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1.
Reflux composition influences the level of NF‐κB activation and upstream kinase preference in oesophageal adenocarcinoma cells
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E. McAdam H.N. Haboubi A.P. Griffiths J.N. Baxter S. Spencer‐Harty C. Davies G.J. Jenkins 《International journal of cancer. Journal international du cancer》2015,136(3):527-535
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Microtubule affinity‐regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non‐small cell lung cancer
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Sonia H.Y. Kung Victor D. Martinez Mitra Mosslemi Daiana D. Becker‐Santos Adi F. Gazdar Stephen Lam Wan L. Lam 《International journal of cancer. Journal international du cancer》2015,137(9):2072-2082
Microtubule affinity‐regulating kinases (MARKs) are involved in several cellular functions but few studies have correlated MARK kinase expression with cancer, and none have explored their role in lung cancer. In this study, we identified MARK2 as frequently disrupted by DNA hypomethylation and copy gain, resulting in concordant overexpression in independent lung tumor cohorts and we demonstrate a role for MARK2 in lung tumor biology. Manipulation of MARK2 in lung cell lines revealed its involvement in cell viability and anchorage‐independent growth. Analyses of both manipulated cell lines and clinical tumor specimens identified a potential role for MARK2 in cell cycle activation and DNA repair. Associations between MARK2 and the E2F, Myc/Max and NF‐κB pathways were identified by luciferase assays and in‐depth assessment of the NF‐κB pathway suggests a negative association between MARK2 expression and NF‐κB due to activation of non‐canonical NF‐κB signaling. Finally, we show that high MARK2 expression levels correlate with resistance to cisplatin, a standard first line chemotherapy for lung cancer. Collectively, our work supports a role for MARK2 in promoting malignant phenotypes of lung cancer and potentially modulating response to the DNA damaging chemotherapeutic, cisplatin. 相似文献
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G Piro S Giacopuzzi M Bencivenga C Carbone G Verlato M Frizziero M Zanotto M M Mina V Merz R Santoro A Zanoni G De Manzoni G Tortora D Melisi 《British journal of cancer》2015,113(6):878-885
Background:
About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor β activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma.Methods:
TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT–PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma.Results:
In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandard''s tumour regression grade classifications, respectively).Conclusions:
The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy. 相似文献5.
Yanwei Xing Zhiqiang Zhang Fengxu Chi Yang Zhou Shuo Ren Zhiwei Zhao Yuekun Zhu Daxun Piao 《Molecular carcinogenesis》2019,58(10):1795-1808
The abnormal expression of adipocyte enhancer binding protein 1 (AEBP1) has been implicated in the carcinogenesis and progression of various types of human tumors. However, the role of AEBP1 in colon adenocarcinoma (COAD) remains largely unelucidated. In this study, we explored the clinical significance and biological function of AEBP1 in COAD. We observed that AEBP1 was overexpressed in COAD tissues and cells and that the expression of AEBP1 was correlated with tumor size, the level of histologic differentiation, lymph node metastasis, and cancer stage in COAD patients. In addition, univariate and multivariate Cox regression analyses revealed that high AEBP1 expression suggested poor prognosis in COAD. Moreover, AEBP1 silencing suppressed COAD cell proliferation, migration, and invasion, whereas the upregulation of AEBP1 promoted these behaviors. Additionally, mechanistic studies further demonstrated that AEBP1 promoted COAD cell proliferation, migration, and invasion by upregulating the expression of matrix metalloproteinase‐2, vimentin, and TWIST whereas downregulating that of E‐cadherin through the nuclear factor‐κB pathway. Collectively, these data indicated that AEBP1 may be a new prognostic factor and a potential gene therapy target in COAD. 相似文献
