Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway.

Abstract:

BACKGROUND:The cisplatin-resistance is still a main course for chemotherapy failure of lung cancer patients. Cisplatin-resistant cancer cells own higher malignance and exhibited increased metastatic ability, but the mechanism is not clear. In this study, we investigated the effects of Ataxia Telangiectasia Mutated (ATM) on lung cancer metastasis. MATERIALS AND METHODS:Cisplatin-resistant A549CisR and H157CisR cell line were generated by long-term treating parental A549 and H157 cells (A549P and H157P) with cisplatin. Cell growth, cell migration and cell invasion were determined. Gene expressions were determined by Western Blot and qPCR. Tumor metastasis was investigated using a xenograft mouse model. RESULTS:The IC50 of the cisplatin-resistant cells (A549CisR and H157CisR cells) to cisplatin was 6-8 higher than parental cells. The A549CisR and H157CisR cells expressed lower level of E-cadherin and higher levels of N-cadherin, Vimentin and Snail compared to the parental A549P and H157P cells, and exhibited stronger capabilities of metastatic potential compared to the parental cells. The ATM expression was upregulated in A549CisR and H157CisR cells and cisplatin treatment also upregulated expression of ATM in parental cells, The inhibition of ATM by using specific ATM inhibitor CP466722 or knock-down ATM by siRNA suppressed Epithelial-to-Mesenchymal transition (EMT) and metastatic potential of A549CisR and H157CisR cells. These data suggest that ATM mediates the cisplatin-resistance in lung cancer cells. Expressions of JAK1,2,、 STAT3 、PD-L1 and ATM were increased in A549CisR and H157CisR cells and could by induced by cisplatin in parental lung cancer cells. Interestedly, ATM upregulated PD-L1 expression via JAK1,2/STAT3 pathway and inhibition of ATM decreased JAK/STAT3 signaling and decreased PD-L1 expression. The treatment of PD-L1 neutralizing Ab reduced EMT and cell invasion. Inhibition of JAK1,2/STAT3 signaling by specific inhibitors suppressed ATM-induced PD-L1 expression, EMT and cell invasion. Importantly, inhibition of ATM suppressed EMT and tumor metastasis in cisplatin-resistant lung cancer cells in an orthotopic xenograft mouse model. CONCLUSIONS:Our results show that ATM regulates PD-L1 expression through activation of JAK/STAT3 signaling in cisplatin-resistant cells. Overexpression of ATM contributes to cisplatin-resistance in lung cancer cells. Inhibition of ATM reversed EMT and inhibited cell invasion and tumor metastasis. Thus, ATM may be a potential target for the treatment of cisplatin-resistant lung cancer.

journal_name

J Exp Clin Cancer Res

authors

Shen M,Xu Z,Xu W,Jiang K,Zhang F,Ding Q,Xu Z,Chen Y

doi

10.1186/s13046-019-1161-8

subject

Has Abstract

pub_date

2019-04-08 00:00:00

pages

149

issue

1

eissn

0392-9078

issn

1756-9966

pii

10.1186/s13046-019-1161-8

journal_volume

38

pub_type

杂志文章
  • CDK4 IVS4-nt40 AA genotype and obesity-associated tumors/cancer in Italians - a case-control study.

    abstract:BACKGROUND:Cell cycle checkpoint regulation is crucial for prevention of tumor in mammalian cells. Cyclin-dependant kinase 4 (CDK4) is important in cell cycle regulation, as it controls the G1-S phase of the cell cycle. CDK4 has potential mitogenic properties through phosphorylation of target proteins. We aimed at iden...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/1756-9966-28-42

    authors: Meenakshisundaram R,Gragnoli C

    更新日期:2009-03-28 00:00:00

  • Oncolytic tanapoxvirus expressing FliC causes regression of human colorectal cancer xenografts in nude mice.

