Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2016

Open Access 01-12-2016 | Primary research

MicroRNA-210 induces apoptosis in colorectal cancer via induction of reactive oxygen

Authors: Katrin E. Tagscherer, Anne Fassl, Tabea Sinkovic, Jutta Richter, Sabrina Schecher, Stephan Macher-Goeppinger, Wilfried Roth

Published in: Cancer Cell International | Issue 1/2016

Login to get access

Abstract

Background

Deregulation of miRNA-210 is a common event in several types of cancer. However, increased expression levels in the cancer tissue have been associated with both poor and good prognosis of patients. Similarly, the function of miR-210 with regard to cell growth and apoptosis is still controversial.

Methods

Overexpression of miR-210 was performed in HCT116, SW480 and SW707 colorectal cancer (CRC) cell lines. Functional effects of a modulated miR-210 expression were analyzed with regard to proliferation, clonogenicity, cell cycle distribution, reactive oxygen species (ROS) generation, and apoptosis. Furthermore, quantitative real time (RT)-PCR and immunoblot analyses were performed to investigate signaling pathways affected by miR-210.

Results

We show that in CRC cells miR-210 inhibits clonogenicity and proliferation which was accompanied by an accumulation of cells in the G2/M phase of the cell cycle. Additionally, overexpression of miR-210 results in an increase of ROS generation. Moreover, miR-210 mediated the induction of apoptosis which was associated with an upregulation of pro-apoptotic Bim expression and enhanced processing of Caspase 2. Importantly, inhibition of ROS generation rescued cells from miR-210-induced apoptosis.

