Mitochondrial translocation of human telomerase reverse enzyme promotes stemness and drug-resistance of hepatocellular carcinoma cells

Xin Chang; Changjiang Hu; Shengyu Deng; Xin Yang; Shiming Yang; Xianlong Ling

doi:10.16016/j.1000-5404.201610159

您当前的位置：

首页 >

文章列表页 >

Mitochondrial translocation of human telomerase reverse enzyme promotes stemness and drug-resistance of hepatocellular carcinoma cells

更新时间：2026-01-09

- Mitochondrial translocation of human telomerase reverse enzyme promotes stemness and drug-resistance of hepatocellular carcinoma cells
- Journal of Third Military Medical University Vol. 39, Issue 8, Pages: 781-786(2017)
- 作者机构：
- 作者简介：
- 基金信息：
- DOI：10.16016/j.1000-5404.201610159
  CLC：
- Published：2017-04
- 稿件说明：
移动端阅览
Xin Chang, Changjiang Hu, Shengyu Deng, et al. Mitochondrial translocation of human telomerase reverse enzyme promotes stemness and drug-resistance of hepatocellular carcinoma cells[J]. Journal of Third Military Medical University, 2017, 39(8): 781-786.
DOI：

Xin Chang, Changjiang Hu, Shengyu Deng, et al. Mitochondrial translocation of human telomerase reverse enzyme promotes stemness and drug-resistance of hepatocellular carcinoma cells[J]. Journal of Third Military Medical University, 2017, 39(8): 781-786. DOI： 10.16016/j.1000-5404.201610159.

摘要

Abstract

Objective

To determine the effect of mitochondrial translocation of human telomerase reverse enzyme (hTERT) on the stemness and drug-resistance of hepatocellular carcinoma (HCC) cells.

Methods

Human HCC cell lines HepG2 and Huh7 were exposed intermittently to cisplatin (CDDP) to obtain cisplatin-resistant cell lines HepG2/CDDP and Huh7/CDDP. CCK-8 assay was employed to detect cell sensitivity to CDDP. Western blotting was adopted to detect hTERT protein level in the mitochondria

and mitochondrial membrane potential was measured by confocal laser scanning microscopy. Flow cytometry was used to detect the expression of cell stemness-related proteins CD133 and EpCAM

and the colony formation ability of the cells was assessed with colony formation assay; Western blotting was used to detect the expression level of stemness-related factor OCT-4.

Results

The resistance indexes of CDDP-resistant HepG2 and Huh7 cells were significantly increased compared with their parental cells (HepG2: 41.16±0.42

7.69±0.86 μg/mL; Huh7: 33.48±0.33

7.18±0.35 μg/mL

0.01). The CDDP-resistant cells exhibited significantly increased mitochondrial hTERT expression and mitochondrial membrane potential with increased proportions of CD133

cells (HepG2: 1.44±0.41

HepG2/CDDP: 23.15±1.55

0.01) and EpCAM

cells (HepG2: 0.85±0.10

HepG2/CDDP: 3.96±0.10

0.01). The resistant cells also showed significantly enhanced colony formation ability and increased expression of OCT-4 protein.

Conclusion

The translocation of mitochondrial hTERT is significantly increased in CDDP-resistant cells

which possess obvious phenotypes of tumor stem cells.

关键词

Keywords

references

Miyajima A Tanaka M Itoh T Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogram-ming Cell Stem Cell 2014 14 5 561 574 10.1016/j.stem.2014.04.010 Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogram-ming [J]. Cell Stem Cell, 2014, 14(5): 561-574. DOI:10. 1016/j.stem.2014.04.010.

Siddik Z H Cisplatin: mode of cytotoxic action and molecular basis of resistance Oncogene 2003 22 47 7265 7279 10.1038/sj.onc.1206933 Siddik Z H. Cisplatin: mode of cytotoxic action and molecular basis of resistance[J]. Oncogene, 2003, 22(47): 7265-7279. DOI:10.1038/sj.onc.1206933.