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Kota Iwahori Satoshi Serada Minoru Fujimoto Barry Ripley Shintaro Nomura Hiroyuki Mizuguchi Kazuki Shimada Tsuyoshi Takahashi Ichiro Kawase Tadamitsu Kishimoto Tetsuji Naka 《International journal of cancer. Journal international du cancer》2013,132(2):459-471
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. This study investigated the therapeutic potential of gene delivery using suppressor of cytokine signaling 1 (SOCS‐1), an endogenous inhibitor of intracellular signaling pathways, for the treatment of MPM. We infected MPM cells (MESO‐4, H28 and H226) with adenovirus‐expressing SOCS‐1 vector to examine the effect of SOCS‐1 overexpression on MPM cells. We evaluated the antitumor effect of SOCS‐1 gene delivery combined with cisplatin plus pemetrexed by cell proliferation, apoptosis and invasion assay. We also investigated the regulation of NF‐κB and STAT3 signaling related to apoptotic pathways. Furthermore, we evaluated the inhibition of tumor growth by SOCS‐1 gene delivery combined with cisplatin plus pemetrexed in vivo. SOCS‐1 gene delivery cooperated with cisplatin plus pemetrexed to inhibit cell proliferation, invasiveness and induction of apoptosis in MPM cells. SOCS‐1 regulated NF‐κB and STAT3 signaling to induce apoptosis in MESO‐4 and H226 cells. Furthermore, SOCS‐1 gene delivery cooperated with cisplatin plus pemetrexed to regulate NF‐κB signaling and significantly inhibit tumor growth of MPM in vivo. These results suggest that SOCS‐1 gene delivery has a potent antitumor effect against MPM and a potential for clinical use in combination with cisplatin plus pemetrexed. 相似文献
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Hui Ling Xiaobin Jia Yaochun Zhang Leslie A. Gapter Yin‐shan Lim Rajesh Agarwal Ka‐yun Ng 《Molecular carcinogenesis》2010,49(3):271-282
Aberrant arachidonic acid (AA) metabolism has been involved in inflammation and carcinogenesis. The key enzymes in AA metabolism such as cytosolic phospholipase A2 (cPLA2) and cyclooxygenase‐2 (COX‐2) have been implicated in the development and progression of many human cancers, including lung cancer. Hence, the blockade of these enzymes may suppress promotion and survival of human cancer cells. We and others have shown that a natural triterpenoid, pachymic acid (PA), can exhibit antiinflammatory and anticancer properties; however, its potential mechanism has not been fully clarified. In this study, we examined the effect of PA on the proliferation of human nonsmall cell lung cancer A549 cells. Furthermore, we investigated the influences of nontoxic levels of PA on AA metabolism. Additionally, the cellular events and signal transduction pathways influenced by PA were also examined. Our results showed that PA (1) inhibited anchorage‐dependent and ‐independent A549 growth in a concentration‐dependent manner, (2) induced apoptosis and disrupted mitochondrial membrane potential in A549 cells, and at nonlethal levels, (3) decreased IL‐1β‐induced activation of cPLA2 and COX‐2, (4) suppressed IL‐1β‐induced activation of mitogen‐activated protein kinases (MAPKs), and (5) inhibited IL‐1β‐stimulated nuclear factor kappa B (NF‐κB) signaling pathways. We speculate that inhibition of AA metabolism by PA is mediated in part by its inhibition of MAPKs and NF‐κB signaling pathways. Our study reveals that, apart from its cytotoxic effect, PA has the chemopreventive potential by reducing production of eicosanoids from AA metabolism. © 2009 Wiley‐Liss, Inc. 相似文献
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Trefoil factor 1 expression suppresses Helicobacter pylori–induced inflammation in gastric carcinogenesis
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Mohammed Soutto PhD Zheng Chen MD PhD Ahmed M. Katsha PhD Judith Romero‐Gallo PhD Uma S. Krishna PhD M. Blanca Piazuelo PhD M. Kay Washington MD Richard M. Peek MD Jr Abbes Belkhiri PhD Wael M. El‐Rifai MD PhD 《Cancer》2015,121(24):4348-4358
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Rong Guo Yong Li Zhijie Wang Hua Bai Jianchun Duan Shuhang Wang Lvhua Wang Jie Wang 《Cancer science》2019,110(5):1665-1675
