Downregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression.

Abstract:

:Kelch‑like ECH‑associated protein 1 (Keap1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling has a protective effect on normal cells. A number of previous studies demonstrated that Keap1/Nrf2 signaling is associated with drug resistance in numerous tumors. The aim of the present study was to investigate the roles of Keap1 in renal cell carcinoma (RCC) and its effect on sensitivity to chemotherapy. Reverse transcription‑quantitative polymerase chain reaction was used to detect the mRNA expression of Keap1 in 45 cases of RCC tumors and adjacent normal tissues. A total of five randomly selected patients with RCC, five RCC cell lines and normal renal tubular cells were examined to detect the protein and mRNA expressions of Keap1. The 5‑year survival rate was analyzed by Kaplan‑Meier analysis. The cell viability was assessed by a Cell Counting kit‑8 assay. The cell apoptosis and reactive oxygen species (ROS) were determined by flow cytometry. The expressions of associated proteins were determined by western blot analysis. It was identified that in RCC tissues and RCC cell lines, the expression of Keap1 was downregulated, which was considered to be associated with poor prognosis. In total, 1 µM Axitinib significantly decreased cell viability, promoted ROS release and induced cell apoptosis in ACHN cells. Silencing Keap1 was able to reverse the inhibitory effect of Axitinib and enhance the protein expressions of Nrf2, NAD(P)H dehydrogenase [quinone] 1 and heme oxygenase 1. However, silencing Nrf2 increased the cell sensitivity to Axitinib. Under Axitinib condition, overexpressing Nrf2 was able to increase cell viability; however, overexpressing Keap1 resulted in an opposite effect. Keap1 serves as a tumor suppressor; its low expression was associated with poor prognosis and a decreased sensitivity of RCC cells to Axitinib. A possible mechanism underlying Axitinib resistance may involve Nrf2 overexpression.

journal_name

Int J Mol Med

authors

Huang H,Wu Y,Fu W,Wang X,Zhou L,Xu X,Huang F,Wu Y

doi

10.3892/ijmm.2019.4134

subject

Has Abstract

pub_date

2019-05-01 00:00:00

pages

2044-2054

issue

5

eissn

1107-3756

issn

1791-244X

journal_volume

43

pub_type

杂志文章
  • Triticum aestivum sprout-derived polysaccharide exerts hepatoprotective effects against ethanol-induced liver damage by enhancing the antioxidant system in mice.

    abstract::Triticum aestivum sprout-derived polysaccharide (TASP) has anti-diabetic properties, but no information is available in regards to its protective effect against ethanol-induced hepatic injury. This study aimed to investigate the mechanism behind the protective role of TASP against ethanol-induced liver injury in vivo....

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2017.3095

    authors: Nepali S,Ki HH,Lee JH,Cha JY,Lee YM,Kim DK

    更新日期:2017-10-01 00:00:00

  • Poly-ε-caprolactone composite scaffolds for bone repair.

    abstract::Synthetic biomaterials combined with cells and osteogenic factors represent a promising approach for the treatment of a number of orthopedic diseases, such as bone trauma and congenital malformations. To guarantee optimal biological properties, bone substitutes are prepared with a 3D structure and porosity grade funct...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2014.1954

    authors: Di Liddo R,Paganin P,Lora S,Dalzoppo D,Giraudo C,Miotto D,Tasso A,Barbon S,Artico M,Bianchi E,Parnigotto PP,Conconi MT,Grandi C

    更新日期:2014-12-01 00:00:00

  • Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells.

    abstract::Adipose tissue tumors (lipomas) frequently develop in patients with heterozygous germ line phosphatase and tensin homolog (PTEN) mutations. simvastatin has been demonstrated to exhibit antitumor effects, and so the aim of the present study was to assess the effects of simvastatin on the growth of human PTEN haploinsuf...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2018.3568

    authors: Kässner F,Sauer T,Penke M,Richter S,Landgraf K,Körner A,Kiess W,Händel N,Garten A