Liu F S Mechanisms of chemotherapeutic drug resistance in cancer therapy--a quick review Taiwan J Obstet Gynecol 2009 48 3 239 244 10.1016/S1028-4559(09)60296-5 Liu F S. Mechanisms of chemotherapeutic drug resistance in cancer therapy--a quick review[J]. Taiwan J Obstet Gynecol, 2009, 48(3): 239-244. DOI:10.1016/S1028-4559(09)60296-5.

Kuo K K Lee K T Chen K K Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer Stem Cells 2016 34 11 2613 2624 10.1002/stem.2447 Kuo K K, Lee K T, Chen K K, et al. Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer[J]. Stem Cells, 2016, 34(11): 2613-2624. DOI:10. 1002/stem.2447.

Bram E E Stark M Raz S Chemotherapeutic drug-induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance Neoplasia 2009 11 12 1359 1370 10.1593/neo.91314 Bram E E, Stark M, Raz S, et al. Chemotherapeutic drug-induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance[J]. Neoplasia, 2009, 11(12): 1359-1370. DOI:10.1593/neo.91314.

McIntosh K Balch C Tiwari A K Tackling multidrug resistance mediated by efflux transporters in tumor-initiating cells Expert Opin Drug Metab Toxicol 2016 12 6 633 644 10.1080/17425255.2016.1179280 McIntosh K, Balch C, Tiwari A K. Tackling multidrug resistance mediated by efflux transporters in tumor-initiating cells[J]. Expert Opin Drug Metab Toxicol, 2016, 12(6): 633-644. DOI:10.1080/17425255.2016.1179280.

Deville L Hillion J Pendino F hTERT promotes imatinib resistance in chronic myeloid leukemia cells: therapeutic implications Mol Cancer Ther 2011 10 5 711 719 10.1158/1535-7163.MCT-10-0979 Deville L, Hillion J, Pendino F, et al. hTERT promotes imatinib resistance in chronic myeloid leukemia cells: therapeutic implications[J]. Mol Cancer Ther, 2011, 10(5): 711-719. DOI:10.1158/1535-7163.MCT-10-0979.

Liu N Ding D Hao W hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor Nucleic Acids Res 2016 44 18 8693 8703 10.1093/nar/gkw549 Liu N, Ding D, Hao W, et al. hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor[J]. Nucleic Acids Res, 2016, 44(18): 8693-8703. DOI:10.1093/nar/gkw549.

Jafri M A Ansari S A Alqahtani M H Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies Genome Med 2016 8 1 69 10.1186/s13073-016-0324-x Jafri M A, Ansari S A, Alqahtani M H, et al. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies[J]. Genome Med, 2016, 8(1): 69. DOI:10.1186/s13073-016-0324-x.

张丹郝宁波唐波 miR-1182调控胃癌细胞人端粒酶反转录酶的分子机制及其对迁移能力的影响第三军医大学学报 2014 36 10 1074 1077 10.16016/j.1000-5404.2014.10.033 http://aammt.tmmu.edu.cn/oa/DArticle.aspx?type=view&id=201401234 张丹, 郝宁波, 唐波, 等. miR-1182调控胃癌细胞人端粒酶反转录酶的分子机制及其对迁移能力的影响[J].第三军医大学学报, 2014, 36(10):1074-1077. DOI:10.16016/j.1000-5404.2014.10.033.

Zhang Dan Hao Ningbo Tang Bo Mechanism of miR-1182 regulating human telomerase reverse transcriptase in gastric cancer cells and its effect on cell migration capability J Third Mil Med Univ 2014 36 10 1074 1077 10.16016/j.1000-5404.2014.10.033 http://aammt.tmmu.edu.cn/oa/DArticle.aspx?type=view&id=201401234 Zhang Dan, Hao Ningbo, Tang Bo, et al. Mechanism of miR-1182 regulating human telomerase reverse transcriptase in gastric cancer cells and its effect on cell migration capability[J]. J Third Mil Med Univ, 2014, 36(10):1074-1077. DOI:10.16016/j.1000-5404.2014.10.033.

