miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2 article

M.E. Fiori, L. Villanova, C. Barbini, M.L. De Angelis, R. De Maria

Research output: Contribution to journalArticle

Abstract

Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs' expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo. © 2018 The Author(s).
Original languageEnglish
JournalCell Death and Disease
Volume9
Issue number2
DOIs
Publication statusPublished - 2018

Fingerprint

Mitochondrial Membranes
Non-Small Cell Lung Carcinoma
MicroRNAs
Neoplasms
Cell Death
Growth
Lung Neoplasms
Carcinogenesis
Cell Proliferation
Apoptosis
Therapeutics
Proteins

Keywords

  • BH3 protein
  • BTG2 protein
  • microRNA
  • microRNA 663
  • protein
  • PUMA protein
  • unclassified drug
  • animal experiment
  • animal model
  • apoptosis
  • Article
  • cell death
  • controlled study
  • female
  • human
  • human cell
  • in vivo study
  • membrane depolarization
  • mitochondrial membrane
  • mouse
  • non small cell lung cancer
  • nonhuman
  • outer membrane
  • priority journal
  • protein expression

Cite this

miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2 article. / Fiori, M.E.; Villanova, L.; Barbini, C.; De Angelis, M.L.; De Maria, R.

In: Cell Death and Disease, Vol. 9, No. 2, 2018.

