| Sumario: | Abstract
Purpose: The oncogenic miR-155 is upregulated in many humancancers,anditsexpressionisincreasedinmoreaggressive 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 theroleofmiR-155inresistancetochemotherapyandtoevaluate 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 expressionandthecombinationofmiR-155andTP53expression 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 downregulationofmiR-155successfullyresensitizestumorstochemotherapy invivo.Weshowthatanti-miR-155-DOPCcanbeconsiderednontoxic in vivo. We further demonstrate that miR-155 and TP53 are linkedinanegativefeedbackmechanismandthatacombination 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 overcomedrugresistance,animportantcauseofcancer-relateddeath. Clin Cancer Res; 23(11); 2891–904. �2016 AACR.
|
|---|