Saretzki G Extra-telomeric functions of human telomerase: cancer, mitochondria and oxidative stress Curr Pharm Des 2014 20 41 6386 6403 10.2174/1381612820666140630095606 Saretzki G. Extra-telomeric functions of human telomerase: cancer, mitochondria and oxidative stress[J]. Curr Pharm Des, 2014, 20(41): 6386-6403. DOI:10.2174/1381612820666140630095606.

Santos J H Meyer J N Skorvaga M Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage Aging Cell 2004 3 6 399 411 10.1111/j.1474-9728.2004.00124.x Santos J H, Meyer J N, Skorvaga M, et al. Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage[J]. Aging Cell, 2004, 3(6): 399-411. DOI:10.1111/j.1474-9728.2004.00124.x.

Sharma N K Reyes A Green P Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria Nucleic Acids Res 2012 40 2 712 725 10.1093/nar/gkr758 Sharma N K, Reyes A, Green P, et al. Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria[J]. Nucleic Acids Res, 2012, 40(2): 712-725. DOI:10. 1093/nar/gkr758.

Haendeler J Drose S Buchner N Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage Arterioscler Thromb Vasc Biol 2009 29 6 929 935 10.1161/atvbaha.109.185546 Haendeler J, Drose S, Buchner N, et al. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage[J]. Arterioscler Thromb Vasc Biol, 2009, 29(6): 929-935. DOI:10.1161/atvbaha.109.185546.

Indran I R Hande M P Pervaiz S hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells Cancer Res 2010 71 1 266 276 10.1158/0008-5472.can-10-1588 Indran I R, Hande M P, Pervaiz S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells[J]. Cancer Res, 2010, 71(1): 266-276. DOI:10. 1158/0008-5472.can-10-1588.

Singhapol C Pal D Czapiewski R Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis PLoS ONE 2013 8 1 e52989 10.1371/journal.pone.0052989 Singhapol C, Pal D, Czapiewski R, et al. Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis[J]. PLoS ONE, 2013, 8(1): e52989. DOI:10.1371/journal.pone.0052989.

Ling X Zhou Y Li S W Modulation of mitochondrial permeability transition pore affects multidrug resistance in human hepatocellular carcinoma cells Int J Biol Sci 2010 6 7 773 783 10.7150/ijbs.6.773 Ling X, Zhou Y, Li S W, et al. Modulation of mitochondrial permeability transition pore affects multidrug resistance in human hepatocellular carcinoma cells[J]. Int J Biol Sci, 2010, 6(7): 773-783. DOI:10.7150/ijbs.6.773.

Ling X Wen L Zhou Y Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance Int J Med Sci 2012 9 7 545 554 10.7150/ijms.4648 Ling X, Wen L, Zhou Y. Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance[J]. Int J Med Sci, 2012, 9(7): 545-554. DOI:10.7150/ijms.4648.

Yan J Zhou Y Chen D Effects of mitochondrial translocation of telomerase on drug resistance in hepatocellular carcinoma cells J Cancer 2015 6 2 151 159 10.7150/jca.10419 Yan J, Zhou Y, Chen D, et al. Effects of mitochondrial translocation of telomerase on drug resistance in hepatocellular carcinoma cells[J]. J Cancer, 2015, 6(2): 151-159. DOI:10.7150/jca.10419.

Santos J H Meyer J N Van Houten B Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis Hum Mol Genet 2006 15 11 1757 1768 10.1093/hmg/ddl098 Santos J H, Meyer J N, Van Houten B. Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis[J]. Hum Mol Genet, 2006, 15(11): 1757-1768. DOI:10.1093/hmg/ddl098.

Indran I R Hande M P Pervaiz S hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells Cancer Res 2011 71 1 266 276 10.1158/0008-5472.can-10-1588 Indran I R, Hande M P, Pervaiz S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells[J]. Cancer Res, 2011, 71(1): 266-276. DOI:10.1158/0008-5472.can-10-1588.

