• Title, Summary, Keyword: chemoresistance

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Ginsenoside Rh2 differentially Mediates microRNA Expression to Prevent Chemoresistance of Breast Cancer

  • Wen, Xu;Zhang, He-Da;Zhao, Li;Yao, Yu-Feng;Zhao, Jian-Hua;Tang, Jin-Hai
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.3
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    • pp.1105-1109
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    • 2015
  • Chemoresistance is the most common cause of chemotherapy failure during breast cancer (BCA) treatment. It is generally known that the mechanisms of chemoresistance in tumors involve multiple genes and multiple signaling pathways,; if appropriate drugs are used to regulate the mechanisms at the gene level, it should be possible to effectively reverse chemoresistance in BCA cells. It has been confirmed that chemoresistance in BCA cells could be reversed by ginsenoside Rh2 (G-Rh2). Preliminary studies of our group identified some drugresistance specific miRNA. Accordingly, we proposed that G-Rh2 could mediate drug-resistance specific miRNA and corresponding target genes through the gene regulatory network; this could cut off the drug-resistance process in tumors and enhance treatment effects. G-Rh2 and breast cancer cells were used in our study. Through pharmaceutical interventions, we could explore how G-Rh2 could inhibit chemotherapy resistance in BCA, and analyze its impact on related miRNA and target genes. Finally, we will reveal the anti-resistance molecular mechanisms of G-Rh2 from a different angle in miRNA-mediated chemoresistance signals among cells.

Roles of GST-π and polβ Genes in Chemoresistance of Esophageal Carcinoma Cells

  • Tang, Yue;Xuan, Xiao-Yan;Li, Min;Dong, Zi-Ming
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.12
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    • pp.7375-7379
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    • 2013
  • The main aim of this study was to investigate the roles of GST-${\pi}$ and $pol{\beta}$ genes in the chemoresistance of esophageal carcinoma cells. Eukaryotic expression vectors containing each gene were constructed and transfected into EC9706 cells, and the biological effects of the two genes assessed based on a resistance index. We additionally investigated the in vitro and in vivo anti-resistance effects of GST-${\pi}$ and $pol{\beta}$ genes using recombinant lentiviruses carrying siRNAs against the two genes. Our results showed that upregulation of GST-${\pi}$ and $pol{\beta}$ genes suppresses chemosensitivity of esophageal carcinoma cells to cisplatin, while downregulation of these two genes with RNAi technology reverses this chemoresistance. Multi-site injection of recombinant lentivirus targeting the GST-${\pi}$ gene into transplanted cDDP tumors effectively reversed their chemoresistant phenotype. However, the same treatment against the $pol{\beta}$ gene did not lead to significant efficacy against chemoresistance.

Involvement of NRF2 Signaling in Doxorubicin Resistance of Cancer Stem Cell-Enriched Colonospheres

  • Ryoo, In-geun;Kim, Geon;Choi, Bo-hyun;Lee, Sang-hwan;Kwak, Mi-Kyoung
    • Biomolecules & Therapeutics
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    • v.24 no.5
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    • pp.482-488
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    • 2016
  • Cancer stem cells (CSCs) are a subset of tumor cells, which are characterized by resistance against chemotherapy and environmental stress, and are known to cause tumor relapse after therapy. A number of molecular mechanisms underlie the chemoresistance of CSCs, including high expression levels of drug efflux transporters. We investigated the role of the antioxidant transcription factor NF-E2-related factor 2 (NRF2) in chemoresistance development, using a CSC-enriched colonosphere system. HCT116 colonospheres were more resistant to doxorubicin-induced cell death and expressed higher levels of drug efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) compared to HCT116 monolayers. Notably, levels of NRF2 and expression of its target genes were substantially elevated in colonospheres, and these increases were linked to doxorubicin resistance. When NRF2 expression was silenced in colonospheres, Pgp and BCRP expression was downregulated, and doxorubicin resistance was diminished. Collectively, these results indicate that NRF2 activation contributes to chemoresistance acquisition in CSC-enriched colonospheres through the upregulation of drug efflux transporters.

HIF-1α and GLUT1 Gene Expression is Associated with Chemoresistance of Acute Myeloid Leukemia

  • Song, Kui;Li, Min;Xu, Xiao-Jun;Xuan, Li;Huang, Gui-Nian;Song, Xiao-Ling;Liu, Qi-Fa
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.4
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    • pp.1823-1829
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    • 2014
  • Aims: Much evidence suggests that increased glucose metabolism in tumor cells might contribute to the development of acquired chemoresistance. However, the molecular mechanisms are not fully clear. Therefore, we investigated a possible correlation of mRNA expression of HIF-$1{\alpha}$ and GLUT1 with chemoresistance in acute myeloid leukemia (AML). Methods: Bone marrow samples were obtained from newly diagnosed and relapsed AML (M3 exclusion) cases. RNA interference with short hairpin RNA (shRNA) was used to stably silence GLUT1 or HIF-$1{\alpha}$ gene expression in an AML cell line and HIF-$1{\alpha}$ and GLUT1 mRNA expression was measured by real-time quantitative polymerase chain reaction assay (qPCR). Results: High levels of HIF-$1{\alpha}$ and GLUT1 were associated with poor responsiveness to chemotherapy in AML. Down-regulation of the expression of GLUT1 by RNA interference obviously sensitized drug-resistant HL-60/ADR cells to adriamycin (ADR) in vitro, comparable with RNA interference for the HIF-$1{\alpha}$ gene. Conclusions: Our data revealed that over-expression of HIF-$1{\alpha}$ and GLUT1 might play a role in the chemoresistance of AML. GLUT1 might be a potential target to reverse such drug resistance.

