Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 11, Pages 2891-2904Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-1025
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Funding
- Developmental Research Award by Leukemia SPORE [P50 CA100632]
- National Institutes of Health (NIH/NCATS) through the NIHCommon Fund, Office of Strategic Coordination (OSC) [UH3TR00943-01]
- NIH/NCI [1 R01 CA182905-01]
- UT MD Anderson Cancer Center SPORE in Melanoma grant from NCI [P50 CA093459]
- Aim at Melanoma Foundation
- Miriam and Jim Mulva research funds
- UT MD Anderson Cancer Center Brain SPORE [2P50CA127001]
- Developmental Research award from Leukemia SPORE
- CLL Moonshot Flagship project
- Knowledge GAP MDACC grant
- Owens Foundation
- Estate of C.G. Johnson
- Concern Foundation
- Hyundai Hope of Wheels
- STOP Cancer
- Alex's Lemonade
- William Lawrence and Blanche Hughes Foundation
- Jean Perkins Foundation
- Nautica Malibu Triathlon Funds
- National Cancer Institute at the National Institutes of Health [P30CA014089, U54 CA151668]
- Hugh and Audy Lou Colvin Foundation
- Shirley McKernan donation
- POSCCE grant [709/2010]
- Associazione Italiana per la Ricerca sul Cancro (the Italian Association for Cancer Research (AIRC)) [9980]
- AIRC Innovative immunotherapeutic treatments of human cancer [16695]
- Betty Anne Asche Murray Distinguished Professorship
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Purpose: The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design: We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Results: We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. Weshow that anti-miR-155-DOPC can be considered nontoxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions: Our findings support the existence of an miR155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death. (C) 2016 AACR.
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