Kovalenko OA Kaplunov J Herbig U Expression of (NES-) hTERT in cancer cells delays cell cycle progression and increases sensitivity to genotoxic stress PLoS ONE 2010 5 5 e10812 10.1371/journal.pone.0010812 Kovalenko OA, Kaplunov J, Herbig U, et al. Expression of (NES-) hTERT in cancer cells delays cell cycle progression and increases sensitivity to genotoxic stress[J]. PLoS ONE, 2010, 5(5): e10812. DOI:10.1371/journal.pone.0010812.

Kovalenko O A Caron M J Ulema P A mutant telomerase defective in nuclear-cytoplasmic shuttling fails to immortalize cells and is associated with mitochondrial dysfunction Aging Cell 2010 9 2 203 219 10.1111/j.1474-9726.2010.00551.x Kovalenko O A, Caron M J, Ulema P, et al. A mutant telomerase defective in nuclear-cytoplasmic shuttling fails to immortalize cells and is associated with mitochondrial dysfunction[J]. Aging Cell, 2010, 9(2): 203-219. DOI:10.1111/j.1474-9726.2010.00551.x.

Balaban R S Nemoto S Finkel T Mitochondria, oxidants, and aging Cell 2005 120 4 483 495 10.1016/j.cell.2005.02.001 Balaban R S, Nemoto S, Finkel T. Mitochondria, oxidants, and aging[J]. Cell, 2005, 120(4): 483-495. DOI:10.1016/j.cell.2005.02.001.

Zhou D Shao L Spitz D R Reactive oxygen species in normal and tumor stem cells Adv Cancer Res 2014 122 1 67 10.1016/B978-0-12-420117-0.00001-3 Zhou D, Shao L, Spitz D R. Reactive oxygen species in normal and tumor stem cells[J]. Adv Cancer Res, 2014, 122: 1-67. DOI:10.1016/B978-0-12-420117-0.00001-3.

Madungwe N B Zilberstein N F Feng Y Critical role of mitochondrial ROS is dependent on their site of production on the electron transport chain in ischemic heart Am J Cardiovasc Dis 2016 6 3 93 108 https://www.researchgate.net/publication/308762709_Critical_role_of_mitochondrial_ROS_is_dependent_on_their_site_of_production_on_the_electron_transport_chain_in_ischemic_heart Madungwe N B, Zilberstein N F, Feng Y, et al. Critical role of mitochondrial ROS is dependent on their site of production on the electron transport chain in ischemic heart[J]. Am J Cardiovasc Dis, 2016, 6(3): 93-108.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Chronic hypoxia reduces cold tolerance via hepatic ANGPTL3-driven mitochondrial damage and adipose thermogenesis suppression

Effect of TNTs-mediated mitochondrial transfer between mesenchymal stem cells and endothelial cells on vascularization in vitro

Palmitic acid increases apoptosis by mitochondrial pathway in hepatocytes with growth hormone deficiency

Luteolin attenuates oxidative stress in mice with cerebral ischemia-reperfusion by inhibiting Drp1 activation and promoting autophagy flux

Effects of esmolol on cardiomyocyte apoptosis in septic rats

Related Author

HUANG Yujie

HUANG Lingfang

ZHEGN Minghai

XIONG Kun

TAN Xiaoling

Yunying HE

Hua ZHANG

Ping JI

Related Institution

Department of Clinical Nursing, School of Nursing， Army Medical University （Third Military Medical University）

Key Laboratory of Extreme Environmental Medicine of Ministry of Education, School of Nursing， Army Medical University （Third Military Medical University）

Department of Frigid Zone Medicine， College of High Altitude Military Medicine, School of Nursing， Army Medical University （Third Military Medical University）

Department of Obstetrics and Gynaecology, the First Affiliated Hospital of Chongqing Medical University

Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Key Laboratory of Oral Biomedical Engineering of Higher Education, College of Stomatology, Chongqing Medical University

⁰