    更新日期:2018-06-01 00:00:00

  • Mutation analysis of K-ras and beta-catenin genes related to O6-methylguanin-DNA methyltransferase and mismatch repair protein status in human gallbladder carcinoma.

    abstract::O6-methylguanin-DNA methyltransferase (MGMT) is a DNA repair enzyme that transfers methyl groups from O6-methylguanine to itself. Alkylation of DNA at the O6 position of guanine is the first step by alkylating agents in inducing DNA mutations in an organism. When MGMT and the mismatch repair (MMR) system are impaired,...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Kohya N,Kitajima Y,Kitahara K,Miyazaki K

    更新日期:2003-01-01 00:00:00

  • Are aberrant transcripts of FHIT, TSG101, and PTEN/MMAC1 oncogenesis related?

    abstract::Tumor suppressor gene mutations in TSG101, FHIT, and PTEN/MMAC1 were found in many types of cancer and the defects in these genes are responsible for the tumor development. Since aberrant transcripts of these genes were also identified in normal tissues, the significance of these mutations in carcinogenesis has become...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章,评审

    doi:10.3892/ijmm.3.5.491

    authors: Wang NM,Chang JG

    更新日期:1999-05-01 00:00:00

  • Hydrogen sulfide attenuates cytokine production through the modulation of chromatin remodeling.

    abstract::Hydrogen sulfide (H2S) is an endogenous gaseous biological mediator, which regulates, among others, the oxidative balance of cells under normal physiological conditions, as well as in various diseases. Several previous studies have reported that H2S attenuates inflammatory mediator production. In this study, we invest...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2015.2176

    authors: Rios EC,Szczesny B,Soriano FG,Olah G,Szabo C

    更新日期:2015-06-01 00:00:00

  • Inhibitory effect of Trolox on the migration and invasion of human lung and cervical cancer cells.

    abstract::The antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) is implicated in migration and invasion of metastatic tumors. However, the molecular mechanism underlying the effect of Trolox on metastatic cancer cells is not known. We found that a non-cytotoxic dose ...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2011.832

    authors: Sung HJ,Kim Y,Kang H,Sull JW,Kim YS,Jang SW,Ko J

    更新日期:2012-02-01 00:00:00

  • miR-204-5p promotes the adipogenic differentiation of human adipose-derived mesenchymal stem cells by modulating DVL3 expression and suppressing Wnt/β-catenin signaling.

    abstract::MicroRNAs (miRNAs or miRs) play an important regulatory role during adipogenesis, and have been studied extensively in this regard. Specifically, the switch between the differentiation of mesenchymal stem cells (MSCs) towards adipogenic vs. osteogenic lineages is regulated by miR-204 which controls the expression of R...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2015.2160

    authors: He H,Chen K,Wang F,Zhao L,Wan X,Wang L,Mo Z

    更新日期:2015-06-01 00:00:00

  • Association study of +45G15G(T/G) and +276(G/T) polymorphisms in the adiponectin gene in patients with polycystic ovary syndrome.

    abstract::The polycystic ovary syndrome (PCOS) is considered as one of the most common endocrine and reproductive dysfunctional diseases. Recent research for genetic variants has identified genetic influences between the polymorphisms of the adiponectin gene and the metabolic syndromes. The aim of our study was to investigate t...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2010.565

    authors: Li L,Yun JH,Lee JH,Song S,Choi BC,Baek KH

    更新日期:2011-02-01 00:00:00

  • Derivation of hepato-pancreatic intermediate progenitor cells from a clonal mesenchymal stem cell line of rat bone marrow origin.

    abstract::We have recently established a clonal mesenchymal stem cell line (rBM25/S3) from adult rat bone marrow. The cells have practically unlimited proliferation capacity (over 300 PDL), maintaining multipotency for differentiation. In the present study, we examined the potential for rBM25/S3 cells to differentiate into insu...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Masaka T,Miyazaki M,Du G,Hardjo M,Sakaguchi M,Takaishi M,Kataoka K,Yamamoto K,Huh NH