Clinical implications of APEX1 and Jagged1 as chemoresistance factors in biliary tract cancer

  • Kim, Hong-Beum;Cho, Won Jin;Choi, Nam Gyu;Kim, Sung-Soo;Park, Jun Hee;Lee, Hee-Jeong;Park, Sang Gon
    • Annals of Surgical Treatment and Research
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    • v.92 no.1
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    • pp.15-22
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    • 2017
  • Purpose: Biliary cancer is a highly malignant neoplasm with poor prognosis and most patients need to undergo palliative chemotherapy, however major clinical problem associated with the use of chemotherapy is chemoresistance. So far, we aimed at investigating clinical implications of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and Jagged1 as chemoresistance factors in biliary tract cancer Methods: We used 5 human biliary tract cancer cell lines (SNU-245, SNU-308, SNU-478, SNU-1079, and SNU-1196), and investigated the chemosensitivity of APEX1 and Jagged1 through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Western blot. Alternately, the 10 patients of advanced biliary cancer consist of 2 group according to the chemotherapy response examined by immunohistochemistry using APEX1 and Jagged1 antibody, and protein expression level was scored for staining intensity and percent positive cell. Results: The result of MTT assay after APEX1 knockdown showed that strong coexpression of APEX1 and Jagged1 cell line (SNU-245, SNU-1079, and SNU-1196) showed a greater decrease in $IC_{50}$ of chemotherapeutic agent (5-fluorouracil, gemcitabine and cisplatin). The Western blot analysis of APEX1 and Jagged1 expression in biliary cancer cell lines after APEX1 knockdown definitively demonstrated decreased Jagged1 expression. The APEX1 and Jagged1expression level of immunohistochemistry represented that chemorefractory patients had higher than chemoresponsive patients. Conclusion: These results demonstrate that simultaneous high expression of APEX1 and Jagged1 is associated with chemoresistance in biliary cancer and suggest that is a potential therapeutic target for chemoresistance in advanced biliary cancer.

MiR-363 inhibits cisplatin chemoresistance of epithelial ovarian cancer by regulating snail-induced epithelial-mesenchymal transition

  • Cao, Lanqin;Wan, Qian;Li, Fengjie;Tang, Can-e
    • BMB Reports
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    • v.51 no.9
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    • pp.456-461
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    • 2018
  • Chemoresistance is a major barrier to successful cisplatin-based chemotherapy for epithelial ovarian cancer (EOC), and emerging evidences suggest that microRNAs (miRNAs) are involved in the resistance. In this study, it was indicated that miR-363 downregulation was significantly correlated with EOC carcinogenesis and cisplatin resistance. Moreover, miR-363 overexpression could resensitise cisplatin-resistant EOC cells to cisplatin treatment both in vitro and in vivo. In addition, data revealed that EMT inducer Snail was significantly upregulated in cisplatin-resistant EOC cell lines and EOC patients and was a functional target of miR-363 in EOC cells. Furthermore, snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells. Taken together, findings suggest that miR-363 may be a biomarker for predicting responsiveness to cisplatin-based chemotherapy and a potential therapeutic target in EOC.

Sensitization of 5-Fluorouracil-Resistant SNUC5 Colon Cancer Cells to Apoptosis by α-Mangostin

  • Lee, June;Kang, Jong-Su;Choi, Bu-Young;Keum, Young-Sam
    • Biomolecules & Therapeutics
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    • v.24 no.6
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    • pp.604-609
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    • 2016
  • 5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5-fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5-FU bears a significant importance. In the present study, we have found that ${\alpha}$-mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of ${\alpha}$-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4-HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that ${\alpha}$-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated ${\alpha}$-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that ${\alpha}$-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5-FU by activating apoptosis pathway.

Prognostic Significance of CD109 Expression in Patients with Ovarian Epithelial Cancer

  • Kim, So Young;Choi, Kyung Un;Hwang, Chungsu;Lee, Hyung Jung;Lee, Jung Hee;Shin, Dong Hoon;Kim, Jee Yeon;Sol, Mee Young;Kim, Jae Ho;Kim, Ki Hyung;Suh, Dong Soo;Kwon, Byung Su
    • Journal of Pathology and Translational Medicine
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    • v.53 no.4
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    • pp.244-252
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    • 2019
  • Background: Ovarian epithelial cancer (OEC) is the second-most common gynecologic malignancy. CD109 expression is elevated in human tumor cell lines and carcinomas. A previous study showed that CD109 expression is elevated in human tumor cell lines and CD109 plays a role in cancer progression. Therefore, this study aimed to determine whether CD109 is expressed in OEC and can be useful in predicting the prognosis. Methods: Immunohistochemical staining for CD109 and reverse transcription-quantitative polymerase chain reaction was performed. Then we compared CD109 expression and chemoresistance, overall survival, and recurrence-free survival of OEC patients. Chemoresistance was evaluated by dividing into good-response group and poor-response group by the time to recurrence after chemotherapy. Results: CD109 expression was associated with overall survival (p=.020), but not recurrence-free survival (p=.290). CD109 expression was not an independent risk factor for overall survival due to its reliability (hazard ratio, 1.58; p=.160; 95% confidence interval, 0.82 to 3.05), although we found that CD109 positivity was related to chemoresistance. The poor-response group showed higher rates of CD109 expression than the good-response group (93.8% vs 66.7%, p=.047). Also, the CD109 mRNA expression level was 2.88 times higher in the poor-response group as compared to the good-response group (p=.001). Conclusions: Examining the CD109 expression in patients with OEC may be helpful in predicting survival and chemotherapeutic effect.