Research output: Contribution to journalArticle

@article{42fd0bd7067f43bb9214ba7b8ab7318e,
title = "miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2 article",
abstract = "Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs' expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo. {\circledC} 2018 The Author(s).",
keywords = "BH3 protein, BTG2 protein, microRNA, microRNA 663, protein, PUMA protein, unclassified drug, animal experiment, animal model, apoptosis, Article, cell death, controlled study, female, human, human cell, in vivo study, membrane depolarization, mitochondrial membrane, mouse, non small cell lung cancer, nonhuman, outer membrane, priority journal, protein expression",
author = "M.E. Fiori and L. Villanova and C. Barbini and {De Angelis}, M.L. and {De Maria}, R.",
note = "Cited By :4 Export Date: 11 April 2019 Correspondence Address: Fiori, M.E.; Institute of General Pathology, Catholic University of the Sacred Heart and Gemelli PolyclinicItaly; email: fiorimicol@gmail.com Chemicals/CAS: protein, 67254-75-5 Funding details: Associazione Italiana per la Ricerca sul Cancro Funding details: PGR00674 Funding details: Fondazione Italiana per la Ricerca sul Cancro Funding details: TV3, 432/C/2013 Funding details: Associazione Italiana per la Ricerca sul Cancro, 13431 Funding text 1: R.D.M. was supported by Italian Association for Cancer Research (AIRC) (Investigator Grant 13431), Fundaci{\`o} La Marat{\`o} de TV3 (project 432/C/2013) and Italian Ministry of Foreign Affairs and International Cooperation & Italian Ministry of Education, University and Research to RDM (project PGR00674). L.V. is supported by FIRC (Triennial Fellowship 2015). We thank Adriana Eramo for sharing material, Mario Falchi for precious assistance with confocal imaging, Alessandra Boe for FACS analyses and Stefano Forte for bio-statistical support. References: Siegel, R., Naishadham, D., Jemal, A., Cancer statistics 2013 (2013) CA Cancer J. Clin, 63, pp. 11-30; Izumchenko, E., Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA (2015) Nat. Commun, 6, p. 8258; Alberg, A.J., Brock, M.V., Ford, J.G., Samet, J.M., Spivack, S.D., Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines (2013) Chest, 143, pp. e1S-e129; McIntyre, A., Ganti, A.K., Lung cancer-A global perspective (2017) J. Surg. Oncol, 115, pp. 550-554; Ha, M., Kim, V.N., Regulation ofmicroRNA biogenesis (2014) Nat. Rev. Mol. Cell Biol, 15, pp. 509-524; Jonas, S., Izaurralde, E., Towards a molecular understanding of microRNAmediated gene silencing (2015) Nat. Rev. Genet, 16, pp. 421-433; Hayes, J., Peruzzi, P.P., Lawler, S., MicroRNAs in cancer: Biomarkers, functions and therapy (2014) Trends Mol. Med, 20, pp. 460-469; Lin, S., Gregory, R.I., MicroRNA biogenesis pathways in cancer (2015) Nat. Rev. Cancer, 15, pp. 321-333; Nana-Sinkam, S.P., Croce, C.M., Clinical applications for microRNAs in cancer (2013) Clin. Pharmacol. Ther, 93, pp. 98-104; Cotter, T.G., Apoptosis and cancer: The genesis of a research field (2009) Nat. Rev. Cancer, 9, pp. 501-507; Hanahan, D., Weinberg, R.A., Hallmarks of cancer: The next generation (2011) Cell, 144, pp. 646-674; Fiori, M.E., Antitumor effect of miR-197 targeting in p53 wild-Type lung cancer (2014) Cell Death Differ, 21, pp. 774-782; Yu, J., Zhang, L., Hwang, P.M., Kinzler, K.W., Vogelstein, B., PUMA induces the rapid apoptosis of colorectal cancer cells (2001) Mol. Cell, 7, pp. 673-682; Nakano, K., Vousden, K.H., PUMA a novel proapoptotic gene, is induced by p53 (2001) Mol. Cell, 7, pp. 683-694; Han, J., Expression ofbbc3, a pro-Apoptotic BH3-only gene, is regulated by diverse cell death and survival signals (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 11318-11323; Jeffers, J.R., Puma is an essential mediator of p53-dependent and -independent apoptotic pathways (2003) Cancer Cell, 4, pp. 321-328; Chipuk, J.E., Bouchier-Hayes, L., Kuwana, T., Newmeyer, D.D., Green, D.R., PUMA couples the nuclear and cytoplasmic proapoptotic function ofp53 (2005) Science, 309, pp. 1732-1735; Yu, J., Zhang, L., PUMA a potent killer with or without p53 (2008) Oncogene, 27, pp. S71-S83; Vousden, K.H., Apoptosis p53 and PUMA: A deadly duo (2005) Science, 309, pp. 1685-1686; Beroukhim, R., The landscape of somatic copy-number alteration across human cancers (2010) Nature, 463, pp. 899-905; Yi, C., MiR-663, a microRNA targeting p21(WAF1/CIP1), promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma (2012) Oncogene, 31, pp. 4421-4433; Okamura, S., P53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis (2001) Mol. Cell, 