    更新日期:2008-10-01 00:00:00

  • Penehyclidine hydrochloride alleviates lipopolysaccharide‑induced acute lung injury in rats: Potential role of caveolin‑1 expression upregulation.

    abstract::The aim of the present study was to examine the protective effect of caveolin‑1 (Cav‑1) in the penehyclidine hydrochloride (PHC)‑based inhibition of lipopolysaccharide (LPS)‑induced acute lung injury (ALI) in vivo and in vitro, in addition to the potential underlying mechanisms. In vivo, an ALI rat model was establish...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2019.4117

    authors: Wu X,Kong Q,Xia Z,Zhan L,Duan W,Song X

    更新日期:2019-05-01 00:00:00

  • Transcript heterogeneity of the human gene for Ca2+-binding protein regucalcin.

    abstract::Regucalcin is a Ca2+-binding protein which plays a regulatory role in liver cell functions related to Ca2+. In this study we have cloned and characterized cDNA for regucalcin from human liver and human hepatoma cell line Hep G2 by screening and rapid amplification of cDNA ends (RACE). The nucleotide sequences of the c...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Misawa H,Yamaguchi M

    更新日期:2000-03-01 00:00:00

  • The role of gap junctions in inflammatory and neoplastic disorders (Review).

    abstract::Gap junctions are intercellular channels made of connexin proteins, mediating both electrical and biochemical signals between cells. The ability of gap junction proteins to regulate immune responses, cell proliferation, migration, apoptosis and carcinogenesis makes them attractive therapeutic targets for treating infl...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章,评审

    doi:10.3892/ijmm.2017.2859

    authors: Wong P,Laxton V,Srivastava S,Chan YW,Tse G

    更新日期:2017-03-01 00:00:00

  • Secretogranin III may be an indicator of paraquat-induced astrocyte activation and affects the recruitment of BDNF during this process.

    abstract::Astrocyte activation has been described as a multi‑stage defensive response, which is characterized by the morphological alteration of astrocytes and the overexpression of intermediate filament proteins. However, the functional mechanism of the secretion system in activated astroglia remains unclear. It has previously...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2018.3909

    authors: Zhan X,Li F,Chu Q,Pang H

    更新日期:2018-12-01 00:00:00

  • 17β-estradiol protects INS-1 insulinoma cells from mitophagy via G protein-coupled estrogen receptors and the PI3K/Akt signaling pathway.

    abstract::17β-estradiol (17β-E2) is a steroid hormone that is known to exert effects on blood glucose homeostasis. The G protein‑coupled estrogen receptor (GPER) has been identified as a non-genomic estrogenic receptor, and is involved in numerous physiological processes, including cell survival, energy provision and metabolism...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2018.3470

    authors: Zhang L,Zhao Y,Guo L

    更新日期:2018-05-01 00:00:00

  • Centipedegrass extract induces apoptosis through the activation of caspases and the downregulation of PI3K/Akt and MAPK phosphorylation in leukemia cells.

    abstract::Acute lymphoblastic leukemia (ALL), which involves the blood and bone marrow, is the most common type of cancer in children younger than 5 years of age. Previous studies have investigated the effects of centipedegrass extract (CGE), which is mainly composed of maysin and its derivatives, and have demonstrated that it ...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2014.2012

    authors: Bai HW,Badaboina S,Park CH,Choi BY,Na YH,Chung BY

    更新日期:2015-02-01 00:00:00

  • Identification of a trypsinogen activity stimulating factor produced by pancreatic cancer cells: its role in tumor invasion and metastasis.

    abstract::Trypsinogen/trypsin is one of the major serine proteases and is produced by pancreatic acinar cells. Tumor-associated trypsinogen (TAT) has been reported to be produced by several cancer cell lines. The biological roles and activation mechanisms of both TAT and pancreatic acinar trypsinogen (PAT) have not been elucida...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Uchima Y,Sawada T,Nishihara T,Umekawa T,Ohira M,Ishikawa T,Nishino H,Hirakawa K