    abstract::Colorectal cancers are significant causes of morbidity and mortality and existing therapies often perform poorly for individuals afflicted with advanced disease. Oncolytic virotherapy is an emerging therapeutic modality with great promise for addressing this medical need. Herein we describe the in vivo testing of reco...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-015-0131-z

    authors: Conrad SJ,El-Aswad M,Kurban E,Jeng D,Tripp BC,Nutting C,Eversole R,Mackenzie C,Essani K

    更新日期:2015-02-19 00:00:00

  • ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis.

    abstract:BACKGROUND:The primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. The search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects; however, its role in GBM and the...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-015-0174-1

    authors: Qin LS,Jia PF,Zhang ZQ,Zhang SM

    更新日期:2015-05-30 00:00:00

  • Serum concentrations of proinflammatory cytokines in advanced non small cell lung cancer patients.

    abstract::To assess the relationship between serum concentrations of proinflammatory cytokines and prognosis of non small cell lung cancer (NSCLC), we evaluated the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1-beta) and interleukin-6 (IL-6) in 60 patients with untreated advanced NSCLC. Mean ...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: De Vita F,Orditura M,Auriemma A,Infusino S,Catalano G

    更新日期:1998-12-01 00:00:00

  • Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K/AKT signaling.

    abstract:BACKGROUND:Bone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Downexpression of miR-133a-3p has been found to contribute to the progression, recurrence and distant metastasis in PCa. However, clinical significance of miR-133a-3p in bone metastasis of PCa, and the biological...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-018-0813-4

    authors: Tang Y,Pan J,Huang S,Peng X,Zou X,Luo Y,Ren D,Zhang X,Li R,He P,Wa Q

    更新日期:2018-07-18 00:00:00

  • Physical interaction of STAT1 isoforms with TGF-β receptors leads to functional crosstalk between two signaling pathways in epithelial ovarian cancer.

    abstract:BACKGROUND:The signal transducer and activator of transcription (STAT) and transforming growth factor-β (TGF-β) signaling pathways play important roles in epithelial ovarian cancer (EOC). However, the mechanism of crosstalk between two pathways is not completely understood. METHODS:The expression of STAT1 protein was ...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-018-0773-8

    authors: Tian X,Guan W,Zhang L,Sun W,Zhou D,Lin Q,Ren W,Nadeem L,Xu G

    更新日期:2018-05-11 00:00:00

  • Treatment of MDS patients with recombinant human erythropoietin and the role of GSTs.

    abstract::Glutathione S-transferases (GSTs) are a group of enzymes involved in the detoxification process of carcinogens and other substances. The genes encoding isoenzymes M1 and T1 have "null" alleles, which are polymorphic in humans. Our purpose was to examine whether the GSTM1 and GSTT1 homozygous null genotypes have an imp...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Tsabouri SE,Georgiou I,Katsaraki A,Bourantas KL

    更新日期:2004-09-01 00:00:00

  • Expression of bone morphogenetic protein-2 and its receptors in epithelial ovarian cancer and their influence on the prognosis of ovarian cancer patients.

    abstract:BACKGROUND:To determine the expression of bone morphogenetic protein-2 (BMP-2) and its receptors BMPRIA, BMPRIB, and BMPRII in epithelial ovarian cancer (EOC) and to analyze their influence on the prognosis of ovarian cancer patients. METHODS:Semi-quantitative RT-PCR and western blot were applied to detect the express...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/1756-9966-29-85

    authors: Ma Y,Ma L,Guo Q,Zhang S

    更新日期:2010-06-30 00:00:00

  • Effect of bacterial metabolism in the intestine on colorectal tumors induced by 1,2-dimethylhydrazine in transgenic mice harboring human prototype c-Ha-ras genes.

    abstract::The number of colorectal tumors per mouse induced by 1,2-dimethylhydrazine in transgenic (Tg) mice carrying human c-Ha-ras genes was significantly reduced by ingestion of apple pectin (AP) or a culture condensate of Bifidobacterium longum(MB) compared with a control diet and non-Tg mice. However, there were no differe...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Ohno K,Narushima S,Takeuchi S,Itoh K,Itoh T,Hioki K,Nomura T