8, pp. 85-94; Seillier, M., TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death (2012) Cell Death Differ, 19, pp. 1525-1535; Tomasini, R., TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity (2003) J. Biol. Chem, 278, pp. 37722-37729; Melamed, J., Kernizan, S., Walden, P.D., Expression of B-cell translocation gene 2 protein in normal human tissues (2002) Tissue Cell, 34, pp. 28-32; Rouault, J.P., Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway (1996) Nat. Genet, 14, pp. 482-486; Guardavaccaro, D., Arrest of G 1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription (2000) Mol. Cell Biol, (20), pp. 1797-1815; Lim, I.K., TIS21 (/BTG2/PC3) as a link between ageing and cancer: Cell cycle regulator and endogenous cell death molecule (2006) J. Cancer Res. Clin. Oncol, 132, pp. 417-426; Boiko, A.D., A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Rasinduced transformation (2006) Genes Dev, 20, pp. 236-252; Struckmann, K., Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma (2004) Cancer Res, 64, pp. 1632-1638; Kawakubo, H., Loss of B-cell translocation gene-2 in estrogen receptorpositive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein (2006) Cancer Res, 66, pp. 7075-7082; Ficazzola, M.A., Antiproliferative B cell translocation gene 2 protein is down-regulated post-Transcriptionally as an early event in prostate carcinogenesis (2001) Carcinogenesis, 22, pp. 1271-1279; Hong, J.W., Ryu, M.S., Lim, I.K., Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death (2005) J. Biol. Chem, 280, pp. 21256-21263; Sorrentino, G., The prolyl-isomerase Pin1 activates the mitochondrial death program of p53 (2013) Cell Death Differ, 20, pp. 198-208; Sorrentino, G., Comel, A., Mantovani, F., Del Sal, G., Regulation of mitochondrial apoptosis by Pin1 in cancer and neurodegeneration (2014) Mitochondrion, 19, pp. 88-96; Marchenko, N.D., Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-Alpha3 binding (2010) Cell Death Differ, 17, pp. 255-267; Marchenko, N.D., Wolff, S., Erster, S., Becker, K., Moll, U.M., Monoubiquitylation promotes mitochondrial p53 translocation (2007) EMBO J, 26, pp. 923-934; Zacchi, P., The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults (2002) Nature, 419, pp. 853-857; Leu, J.I., Dumont, P., Hafey, M., Murphy, M.E., George, D.L., Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex (2004) Nat. Cell. Biol, 6, pp. 443-450; Eramo, A., Identification and expansion of the tumorigenic lung cancer stem cell population (2008) Cell Death Differ, 15, pp. 504-514; Pan, J., Tumor-suppressive mir-663 gene induces mitotic catastrophe growth arrest in human gastric cancer cells (2010) Oncol. Rep, 24, pp. 105-112; Croce, C.M., Causes and consequences of microRNA dysregulation in cancer (2009) Nat. Rev. Genet, 10, pp. 704-714; Shi, Y., MiR-663 suppresses oncogenic function of CXCR4 in glioblastoma (2015) Clin. Cancer Res, 21, pp. 4004-4013; Shi, Y., Primate-specific miR-663 functions as a tumor suppressor by targeting PIK3CD and predicts the prognosis of human glioblastoma (2014) Clin. Cancer Res, 20, pp. 1803-1813; Zang, W., miR-663 attenuates tumor growth and invasiveness by targeting eEF1A2 in pancreatic cancer (2015) Mol. Cancer, 14, p. 37; Wang, Z., Zhang, H., Zhang, P., Dong, W., He, L., MicroRNA-663 suppresses cell invasion and migration by targeting transforming growth factor beta 1 in papillary thyroid carcinoma (2015) Tumour Biol, 37, pp. 7633-7644; Jiao, L., MiR-663 induces castration-resistant prostate cancer transformation and predicts clinical recurrence (2014) J. Cell. Physiol, 229, pp. 834-844; Liu, Z.Y., Zhang, G.L., Wang, M.M., Xiong, Y.N., Cui, H.Q., MicroRNA-663 targets TGFB1 and regulates lung cancer proliferation (2011) Asian Pac. J. Cancer Prev, 12, pp. 2819-2823; Evan, G.I., Vousden, K.H., Proliferation cell cycle and apoptosis in cancer (2001) Nature, 411, pp. 342-348; Fulda, S., Galluzzi, L., Kroemer, G., Targeting mitochondria for cancer therapy (2010) Nat. Rev. Drug Discov, 9, pp. 447-464; Delbridge, A.R., Strasser, A., The BCL-2 protein family BH3-mimetics and cancer therapy (2015) Cell Death Differ, 22, pp. 1071-1080; Souers, A.J., ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets (2013) Nat. Med, 19, pp. 202-208; Ashkenazi, A., Fairbrother, W.J., Leverson, J.D., Souers, A.J., From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors (2017) Nat. Rev. Drug Discov, 16, pp. 273-284",
year = "2018",
doi = "10.1038/s41419-017-0080-x",
language = "English",
volume = "9",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2 article