    更新日期:2003-12-01 00:00:00

  • Hypersensitive cytokine response to beta-amyloid 25-35 in astroglial cells from IL-1 receptor type I-deficient mice.

    abstract::betaA25-35, a neurotoxic fragment of the Alzheimer beta-amyloid peptide (betaA), acts as a strong inducer of pro-inflammatory cytokines, such as interleukin (IL)-1 and IL-6, in glial cells. Since IL-1 is known to induce expression of both IL-1 and IL-6, we have investigated to what extent the induction of IL-1alpha an...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.1.1.201

    authors: Eriksson G,Zetterström M,Cortes Toro V,Bartfai T,Iverfeldt K

    更新日期:1998-01-01 00:00:00

  • Resistance to TRAIL in mantle cell lymphoma cells is associated with the decreased expression of purine metabolism enzymes.

    abstract::Mantle cell lymphoma (MCL) is a rare aggressive type of B-cell non-Hodgkin's lymphoma. Response to chemotherapy tends to be short and virtually all patients sooner or later relapse. The prognosis of relapsed patients is extremely poor. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered o...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2013.1302

    authors: Pospisilova J,Vit O,Lorkova L,Klanova M,Zivny J,Klener P,Petrak J

    更新日期:2013-05-01 00:00:00

  • Ins2Akita mice exhibit hyperphagia and anxiety behavior via the melanocortin system.

    abstract::Elevated anxiety symptoms have been reported to be present in many patients with diabetes mellitus. The underlying mechanisms by which diabetes mellitus influences behavior remain to be determined. We assessed feeding and anxiety behaviors in spontaneously diabetic Ins2Akita mice. We measured blood glucose, body weigh...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Asakawa A,Toyoshima M,Inoue K,Koizumi A

    更新日期:2007-04-01 00:00:00

  • Effects of preproglucagon-derived peptides and exendins on steroid-hormone secretion from dispersed adrenocortical cells of normal and streptozotocin-induced diabetic rats.

    abstract::Many lines of evidence have shown that preproglucagon-derived peptides affect steroid secretion from dispersed adrenocortical cells, and that streptozotocin (STZ)-induced experimental diabetes alters adrenocortical-cell function. Hence, we compared the effects of glucagon, glucagon-like peptide (GLP)-1 and GLP-2 on ba...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Malendowicz LK,Spinazzi R,Nussdorfer GG,Trejter M

    更新日期:2003-07-01 00:00:00

  • Adiponectin inhibits the differentiation and maturation of osteoclasts via the mTOR pathway in multiple myeloma.

    abstract::The present study sought to investigate the correlation between adipose cytokines (visfatin, leptin and adiponectin) and markers of multiple myeloma bone disease, and to determine the effects and mechanism of action of adiponectin on the differentiation and maturation of osteoclasts in multiple myeloma (MM). The level...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2020.4475

    authors: Liu Z,Liu H,Li Y,Wang Y,Xing R,Mi F,Xiang C,Fu R

    更新日期:2020-04-01 00:00:00

  • Mutational analysis of the BAK gene in 192 advanced gastric and colorectal cancers.

    abstract::The evasion of apoptosis has been linked to the development of cancer. A recent study of a small number of gastric and colorectal cancers found that the BAK gene, which encodes a pro-apoptotic protein, contained somatic mutations in approximately 17% of the samples analyzed. To investigate the precise frequency of BAK...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Sakamoto I,Yamada T,Ohwada S,Koyama T,Nakano T,Okabe T,Hamada K,Kawate S,Takeyoshi I,Iino Y,Morishita Y

    更新日期:2004-01-01 00:00:00

  • Long non‑coding RNA expression profiles identify lncRNA‑XLOC_I2_006631 as a potential novel blood biomarker for Hashimoto's thyroiditis.