    更新日期:2001-03-01 00:00:00

  • Activity and toxicity of oxaliplatin and bolus fluorouracil plus leucovorin in pretreated colorectal cancer patients: a phase II study.

    abstract::The aim of the current study was to evaluate the activity and toxicity of a combination of oxaliplatin with bolus fluorouracil and leucovorin in colorectal cancer (CRC) patients pretreated for advanced disease with various schedules including continuous fluorouracil infusion. Thirty consecutive patients with pretreate...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 临床试验,杂志文章

    doi:

    authors: Ferraresi V,Giampaolo MA,Gabriele A,Mansueto G,Buccilli A,Giannarelli D,Ciccarese M,Gamucci T

    更新日期:2005-06-01 00:00:00

  • MicroRNA-144 inhibits the metastasis of gastric cancer by targeting MET expression.

    abstract::Gastric cancer (GC) remains one of the most common types of malignant cancer, and the molecular mechanism underlying its metastasis is still largely unclear. MicroRNAs have emerged as important regulators of metastasis because of their ability to act on multiple signaling pathways. In our study, we found that miR-144 ...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-015-0154-5

    authors: Liu J,Xue H,Zhang J,Suo T,Xiang Y,Zhang W,Ma J,Cai D,Gu X

    更新日期:2015-04-17 00:00:00

  • Gemcitabine sensitivity-related mRNA expression in endoscopic ultrasound-guided fine-needle aspiration biopsy of unresectable pancreatic cancer.

    abstract:BACKGROUND:The aim of this study was to determine a predictive indicator of gemcitabine (GEM) efficacy in unresectable pancreatic cancer using tissue obtained by endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA). METHODS:mRNAs extracted from 35 pancreatic tubular adenocarcinoma tissues obtained by E...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/1756-9966-28-83

    authors: Ashida R,Nakata B,Shigekawa M,Mizuno N,Sawaki A,Hirakawa K,Arakawa T,Yamao K

    更新日期:2009-06-16 00:00:00

  • Relevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy.

    abstract::Tumor-infiltrating immune cells play a key role against cancer. However, malignant cells are able to evade the immune response and establish a very complex balance in which different immune subtypes may drive tumor progression, metastatization and resistance to therapy. New immunotherapeutic approaches aim at restorin...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章,评审

    doi:10.1186/s13046-020-01586-y

    authors: Galli F,Aguilera JV,Palermo B,Markovic SN,Nisticò P,Signore A

    更新日期:2020-05-18 00:00:00

  • Formononetin inhibits tumor growth by suppression of EGFR-Akt-Mcl-1 axis in non-small cell lung cancer.

    abstract:BACKGROUND:Epidermal growth factor receptor (EGFR) activating mutations play crucial roles in the tumorigenesis of human non-small cell lung cancer (NSCLC). The mechanism regarding how EGFR signaling regulates myeloid cell leukemia sequence 1 (Mcl-1) protein stability and ubiquitination remains undefined. METHODS:MTS ...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-020-01566-2

    authors: Yu X,Gao F,Li W,Zhou L,Liu W,Li M

    更新日期:2020-04-10 00:00:00

  • Identification of novel hypermethylated genes and demethylating effect of vincristine in colorectal cancer.

    abstract:BACKGROUND:Colorectal cancer (CRC) arises as a consequence of genetic events such as gene mutation and epigenetic alteration. The aim of this study was to identify new hypermethylated candidate genes and methylation-based therapeutic targets using vincristine in CRC. METHODS:We analyzed the methylation status of 27,57...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/1756-9966-33-4

    authors: Moon JW,Lee SK,Lee JO,Kim N,Lee YW,Kim SJ,Kang HJ,Kim J,Kim HS,Park SH

    更新日期:2014-01-06 00:00:00

  • How to decrease false-positive cases of ovarian cancer screening by transvaginal sonography.

    abstract::Screening for ovarian cancer is an important step in improving ovarian cancer mortality. This is a report of screening for ovarian cancer using transvaginal sonography (TVS) on 2,095 asymptomatic women during the past four years. Ovarian tumors over 30 mm in diameter were detected in 87 women (4.2%). Fourteen tumors w...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Misawa T,Asai M,Higashide K