AU - Fiori, M.E.

AU - Villanova, L.

AU - Barbini, C.

AU - De Angelis, M.L.

AU - De Maria, R.

N1 - Cited By :4 Export Date: 11 April 2019 Correspondence Address: Fiori, M.E.; Institute of General Pathology, Catholic University of the Sacred Heart and Gemelli PolyclinicItaly; email: fiorimicol@gmail.com Chemicals/CAS: protein, 67254-75-5 Funding details: Associazione Italiana per la Ricerca sul Cancro Funding details: PGR00674 Funding details: Fondazione Italiana per la Ricerca sul Cancro Funding details: TV3, 432/C/2013 Funding details: Associazione Italiana per la Ricerca sul Cancro, 13431 Funding text 1: R.D.M. was supported by Italian Association for Cancer Research (AIRC) (Investigator Grant 13431), Fundaciò La Maratò de TV3 (project 432/C/2013) and Italian Ministry of Foreign Affairs and International Cooperation & Italian Ministry of Education, University and Research to RDM (project PGR00674). L.V. is supported by FIRC (Triennial Fellowship 2015). We thank Adriana Eramo for sharing material, Mario Falchi for precious assistance with confocal imaging, Alessandra Boe for FACS analyses and Stefano Forte for bio-statistical support. References: Siegel, R., Naishadham, D., Jemal, A., Cancer statistics 2013 (2013) CA Cancer J. Clin, 63, pp. 11-30; Izumchenko, E., Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA (2015) Nat. Commun, 6, p. 8258; Alberg, A.J., Brock, M.V., Ford, J.G., Samet, J.M., Spivack, S.D., Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines (2013) Chest, 143, pp. e1S-e129; McIntyre, A., Ganti, A.K., Lung cancer-A global perspective (2017) J. Surg. Oncol, 115, pp. 550-554; Ha, M., Kim, V.N., Regulation ofmicroRNA biogenesis (2014) Nat. Rev. Mol. Cell Biol, 15, pp. 509-524; Jonas, S., Izaurralde, E., Towards a molecular understanding of microRNAmediated gene silencing (2015) Nat. Rev. Genet, 16, pp. 421-433; Hayes, J., Peruzzi, P.P., Lawler, S., MicroRNAs in cancer: Biomarkers, functions and therapy (2014) Trends Mol. Med, 20, pp. 460-469; Lin, S., Gregory, R.I., MicroRNA biogenesis pathways in cancer (2015) Nat. Rev. Cancer, 15, pp. 321-333; Nana-Sinkam, S.P., Croce, C.M., Clinical applications for microRNAs in cancer (2013) Clin. Pharmacol. Ther, 93, pp. 98-104; Cotter, T.G., Apoptosis and cancer: The genesis of a research field (2009) Nat. Rev. Cancer, 9, pp. 501-507; Hanahan, D., Weinberg, R.A., Hallmarks of cancer: The next generation (2011) Cell, 144, pp. 646-674; Fiori, M.E., Antitumor effect of miR-197 targeting in p53 wild-Type lung cancer (2014) Cell Death Differ, 21, pp. 774-782; Yu, J., Zhang, L., Hwang, P.M., Kinzler, K.W., Vogelstein, B., PUMA induces the rapid apoptosis of colorectal cancer cells (2001) Mol. Cell, 7, pp. 673-682; Nakano, K., Vousden, K.H., PUMA a novel proapoptotic gene, is induced by p53 (2001) Mol. Cell, 7, pp. 683-694; Han, J., Expression ofbbc3, a pro-Apoptotic BH3-only gene, is regulated by diverse cell death and survival signals (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 11318-11323; Jeffers, J.R., Puma is an essential mediator of p53-dependent and -independent apoptotic pathways (2003) Cancer Cell, 4, pp. 321-328; Chipuk, J.E., Bouchier-Hayes, L., Kuwana, T., Newmeyer, D.D., Green, D.R., PUMA couples the nuclear and cytoplasmic proapoptotic function ofp53 (2005) Science, 309, pp. 1732-1735; Yu, J., Zhang, L., PUMA a potent killer with or without p53 (2008) Oncogene, 27, pp. S71-S83; Vousden, K.H., Apoptosis p53 and PUMA: A deadly duo (2005) Science, 309, pp. 1685-1686; Beroukhim, R., The landscape of somatic copy-number alteration across human cancers (2010) Nature, 463, pp. 899-905; Yi, C., MiR-663, a microRNA targeting p21(WAF1/CIP1), promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma (2012) Oncogene, 31, pp. 4421-4433; Okamura, S., P53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis (2001) Mol. Cell, 8, pp. 85-94; Seillier, M., TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death (2012) Cell Death Differ, 19, pp. 1525-1535; Tomasini, R., TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity (2003) J. Biol. Chem, 278, pp. 37722-37729; Melamed, J., Kernizan, S., Walden, P.D., Expression of B-cell translocation gene 2 protein in normal human tissues (2002) Tissue Cell, 34, pp. 28-32; Rouault, J.P., Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway (1996) Nat. Genet, 14, pp. 482-486; Guardavaccaro, D., Arrest of G 1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription (2000) Mol. Cell Biol, (20), pp. 1797-1815; Lim, I.K., TIS21 (/BTG2/PC3) as a link between ageing and cancer: Cell cycle regulator and endogenous cell death