    abstract::Long non‑coding RNAs (lncRNAs) have been increasingly recognized as important immune checkpoints involved in the pathogenesis of autoimmune diseases. However, the exact role of lncRNAs in Hashimoto's thyroiditis (HT) has been rarely studied. The aim of the present study was to investigate the role of lncRNAs and the p...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2020.4755

    authors: Peng H,Xiong S,Ding X,Tang X,Wang X,Wang L,Liu Y

    更新日期:2020-12-01 00:00:00

  • Sodium selenite inhibits leukemia HL-60 cell proliferation and induces cell apoptosis by enhancing the phosphorylation of JNK1 and increasing the expression of p21 and p27.

    abstract::Selenium is an essential trace element and has shown chemopreventive or therapeutic activities on human solid cancers; however, whether it has anticancer effects on leukemia has not yet been elucidated. The present study was designed to determine the role of selenium on HL-60 human promyelocytic leukemia cells. We fou...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2014.1854

    authors: Wu S,Bao Y,Ma D,Zi Y,Yang C,Yang M,Xing M,Yang W

    更新日期:2014-10-01 00:00:00

  • Vibrio extracellular protease with prothrombin activation and fibrinolytic activities.

    abstract::A 36 kDa extracellular metalloprotease (designated to as vEP-MO6) was purified and characterized from Vibrio vulnificus sp. strain MO6 24/0. vEP-MO6 cleaved azocasein and a few other proteins such as prothrombin, plasminogen, fibrinogen and Factor Xa, which are associated with the blood coagulation pathway. The enzyme...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Kwon JY,Chang AK,Park JE,Shin SY,Yoon SM,Lee JS

    更新日期:2007-01-01 00:00:00

  • Stimulatory effect of Shoyu polysaccharides from soy sauce on the intestinal immune system.

    abstract::Soy sauce (Shoyu) is a traditional Japanese fermented seasoning and is available worldwide. We investigated the effect of Shoyu polysaccharides (SPS) prepared from soy sauce on the intestinal immune system of mice. SPS enhanced the production of immunoglobulin A (IgA) from Peyer's patch cells in vitro, and its oral ad...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Matsushita H,Kobayashi M,Tsukiyama R,Fujimoto M,Suzuki M,Tsuji K,Yamamoto K

    更新日期:2008-08-01 00:00:00

  • New trends in non-invasive prenatal diagnosis: applications of dielectrophoresis-based Lab-on-a-chip platforms to the identification and manipulation of rare cells.

    abstract::The isolation of rare cells, such as fetal nucleated red blood cells and trophoblasts, from maternal blood for non-invasive prenatal diagnosis is a new field of research exhibiting several difficulties since this strategy requires unresolved basic technological protocols for a successful outcome. However, several achi...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章,评审

    doi:

    authors: Borgatti M,Bianchi N,Mancini I,Feriotto G,Gambari R

    更新日期:2008-01-01 00:00:00

  • Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.

    abstract::Hypertrophic cardiomyopathy (HCM) is mainly associated with myosin, heavy chain 7 (MYH7) and myosin binding protein C, cardiac (MYBPC3) mutations. In order to better explain the clinical and genetic heterogeneity in HCM patients, in this study, we implemented a target-next generation sequencing (NGS) assay. An Ion Amp...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:10.3892/ijmm.2016.2732

    authors: Cecconi M,Parodi MI,Formisano F,Spirito P,Autore C,Musumeci MB,Favale S,Forleo C,Rapezzi C,Biagini E,Davì S,Canepa E,Pennese L,Castagnetta M,Degiorgio D,Coviello DA

    更新日期:2016-10-01 00:00:00

  • High-dose hydrocortisone reduces expression of the pro-inflammatory chemokines CXCL8 and CXCL10 in SARS coronavirus-infected intestinal cells.

    abstract::Clinical observations and our high-density oligonucleotide microarray results demonstrated increased expression of proinflammatory chemokines after SARS-CoV infection. Here, we investigated the influence of SARS-CoV infection on CXCL8 (interleukin 8) and CXCL10 (interferon-gamma-inducible protein 10) in human intestin...

    journal_title:International journal of molecular medicine

    pub_type: 杂志文章

    doi:

    authors: Cinatl J Jr,Michaelis M,Morgenstern B,Doerr HW

    更新日期:2005-02-01 00:00:00