Conclusions

Taken together, miR-210 induces apoptosis in CRC cells via a ROS-dependent mechanism.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
2.
3.
4.
5.
Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–54.CrossRefPubMed
6.
Hogan NM, Joyce MR, Kerin MJ. MicroRNA expression in colorectal cancer. Cancer Biomark. 2012;11(6):239–43.PubMed
7.
Vosa U, Vooder T, Kolde R, Vilo J, Metspalu A, Annilo T. Meta-analysis of microRNA expression in lung cancer. Int J Cancer. 2013;132(12):2884–93.CrossRefPubMed
8.
Guan P, Yin Z, Li X, Wu W, Zhou B. Meta-analysis of human lung cancer microRNA expression profiling studies comparing cancer tissues with normal tissues. J Exp Clin Cancer Res. 2012;31:54.CrossRefPubMedPubMedCentral
9.
Miko E, Czimmerer Z, Csanky E, Boros G, Buslig J, Dezso B, et al. Differentially expressed microRNAs in small cell lung cancer. Exp Lung Res. 2009;35(8):646–64.CrossRefPubMed
10.
Redova M, Poprach A, Besse A, Iliev R, Nekvindova J, Lakomy R, et al. MiR-210 expression in tumor tissue and in vitro effects of its silencing in renal cell carcinoma. Tumour Biol. 2013;34(1):481–91.CrossRefPubMed
11.
Osanto S, Qin Y, Buermans HP, Berkers J, Lerut E, Goeman JJ, et al. Genome-wide microRNA expression analysis of clear cell renal cell carcinoma by next generation deep sequencing. PLoS One. 2012;7(6):e38298.CrossRefPubMedPubMedCentral
12.
Juan D, Alexe G, Antes T, Liu H, Madabhushi A, Delisi C, et al. Identification of a microRNA panel for clear-cell kidney cancer. Urology. 2010;75(4):835–41.CrossRefPubMed
13.
Munari E, Marchionni L, Chitre A, Hayashi M, Martignoni G, Brunelli M, et al. Clear cell papillary renal cell carcinoma: micro-RNA expression profiling and comparison with clear cell renal cell carcinoma and papillary renal cell carcinoma. Hum Pathol. 2014;45(6):1130–8.CrossRefPubMedPubMedCentral
14.
Papaconstantinou IG, Manta A, Gazouli M, Lyberopoulou A, Lykoudis PM, Polymeneas G, et al. Expression of microRNAs in patients with pancreatic cancer and its prognostic significance. Pancreas. 2013;42(1):67–71.CrossRefPubMed
15.
Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K, et al. Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA. Proc Natl Acad Sci USA. 2012;109(8):3024–9.CrossRefPubMedPubMedCentral
16.
Ying Q, Liang L, Guo W, Zha R, Tian Q, Huang S, et al. Hypoxia-inducible microRNA-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma. Hepatology. 2011;54(6):2064–75.CrossRefPubMed
17.
Qu A, Du L, Yang Y, Liu H, Li J, Wang L, et al. Hypoxia-inducible MiR-210 is an independent prognostic factor and contributes to metastasis in colorectal cancer. PLoS One. 2014;9(3):e90952.CrossRefPubMedPubMedCentral
18.
Chen J, Wang W, Zhang Y, Chen Y, Hu T. Predicting distant metastasis and chemoresistance using plasma miRNAs. Med Oncol. 2014;31(1):799.CrossRefPubMed
19.
Ozata DM, Caramuta S, Velazquez-Fernandez D, Akcakaya P, Xie H, Hoog A, et al. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr Relat Cancer. 2011;18(6):643–55.CrossRefPubMedPubMedCentral
20.
Szabo DR, Luconi M, Szabo PM, Toth M, Szucs N, Horanyi J, et al. Analysis of circulating microRNAs in adrenocortical tumors. Lab Invest J Tech Methods Pathol. 2014;94(3):331–9.CrossRef
21.
Tsuchiya S, Fujiwara T, Sato F, Shimada Y, Tanaka E, Sakai Y, et al. MicroRNA-210 regulates cancer cell proliferation through targeting fibroblast growth factor receptor-like 1 (FGFRL1). J Biol Chem. 2011;286(1):420–8.CrossRefPubMed
22.
Giannakakis A, Sandaltzopoulos R, Greshock J, Liang S, Huang J, Hasegawa K, et al. miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer. Cancer Biol Ther. 2008;7(2):255–64.CrossRefPubMed
23.
Qiu S, Lin S, Hu D, Feng Y, Tan Y, Peng Y. Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients. J Transl Med. 2013;11(1):10.CrossRefPubMedPubMedCentral
24.
Hong L, Yang J, Han Y, Lu Q, Cao J, Syed L. High expression of miR-210 predicts poor survival in patients with breast cancer: a meta-analysis. Gene. 2012;507(2):135–8.CrossRefPubMed
25.
Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, et al. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008;14(5):1340–8.CrossRefPubMed
