MicroRNA miR-29 Modulates Expression of Immunoinhibitory Molecule B7-H3: Potential Implications for Immune Based Therapy of Human Solid Tumors

Abstract

B7-H3, a surface immunomodulatory glycoprotein, inhibits natural killer cells and T cells. The monoclonal antibody (mAb) 8H9 is specific for 4Ig-B7-H3, the long and principal form of B7-H3. Early results from radioimmunotherapy using 8H9 have shown promise in patients with metastatic solid tumors to the central nervous system. Whereas B7-H3 transcript was ubiquitously expressed in a wide spectrum of human solid tumors as well as human normal tissues, B7-H3 protein was preferentially expressed only in tumor tissues. By quantitative reverse transcription-PCR, all three isoforms of microRNA miR-29 (a, b, and c) were highly expressed in normal tissues. However, they were down-regulated in a broad spectrum of solid tumors, including neuroblastoma, sarcomas, brain tumors, and tumor cell lines. B7-H3 protein expression was inversely correlated with miR-29 levels in both cell lines and tumor tissues tested. Using luciferase reporter assay, miR-29a was shown to directly target B7-H3 3 ¶ untranslated region, and knock-in and knockdown of miR-29a led to down-regulation and up-regulation, respectively, of B7-H3 protein expression. The ability of miR-29 to control B7-H3 protein expression has implications in immune escape by solid tumors. Differential modulation of this key immunoinhibitory molecule in tumor versus normal tissues may advance both cell-mediated immunotherapy and antibody-based targeted strategies using the B7-H3-specific mAb 8H9. [Cancer Res 2009;69(15):6275-81]

MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma

“…In the present study, using the Src-specific small molecule inhibitors saracatinib and dasatinib, we identified miR-29b as an important mediator of the Src-ID1 pathway, controlling lung cancer cell invasion. Members of the miRNA-29 family (miR-29a, miR-29b and miR-29c) are known to be highly expressed in normal tissues and downregulated in different types of cancer, including neuroblastoma, sarcoma, glioma, high-risk chronic lymphatic leukemia, invasive breast cancer, cholangiocarcinoma and lung cancer (Calin et microRNA-29b in lung cancer SI Rothschild et al et al, 2006;Mott et al, 2007;Wu et al, 2009;Xu et al, 2009). The three miR-29 isoforms are arranged in two clusters: miR-29b1/miR-29a located on chromosome 7q32 and miR-29b2/miR-29c located on chromosome 1q32.…”

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

“…This is a mechanism that is distinct from H-Ras/MAPK regulation of C-myc, which is primarily through protein stabilization. Various microRNAs (mir-34a, mir-101, and let-7) have also been documented to regulate N-myc by targeting mRNA, resulting in reduced N-myc expression and decreased proliferation of MYCN-amplified neuroblastoma cells (75,76).…”

The role of miR-29 family members in malignant hematopoiesis

“…Role of miR-29 family members expression in immune response was observed on B7-H3 and interferon γ (ref. 29,37 ). Currently a number of target genes affected by miR-29 family members in variety of cancers were identified.…”