Some driver gene mutations, including epidermal growth factor receptor (EGFR), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 (PD‐L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD‐L1 expression regulation in non‐small‐cell lung cancer (NSCLC) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD‐L1 overexpression and phosphorylation of AKT and ERK, especially with increased protein levels of phospho‐IκBα (p‐IκBα) and hypoxia‐inducible factor‐1α (HIF‐1α). Flow cytometry results showed stronger membrane co‐expression of EGFR and PD‐L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR. Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK/ERK, PI3K/AKT, mTOR/S6, IκBα, and HIF‐1α indicated strong accordance among protein levels of PD‐L1, p‐IκBα, and HIF‐1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p‐IκBα, HIF‐1α, and PD‐L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p‐IκBα, HIF‐1α, and PD‐L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR. Non‐small‐cell lung cancer tissues with either p‐IκBα or HIF‐1α positive staining were more likely to possess elevated PD‐L1 expression compared with tissues scored negative for both p‐IκBα and HIF‐1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF‐κB and HIF‐1α in PD‐L1 expression regulation by EGFR mutants in NSCLC. 相似文献
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目的:探讨沉默CXCR4对肺癌细胞顺铂耐药的影响,并研究其分子作用机制。方法:利用RT-qPCR测定肺癌耐药(A549/DDP)及药物敏感细胞株(A549)中CXCR4 mRNA的表达水平;利用LipofectamineTM 2000将siRNA-CXCR4转染至肺癌耐药细胞株中,RT-qPCR及蛋白质印迹法(Western blot)验证siRNA对CXCR4基因的靶向沉默效率;利用CCK-8法检测沉默CXCR4后肺癌耐药细胞的增殖活性;利用流式细胞仪测定沉默CXCR4后肺癌耐药细胞的凋亡率;利用MTT法测定沉默CXCR4后肺癌耐药细胞对顺铂的敏感性;利用Western blot实验测定沉默CXCR4后CYP1B1蛋白的表达水平。结果:RT-qPCR实验结果显示,肺癌耐药细胞株A549/DDP中CXCR4 mRNA的表达量显著高于药物敏感细胞株(P<0.01);体外转染siRNA-CXCR4可明显下调A549/DDP细胞株中CXCR4的表达(P<0.001);CCK-8实验结果显示,沉默CXCR4的表达抑制了A549/DDP细胞的增殖活性(P<0.01);流式细胞仪实验结果显示,沉默CXCR4的表达促进了A549/DDP细胞凋亡(P<0.01);MTT实验结果显示,沉默CXCR4的表达增加了A549/DDP细胞对顺铂的敏感性(P<0.01);Western blot实验结果显示,沉默CXCR4后CYP1B1蛋白的表达水平显著降低(P<0.05)。结论:沉默CXCR4的表达抑制肺癌耐药细胞增殖、促进凋亡,逆转肺癌细胞顺铂耐药,CXCR4正向调控CYP1B1的表达,可能是CXCR4逆转肺癌细胞顺铂耐药的作用机制。 相似文献
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Ajaikumar B. Kunnumakkara Parmeswaran Diagaradjane Preetha Anand Harikumar B. Kuzhuvelil Amit Deorukhkar Juri Gelovani Sushovan Guha Sunil Krishnan Bharat B. Aggarwal 《International journal of cancer. Journal international du cancer》2009,125(9):2187-2197
Because of the poor prognosis and the development of resistance against chemotherapeutic drugs, the current treatment for advanced metastatic colorectal cancer (CRC) is ineffective. Whether curcumin (a component of turmeric) can potentiate the effect of capecitabine against growth and metastasis of CRC was investigated. The effect of curcumin on proliferation of CRC cell lines was examined by mitochondrial dye‐uptake assay, apoptosis by esterase staining, nuclear factor‐kappaB (NF‐κB) by electrophoretic mobility shift assay and gene expression by Western blot analysis. The effect of curcumin on the growth and metastasis of CRC was also examined in orthotopically implanted tumors in nude mice. In vitro, curcumin inhibited the proliferation of human CRC cell lines, potentiated capecitabine‐induced apoptosis, inhibited NF‐κB activation and suppressed NF‐κB‐regulated gene products. In nude mice, the combination of curcumin and capecitabine was found to be more effective than either agent alone in reducing tumor volume (p = 0.001 vs. control; p = 0.031 vs. capecitabine alone), Ki‐67 proliferation index (p = 0.001 vs. control) and microvessel density marker CD31. The combination treatment was also highly effective in suppressing ascites and distant metastasis to the liver, intestines, lungs, rectum and spleen. This effect was accompanied by suppressed expression of activated NF‐κB and NF‐κB‐regulated gene products (cyclin D1,c‐myc, bcl‐2, bcl‐xL, cIAP‐1, COX‐2, ICAM‐1, MMP‐9, CXCR4 and VEGF). Overall, our results suggest that curcumin sensitizes CRC to the antitumor and antimetastatic effects of capecitabine by suppressing NF‐κB cell signaling pathway. © 2009 UICC 相似文献
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E‐cadherin expression increases cell proliferation by regulating energy metabolism through nuclear factor‐κB in AGS cells