26.
Greither T, Grochola LF, Udelnow A, Lautenschlager C, Wurl P, Taubert H. Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer. 2010;126(1):73–80.CrossRefPubMed
27.
Gee HE, Camps C, Buffa FM, Patiar S, Winter SC, Betts G, et al. hsa-mir-210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer. Cancer. 2010;116(9):2148–58.PubMed
28.
Lai NS, Dong QS, Ding H, Miao ZL, Lin YC. MicroRNA-210 overexpression predicts poorer prognosis in glioma patients. J Clin Neurosci Off J Neurosurg Soc Australas. 2014;21(5):755–60.
29.
Eilertsen M, Andersen S, Al-Saad S, Richardsen E, Stenvold H, Hald SM, et al. Positive prognostic impact of miR-210 in non-small cell lung cancer. Lung Cancer. 2014;83(2):272–8.CrossRefPubMed
30.
McCormick RI, Blick C, Ragoussis J, Schoedel J, Mole DR, Young AC, et al. miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis. Br J Cancer. 2013;108(5):1133–42.CrossRefPubMedPubMedCentral
31.
Mei Y, Gao C, Wang K, Cui L, Li W, Zhao X, et al. Effect of microRNA-210 on prognosis and response to chemotherapeutic drugs in pediatric acute lymphoblastic leukemia. Cancer Sci. 2014;105(4):463–72.CrossRefPubMedPubMedCentral
32.
Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, et al. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem. 2008;283(23):15878–83.CrossRefPubMedPubMedCentral
33.
Yang W, Sun T, Cao J, Liu F, Tian Y, Zhu W. Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro. Exp Cell Res. 2012;318(8):944–54.CrossRefPubMed
34.
Chio CC, Lin JW, Cheng HA, Chiu WT, Wang YH, Wang JJ, et al. MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells. Arch Toxicol. 2013;87(3):459–68.CrossRefPubMed
35.
Bertero T, Grosso S, Robbe-Sermesant K, Lebrigand K, Henaoui IS, Puissegur MP, et al. ”Seed-milarity” confers to hsa-miR-210 and hsa-miR-147b similar functional activity. PLoS One. 2012;7(9):e44919.CrossRefPubMedPubMedCentral
36.
Nakada C, Tsukamoto Y, Matsuura K, Nguyen TL, Hijiya N, Uchida T, et al. Overexpression of miR-210, a downstream target of HIF1alpha, causes centrosome amplification in renal carcinoma cells. J Pathol. 2011;224(2):280–8.CrossRefPubMed
37.
Puissegur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, et al. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 2011;18(3):465–78.CrossRefPubMed
38.
39.
Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009;10(4):273–84.CrossRefPubMedPubMedCentral
40.
Favaro E, Ramachandran A, McCormick R, Gee H, Blancher C, Crosby M, et al. MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One. 2010;5(4):e10345.CrossRefPubMedPubMedCentral
41.
Yoshioka Y, Kosaka N, Ochiya T, Kato T. Micromanaging iron homeostasis: hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins. J Biol Chem. 2012;287(41):34110–9.CrossRefPubMedPubMedCentral
42.
Chen Z, Li Y, Zhang H, Huang P, Luthra R. Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene. 2010;29(30):4362–8.CrossRefPubMed
43.
Prasad V, Chandele A, Jagtap JC, Kumar PS, Shastry P. ROS-triggered caspase 2 activation and feedback amplification loop in beta-carotene-induced apoptosis. Free Radic Biol Med. 2006;41(3):431–42.CrossRefPubMed
44.
Tamm C, Zhivotovsky B, Ceccatelli S. Caspase-2 activation in neural stem cells undergoing oxidative stress-induced apoptosis. Apoptosis. 2008;13(3):354–63.CrossRefPubMed
45.
Li H, Bergeron L, Cryns V, Pasternack MS, Zhu H, Shi L, et al. Activation of caspase-2 in apoptosis. J Biol Chem. 1997;272(34):21010–7.CrossRefPubMed
46.
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol. 1999;144(2):281–92.CrossRefPubMedPubMedCentral
47.
Kurokawa H, Nishio K, Fukumoto H, Tomonari A, Suzuki T, Saijo N. Alteration of caspase-3 (CPP32/Yama/apopain) in wild-type MCF-7, breast cancer cells. Oncol Rep. 1999;6(1):33–7.PubMed
48.
He J, Wu J, Xu N, Xie W, Li M, Li J, et al. MiR-210 disturbs mitotic progression through regulating a group of mitosis-related genes. Nucleic Acids Res. 2013;41(1):498–508.CrossRefPubMed
49.
Faraonio R, Salerno P, Passaro F, Sedia C, Iaccio A, Bellelli R, et al. A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts. Cell Death Differ. 2012;19(4):713–21.CrossRefPubMed
50.