    更新日期:1997-06-01 00:00:00

  • Primary hepatic endocrinomas (carcinoids and variant neoplasms). A statistical evaluation of 126 reported cases.

    abstract::This study was undertaken to evaluate the statistical results of a large collected series of primary hepatic endocrinomas including carcinoids from extensive clinicopathologic aspect, and to provide the information to investigators engaged in this particular field of research. Primary hepatic endocrinomas variously te...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Soga J

    更新日期:2002-12-01 00:00:00

  • Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma.

    abstract:BACKGROUND:Hepatocellular carcinoma (HCC) is third leading cause of cancer-related death globally. Evidence suggest that long non-coding RNAs (lncRNAs) have emerged as key regulators of tumorigenesis and metastasis in HCC. In this study, we investigated the functional significance of SNHG12 and explored whether SNHG12 ...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-016-0486-9

    authors: Lan T,Ma W,Hong Z,Wu L,Chen X,Yuan Y

    更新日期:2017-01-10 00:00:00

  • Modulation of tumor induced angiogenesis in Ehrlich ascites tumor.

    abstract::In this study the enzyme glutaminase, purified from the ascites fluid of ovarian cancer patients, was analysed for its antiangiogenic activity. Intraperitoneal administration of this enzyme reduces the number of tumor directed capillaries in solid and ascites tumor bearing Swiss mice induced by transplantation of Ehrl...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Ghosh S,Roy S,Banerjee M,Maity P

    更新日期:2004-12-01 00:00:00

  • Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway.

    abstract:BACKGROUND:Infection with the hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC). The osmoregulatory transcription factor nuclear factor of activated T-cells 5 (NFAT5) has been shown to play an important role in the development of many types of human cancers. The role o...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-017-0618-x

    authors: Qin X,Li C,Guo T,Chen J,Wang HT,Wang YT,Xiao YS,Li J,Liu P,Liu ZS,Liu QY

    更新日期:2017-10-19 00:00:00

  • Retraction Note: Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma.

    abstract::An amendment to this paper has been published and can be accessed via the original article. ...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章,撤回出版物

    doi:10.1186/s13046-020-01668-x

    authors: Li Z,Zhang L,Gao M,Han M,Liu K,Zhang Z,Gong Z,Xing L,Shi X,Lu K,Gao H

    更新日期:2020-08-19 00:00:00

  • Grafting of stomach tissue into the duodenum in F344 rats results in chimeric crypts and tumor development.

    abstract::Gastric tissue was transplanted from the fundic and pyloric mucosa of 8-week old female F344 rats into the duodenum of males. Autopsy, 12 months after the operation, revealed grafts associated with persistent stones in the duodenum and/or calcification in the tissue. Pepsinogen positive chimeric glands with goblet cel...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Watanabe H,Ando Y,Uesaka T,Ishimura Y,Shiraki K,Lu H,Ohara M,Shoji S,Katoh O

    更新日期:2000-06-01 00:00:00

  • Whole brain radiotherapy with radiosensitizer for brain metastases.

    abstract:PURPOSE:To study the efficacy of whole brain radiotherapy (WBRT) with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment. METHODS:A meta-analysis of randomized controlled trials (RCT)...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章,meta分析

    doi:10.1186/1756-9966-28-1

    authors: Viani GA,Manta GB,Fonseca EC,De Fendi LI,Afonso SL,Stefano EJ

    更新日期:2009-01-06 00:00:00

  • Attenuation of TGFBR2 expression and tumour progression in prostate cancer involve diverse hypoxia-regulated pathways.

    abstract:BACKGROUND:Dysregulation of transforming growth factor β (TGF-β) signaling and hypoxic microenvironment have respectively been reported to be involved in disease progression in malignancies of prostate. Emerging evidence indicates that downregulation of TGFBR2, a pivotal regulator of TGF-β signaling, may contribute to ...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-018-0764-9

    authors: Zhou H,Wu G,Ma X,Xiao J,Yu G,Yang C,Xu N,Zhang B,Zhou J,Ye Z,Wang Z

    更新日期:2018-04-27 00:00:00

  • Multinucleation followed by an acytokinetic cell division in myxofibrosarcoma with giant cell proliferation.