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β‐Catenin is a central player in Wnt signaling, and activation of Wnt signaling is associated with cancer development. E‐cadherin in complex with β‐catenin mediates cell–cell adhesion, which suppresses β‐catenin‐dependent Wnt signaling. Recently, a tumor‐suppressive role for E‐cadherin has been reconsidered, as re‐expression of E‐cadherin was reported to enhance the metastatic potential of malignant tumors. To explore the role of E‐cadherin, we established an E‐cadherin‐expressing cell line, EC96, from AGS cells that featured undetectable E‐cadherin expression and a high level of Wnt signaling. In EC96 cells, E‐cadherin re‐expression enhanced cell proliferation, although Wnt signaling activity was reduced. Subsequent analysis revealed that nuclear factor‐κB (NF‐κB) activation and consequent c‐myc expression might be involved in E‐cadherin expression‐mediated cell proliferation. To facilitate rapid proliferation, EC96 cells enhance glucose uptake and produce ATP using both mitochondria oxidative phosphorylation and glycolysis, whereas AGS cells use these mechanisms less efficiently. These events appeared to be mediated by NF‐κB activation. Therefore, E‐cadherin re‐expression and subsequent induction of NF‐κB signaling likely enhance energy production and cell proliferation. 相似文献
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Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma 总被引:1,自引:0,他引:1
Kawase A Ishii G Nagai K Ito T Nagano T Murata Y Hishida T Nishimura M Yoshida J Suzuki K Ochiai A 《International journal of cancer. Journal international du cancer》2008,123(5):1053-1059
Recent studies have reported increased podoplanin expression by cancer cells and stromal cells, but little is known about its expression and biological significance in adenocarcinoma of the lung. We examined podoplanin expression by both cancer cells and stromal cells in 177 consecutive lung adenocarcinoma cases and analyzed relations between podoplanin expression and both clinicopathological factors and outcome. Podoplanin expression was observed on the apical membrane of the cancer cells in only 9 of the 177 (5.1%) cases. By contrast, cancer-associated fibroblasts (CAFs) were found to express podoplanin in 54 cases (30.5%). Podoplanin (+) CAFs were found only in invasive adenocarcinoma and none were found in noninvasive adenocarcinoma. Conventional prognostic factors were significantly correlated with podoplanin expression by CAFs. The univariate analyses and log-rank test showed that podoplanin expression was significantly associated with shorter survival time (p < 0.001 and p < 0.001, respectively). We divided the cases into 3 groups according grade based on the proportion of CAFs expressing podoplanin [a grade 0 group (n = 123), a grade 1 group (n = 36) and a grade 2 group (n = 18)]. The result showed that conventional prognostic factors were significantly correlated with the grade of podoplanin expression by CAFs. Furthermore, the grade 2 group tended to have a shorter survival time than the grade 1 group (p = 0.092). The results of this study highlight the importance of podoplanin expression by CAFs and provide new insights into the biology of the cancer microenvironment in adenocarcinoma of the lung. 相似文献
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Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways
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Santosh Kumar Taraka R. Donti Navneet Agnihotri Kapil Mehta 《International journal of cancer. Journal international du cancer》2014,134(12):2798-2807
