeting PDK1

Cited by 36 publications

References 44 publications

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

The Toxic Effects of Aflatoxin B1: An Update

Cellular Responses to Aflatoxin-Associated DNA Adducts

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