    abstract:BACKGROUND:Multinucleated cells are frequently seen in association with a malignant neoplasm. Some of these multinucleated cells are considered to be neoplastic. The mechanism of neoplastic multinucleation remains unknown, but is considered to be induced by either cell-cell fusion or acytokinetic cell division. Myxofib...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/1756-9966-28-44

    authors: Ariizumi T,Ogose A,Kawashima H,Hotta T,Umezu H,Endo N

    更新日期:2009-03-31 00:00:00

  • Mucin 17 inhibits the progression of human gastric cancer by limiting inflammatory responses through a MYH9-p53-RhoA regulatory feedback loop.

    abstract:BACKGROUND:Mucins are key components of the mucosal barrier in the stomach that protects epithelia from carcinogenic effects of chronic inflammation. Analysis of The Cancer Genome Atlas database indicated that mucin-17 (MUC17) was more highly expressed in gastric cancer (GC) specimens, with favourable prognosis for pat...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/s13046-019-1279-8

    authors: Yang B,Wu A,Hu Y,Tao C,Wang JM,Lu Y,Xing R

    更新日期:2019-07-01 00:00:00

  • FGFs/FGFRs-dependent signalling in regulation of steroid hormone receptors - implications for therapy of luminal breast cancer.

    abstract::Stromal stimuli mediated by growth factor receptors, leading to ligand-independent activation of steroid hormone receptors, have long been implicated in development of breast cancer resistance to endocrine therapy. Mutations in fibroblast growth factor receptor (FGFR) genes have been associated with a higher incidence...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章,评审

    doi:10.1186/s13046-019-1236-6

    authors: Piasecka D,Braun M,Kitowska K,Mieczkowski K,Kordek R,Sadej R,Romanska H

    更新日期:2019-05-29 00:00:00

  • Toxicity and morbility after isolated lower limb perfusion in 242 chemo-hyperthermal treatments for cutaneous melanoma: the experience of the Tuscan Reference Centre.

    abstract:BACKGROUND:The aim of this retrospective study was to assess the results concerning the regional and systemic toxicity and complications in 242 chemo-hyperthermal treatments (HILPs) for lower limb melanoma. PATIENTS AND METHODS:60 HILPs (G-A) were performed with mild HT plus L-PAM (10 mg/lt) +/- D-actimomycin; 74 HILP...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:10.1186/1756-9966-27-67

    authors: Pace M,Gattai R,Matteini M,Mascitelli EM,Bechi P

    更新日期:2008-11-12 00:00:00

  • Turcot syndrome: case report and nosological aspects.

    abstract::The Turcot syndrome has been defined as the simultaneous presence of multiple polyposis of the colon and a malignant brain tumor. This association is supposed to be genetically transmitted, even though we still do not exactly know whether this occurs in a dominant or recessive way. The case of a 47-year-old man submit...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Fracasso P,Caviglia R,Grassi A,Lapenta R,Stigliano V,Franco D,Casale V

    更新日期:1997-12-01 00:00:00

  • The late effects of proton irradiation on cell growth, cell cycle arrest and apoptosis in a human melanoma cell line.

    abstract::The aim of this work is the in vitro study of the late effects of single proton irradiation on HTB63 human melanoma cell growth, cell cycle and cell death. The experimental conditions were focused on analyzing the effects of irradiation on the periphery of tumour that can be, in clinical practice, close to critical or...

    journal_title:Journal of experimental & clinical cancer research : CR

    pub_type: 杂志文章

    doi:

    authors: Ristic-Fira A,Nikolic D,Petrovic I,Ruzdijic S,Raffaele L,Sabini MG,Cirrone GA,Cuttone G,Farruggia G,Masotti L,Kanazir DT

    更新日期:2001-03-01 00:00:00