Aberrant glucose metabolism characterized by high levels of glycolysis, even in the presence of oxygen, is an important hallmark of cancer. This metabolic reprogramming referred to as the Warburg effect is essential to the survival of tumor cells and provides them with substrates required for biomass generation. Molecular mechanisms responsible for this shift in glucose metabolism remain elusive. As described herein, we found that aberrant expression of the proinflammatory protein transglutaminase 2 (TG2) is an important regulator of the Warburg effect in mammary epithelial cells. Mechanistically, TG2 regulated metabolic reprogramming by constitutively activating nuclear factor (NF)‐κB, which binds to the hypoxia‐inducible factor (HIF)?1α promoter and induces its expression even under normoxic conditions. TG2/NF‐κB‐induced increase in HIF‐1α expression was associated with increased glucose uptake, increased lactate production and decreased oxygen consumption by mitochondria. Experimental suppression of TG2 attenuated HIF‐1α expression and reversed downstream events in mammary epithelial cells. Moreover, downregulation of p65/RelA or HIF‐1α expression in these cells restored normal glucose uptake, lactate production, mitochondrial respiration and glycolytic protein expression. Our results suggest that aberrant expression of TG2 is a master regulator of metabolic reprogramming and facilitates metabolic alterations in epithelial cells even under normoxic conditions. A TG2‐induced shift in glucose metabolism helps breast cancer cells to survive under stressful conditions and promotes their metastatic competence. 相似文献
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Chiara Laezza Anna M. Malfitano Tiziana Di Matola Paolo Ricchi Maurizio Bifulco 《Molecular carcinogenesis》2010,49(10):892-901
N6‐isopentenyladenosine (i6A) inhibits the tumor cell growth by inducing cell apoptosis in various cancer cell lines. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. In this study, we further explored the molecular mechanisms of i6A as an anticancer agent on a human breast cancer cell line MDA MB 231. Treatment with i6A decreased the cell proliferation of MDA MB 231 cells in a dose‐dependent manner by arresting the cells at G0/G1 phase. This effect was strongly associated with concomitant decrease in the level of cyclin D1, cyclin E, cdk2, and increase of p21waf1 and p27kip. In addition i6A also induced apoptotic cell death by increasing the expression of Bax, and decreasing the levels of Bcl‐2 and Bcl‐xL, and subsequently triggered mitochondria apoptotic pathway (release of cytochrome c and activation of caspase‐3). We observed that i6A suppressed the nuclear factor kappaB (NF‐κB) pathway and inhibited the Akt activation. The results of this study indicate that i6A decreases cell proliferation and induces apoptotic cell death in human breast cancer cells, possibly by decreasing signal transduction through the Akt/NF‐κB cell survival pathway. © 2010 Wiley‐Liss, Inc. 相似文献
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Ru Bai Zhenhua Cui Yongjing Ma Yang Wu Ningping Wang Ling Huang Qing Yao Jianmin Sun 《Molecular carcinogenesis》2019,58(12):2254-2265
Ovarian cancer is the most lethal gynecologic malignancy due to the lack of symptoms until advanced stages, and new diagnosis and treatment strategy is in urgent need. In this study, we found higher expression of miR‐19a‐3p in ovarian cancer tissues compared with that in the adjacent normal tissues. By chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) analysis, we showed that nuclear factor‐kappaB (NF‐κB) binds to the promoter of miR‐19a‐3p, leading to reduced expression in ovarian cancer cells. Further study indicated that miR‐19a‐3p inhibits the expression of insulin‐like growth factor binding protein‐3 (IGFBP‐3), resulting in enhanced growth and migration of ovarian cancer cells in vitro and tumor growth in vivo. These results showed that miR‐19a‐3p enhances the oncogenesis of ovarian cancer through inhibition of IGFBP‐3 expression, and which can be inhibited by NF‐κB, suggesting an NF‐κB/miR‐19a‐3p/IGFBP‐3 pathway in the oncogenesis of ovarian cancer, which expands our understanding of ovarian cancer and they may contribute to the development of new diagnosis and treatment of ovarian cancer. 相似文献
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Homeobox A9 directly targeted by miR‐196b regulates aggressiveness through nuclear Factor‐kappa B activity in non‐small cell lung cancer cells
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Seong‐Lan Yu Dong Chul Lee Hyun Ahm Sohn Soo Young Lee Hyo Sung Jeon Joon H. Lee Chang Gyo Park Hoi Young Lee Young Il Yeom Ji Woong Son Yoo Sang Yoon Jaeku Kang 《Molecular carcinogenesis》2016,55(12):1915-1926