Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma

Abstract

is an oncogenic microRNA that regulates several pathways involved in cell division and immunoregulation. It is overexpressed in numerous cancers, is often correlated with poor prognosis, and is thus a key target for future therapies. In this work we show that overexpression of miR-155 in lymphoid tissues results in disseminated lymphoma characterized by a clonal, transplantable pre-B-cell population of neoplastic lymphocytes. Withdrawal of miR-155 in mice with established disease results in rapid regression of lymphadenopathy, in part because of apoptosis of the malignant lymphocytes, demonstrating that these tumors are dependent on miR-155 expression. We show that systemic delivery of antisense peptide nucleic acids encapsulated in unique polymer nanoparticles inhibits miR-155 and slows the growth of these "addicted" pre-B-cell tumors in vivo, suggesting a promising therapeutic option for lymphoma/leukemia. oncogene | oncomiR addiction | nanotechnology M icroRNAs (miRNAs) govern nearly every biological process investigated (1-8). in particular is one of the most salient miRNAs, and although its role in immune function has been the subject of much attention (9-14), manifold studies also implicate it in cancer pathways, particularly those of hematopoietic origin (11,(15)(16)(17)(18)(19)(20)(21). miR-155 is induced in several lymphomas, such as diffuse large B-cell lymphomas, Hodgkin lymphomas, and subsets of Burkitt lymphomas (16,18,22), and ectopic expression of miR-155 in a transgenic mouse model leads to B-cell malignancy (15, 23). Furthermore, miR-155 induction in hematopoietic cells of myeloid origin results in a myeloproliferative pathology characterized by granulocyte/ monocyte expansion in lymphoid tissues (24,25). At the molecular level, miR-155 directly targets SH2-containing inositol phosphatase (SHIP1), a negative regulator of myeloid cell proliferation and survival. Furthermore, in diffuse large B-cell lymphomas, miR-155 induction and subsequent SHIP1 repression are TNF-α-dependent (23,24,26). Although these studies provide compelling evidence for miR-155 involvement in lymphoproliferative disease, the degree to which the survival of these cancers depend on maintained miR-155 expression has not been established, a crucial point to ascertain in determining whether or not inhibition of miR-155 has therapeutic promise.It is known that several protein-coding oncogenes such as Egfr, Myc, Ras, and Her2 (among others) exhibit oncogene addiction and that tumors can become dependent on maintained expression of these genes in mouse models (27)(28)(29). Recently, we described a miR-21-induced mouse model of lymphoma in which tumors were dependent on maintained expression of miR-21, demonstrating that miRNAs are a unique class of genes that mediate oncogene addiction (30).Toward cancer therapy, anti-miR molecules could potentially be used to attenuate oncogenic miRNAs, ultimately exploiting the miRNA dependence exhibited by certain tumors. In recent years, anti-miRs have emerged as useful tools for inhibiting ...

miR-421, miR-155 and miR-650: Emerging Trends of Regulation of Cancer and Apoptosis

“…More interestingly transplanting ASO expressing MDA-MB-157 cells in mice inhibited growth of tumor . For enhancing the delivery and distribution of antisense against miR-155, polymeric nanoparticles encapsulated antisense peptide nucleic acids have been used (Babar et al, 2012).…”

Knockdown of LMP1-induced miR-155 sensitizes nasopharyngeal carcinoma cells to radiotherapy in vitro

“…Furthermore, the strategy to knockdown miR-155 has been previously investigated for the control of cancer progression (24). Previous studies have demonstrated that knockdown of miR-155 in mice resulted in rapid regression of lymphadenopathy, in part due to apoptosis of the malignant lymphocytes (25). In addition, systemic delivery of antisense peptide nucleic acids against miR-155 that were encapsulated in unique polymer nanoparticles inhibited miR-155 and retarded the growth of pre-B-cell tumors in vivo, suggesting a potential therapeutic option for the treatment of lymphoma/leukemia (25).…”

A domain ontology for the Non-Coding RNA field

“…Differential expression of ncRNAs in malignant tissues compared with normal tissues can be exploited as potential therapeutic targets for cancer therapy or as biomarkers used for diagnosis, prediction of patient outcome, or monitoring the effectiveness of cancer therapeutics [11]. In recent years serious attempts have been made to effectively deliver ncRNA into tumors in animal models [12][13][14].…”