GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer

dc.contributor.authorYu, Beiqin
dc.contributor.authorGu, Dongsheng
dc.contributor.authorZhang, Xiaoli
dc.contributor.authorLi, Jianfang
dc.contributor.authorLiu, Bingya
dc.contributor.authorXie, Jingwu
dc.contributor.departmentPediatrics, School of Medicineen_US
dc.date.accessioned2018-03-14T15:39:12Z
dc.date.available2018-03-14T15:39:12Z
dc.date.issued2017-04-18
dc.description.abstractGastric cancer is the third leading cause of cancer-related mortality worldwide. Chemotherapy is frequently used for gastric cancer treatment. Most patients with advanced gastric cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for cancer relapse following chemotherapy will help design new ways to treat gastric cancer. In this study, we revealed that the residual cancer cells following treatment with chemotherapeutic reagent cisplatin have elevated expression of hedgehog target genes GLI1, GLI2 and PTCH1, suggestive of hedgehog signaling activation. We showed that GLI1 knockdown sensitized gastric cancer cells to CDDP whereas ectopic GLI1 expression decreased the sensitivity. Further analyses indicate elevated GLI1 expression is associated with an increase in tumor sphere formation, side population and cell surface markers for putative cancer stem cells. We have evidence to support that GLI1 is critical for maintenance of putative cancer stem cells through direct regulation of ABCG2. In fact, GLI1 protein was shown to be associated with the promoter fragment of ABCG2 through a Gli-binding consensus site in gastric cancer cells. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, increased drug sensitivity of cancer cells both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance.en_US
dc.identifier.citationYu, B., Gu, D., Zhang, X., Li, J., Liu, B., & Xie, J. (2017). GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer. Oncotarget, 8(16), 27412–27427. http://doi.org/10.18632/oncotarget.16174en_US
dc.identifier.urihttps://hdl.handle.net/1805/15517
dc.language.isoen_USen_US
dc.publisherImpact Journalsen_US
dc.relation.isversionof10.18632/oncotarget.16174en_US
dc.relation.journalOncotargeten_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/
dc.sourcePMCen_US
dc.subjectGLI1en_US
dc.subjectChemoresistanceen_US
dc.subjectCisplatinen_US
dc.subjectGastric canceren_US
dc.subjectHedgehogen_US
dc.titleGLI1-mediated regulation of side population is responsible for drug resistance in gastric canceren_US
dc.typeArticleen_US
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