molecule (2006) J. Cancer Res. Clin. Oncol, 132, pp. 417-426; Boiko, A.D., A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Rasinduced transformation (2006) Genes Dev, 20, pp. 236-252; Struckmann, K., Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma (2004) Cancer Res, 64, pp. 1632-1638; Kawakubo, H., Loss of B-cell translocation gene-2 in estrogen receptorpositive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein (2006) Cancer Res, 66, pp. 7075-7082; Ficazzola, M.A., Antiproliferative B cell translocation gene 2 protein is down-regulated post-Transcriptionally as an early event in prostate carcinogenesis (2001) Carcinogenesis, 22, pp. 1271-1279; Hong, J.W., Ryu, M.S., Lim, I.K., Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death (2005) J. Biol. Chem, 280, pp. 21256-21263; Sorrentino, G., The prolyl-isomerase Pin1 activates the mitochondrial death program of p53 (2013) Cell Death Differ, 20, pp. 198-208; Sorrentino, G., Comel, A., Mantovani, F., Del Sal, G., Regulation of mitochondrial apoptosis by Pin1 in cancer and neurodegeneration (2014) Mitochondrion, 19, pp. 88-96; Marchenko, N.D., Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-Alpha3 binding (2010) Cell Death Differ, 17, pp. 255-267; Marchenko, N.D., Wolff, S., Erster, S., Becker, K., Moll, U.M., Monoubiquitylation promotes mitochondrial p53 translocation (2007) EMBO J, 26, pp. 923-934; Zacchi, P., The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults (2002) Nature, 419, pp. 853-857; Leu, J.I., Dumont, P., Hafey, M., Murphy, M.E., George, D.L., Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex (2004) Nat. Cell. Biol, 6, pp. 443-450; Eramo, A., Identification and expansion of the tumorigenic lung cancer stem cell population (2008) Cell Death Differ, 15, pp. 504-514; Pan, J., Tumor-suppressive mir-663 gene induces mitotic catastrophe growth arrest in human gastric cancer cells (2010) Oncol. Rep, 24, pp. 105-112; Croce, C.M., Causes and consequences of microRNA dysregulation in cancer (2009) Nat. Rev. Genet, 10, pp. 704-714; Shi, Y., MiR-663 suppresses oncogenic function of CXCR4 in glioblastoma (2015) Clin. Cancer Res, 21, pp. 4004-4013; Shi, Y., Primate-specific miR-663 functions as a tumor suppressor by targeting PIK3CD and predicts the prognosis of human glioblastoma (2014) Clin. Cancer Res, 20, pp. 1803-1813; Zang, W., miR-663 attenuates tumor growth and invasiveness by targeting eEF1A2 in pancreatic cancer (2015) Mol. Cancer, 14, p. 37; Wang, Z., Zhang, H., Zhang, P., Dong, W., He, L., MicroRNA-663 suppresses cell invasion and migration by targeting transforming growth factor beta 1 in papillary thyroid carcinoma (2015) Tumour Biol, 37, pp. 7633-7644; Jiao, L., MiR-663 induces castration-resistant prostate cancer transformation and predicts clinical recurrence (2014) J. Cell. Physiol, 229, pp. 834-844; Liu, Z.Y., Zhang, G.L., Wang, M.M., Xiong, Y.N., Cui, H.Q., MicroRNA-663 targets TGFB1 and regulates lung cancer proliferation (2011) Asian Pac. J. Cancer Prev, 12, pp. 2819-2823; Evan, G.I., Vousden, K.H., Proliferation cell cycle and apoptosis in cancer (2001) Nature, 411, pp. 342-348; Fulda, S., Galluzzi, L., Kroemer, G., Targeting mitochondria for cancer therapy (2010) Nat. Rev. Drug Discov, 9, pp. 447-464; Delbridge, A.R., Strasser, A., The BCL-2 protein family BH3-mimetics and cancer therapy (2015) Cell Death Differ, 22, pp. 1071-1080; Souers, A.J., ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets (2013) Nat. Med, 19, pp. 202-208; Ashkenazi, A., Fairbrother, W.J., Leverson, J.D., Souers, A.J., From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors (2017) Nat. Rev. Drug Discov, 16, pp. 273-284

PY - 2018

Y1 - 2018

N2 - Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs' expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo. © 2018 The Author(s).

AB - Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs' expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo. © 2018 The Author(s).

KW - BH3 protein

KW - BTG2 protein

KW - microRNA

KW - microRNA 663

KW - protein

KW - PUMA protein

KW - unclassified drug

KW - animal experiment

KW - animal model

KW - apoptosis

KW - Article

KW - cell death

KW - controlled study

KW - female

KW - human

KW - human cell

KW - in vivo study

KW - membrane depolarization

KW - mitochondrial membrane

KW - mouse

KW - non small cell lung cancer

KW - nonhuman

KW - outer membrane

KW - priority journal

KW - protein expression

U2 - 10.1038/s41419-017-0080-x

DO - 10.1038/s41419-017-0080-x

M3 - Article

VL - 9

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 2

ER -