Zheng G, Tao Y, Yu W, Schwartz RJ. Brief report: SRF-dependent MiR-210 silences the sonic hedgehog signaling during cardiopoesis. Stem Cells. 2013;31(10):2279–85.CrossRefPubMed
51.
Kong LJ, Chang JT, Bild AH, Nevins JR. Compensation and specificity of function within the E2F family. Oncogene. 2007;26(3):321–7.CrossRefPubMed
52.
Burhans WC, Heintz NH. The cell cycle is a redox cycle: linking phase-specific targets to cell fate. Free Radic Biol Med. 2009;47(9):1282–93.CrossRefPubMed
53.
Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813(11):1978–86.CrossRefPubMed
54.
Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 2013;87(7):1157–80.CrossRefPubMed
55.
56.
Luo H, Yang Y, Duan J, Wu P, Jiang Q, Xu C. PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis. 2013;4:e481.CrossRefPubMedPubMedCentral
57.
Kim JH, Park SG, Song SY, Kim JK, Sung JH. Reactive oxygen species-responsive miR-210 regulates proliferation and migration of adipose-derived stem cells via PTPN2. Cell Death Dis. 2013;4:e588.CrossRefPubMedPubMedCentral
58.
Muralimanoharan S, Maloyan A, Mele J, Guo C, Myatt LG, Myatt L. MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. Placenta. 2012;33(10):816–23.CrossRefPubMedPubMedCentral
59.
60.
Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal. 2007;9(12):2277–93.CrossRefPubMed
61.
Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993;75(2):241–51.CrossRefPubMed
62.
Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, et al. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993;262(5137):1274–7.CrossRefPubMed
63.
Armstrong JS, Jones DP. Glutathione depletion enforces the mitochondrial permeability transition and causes cell death in Bcl-2 overexpressing HL60 cells. FASEB J Off Publ Fed Am Soc Exp Biol. 2002;16(10):1263–5.
64.
65.
Kumar S. Caspase 2 in apoptosis, the DNA damage response and tumour suppression: enigma no more? Nat Rev Cancer. 2009;9(12):897–903.CrossRefPubMed
66.
Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES. Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem. 2002;277(16):13430–7.CrossRefPubMed
67.
Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist. 2008;13(Suppl 3):21–6.CrossRefPubMed
68.
Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, et al. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell. 2009;35(6):856–67.CrossRefPubMedPubMedCentral
69.
70.
71.
Castro F, Dirks WG, Fahnrich S, Hotz-Wagenblatt A, Pawlita M, Schmitt M. High-throughput SNP-based authentication of human cell lines. Int J Cancer. 2013;132(2):308–14.CrossRefPubMed
72.
Tagscherer KE, Fassl A, Sinkovic T, Combs SE, Roth W. p53-dependent regulation of Mcl-1 contributes to synergistic cell death by ionizing radiation and the Bcl-2/Bcl-XL inhibitor ABT-737. Apoptosis. 2012;17(2):187–99.CrossRefPubMed
73.
Fassl A, Tagscherer KE, Richter J, Berriel Diaz M, Alcantara Llaguno SR, Campos B, et al. Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1. Oncogene. 2012;31(44):4698–708.CrossRefPubMed
Metadata
Title
MicroRNA-210 induces apoptosis in colorectal cancer via induction of reactive oxygen
Authors
Katrin E. Tagscherer
Anne Fassl
Tabea Sinkovic
Jutta Richter
Sabrina Schecher
Stephan Macher-Goeppinger
Wilfried Roth
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2016
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0321-6

Other articles of this Issue 1/2016

Cancer Cell International 1/2016 Go to the issue

Primary Research

The availability of the embryonic TGF-β protein Nodal is dynamically regulated during glioblastoma multiforme tumorigenesis

Primary research

Knockdown of PSCA induces EMT and decreases metastatic potentials of the human prostate cancer DU145 cells

Primary research

Identification of biological targets of therapeutic intervention for clear cell renal cell carcinoma based on bioinformatics approach

Primary research

Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth

Primary research

Alpha-synuclein contributes to malignant progression of human meningioma via the Akt/mTOR pathway

Review

Survivin: a unique target for tumor therapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits