Multiple Tumor-Associated MicroRNAs Modulate the Survival and Longevity of Dendritic Cells by Targeting YWHAZ and Bcl2 Signaling Pathways

Abstract

Tumors use a wide array of immunosuppressive strategies, such as reducing the longevity and survival of dendritic cells (DCs), to diminish immune responses and limit the effect of immunotherapy. In this study, we found that tumors upregulate the expression of multiple microRNAs (miRNAs), such as miR-16-1, miR-22, miR-155, and miR-503. These tumor-associated miRNAs influenced the survival and longevity of DCs by affecting the expression of multiple molecules that are associated with apoptotic signaling pathways. Specifically, miR-22 targeted YWHAZ to interrupt the PI3K/Akt and MAPK signaling pathways, and miR-503 downregulated Bcl2 expression. The result of the increased expression of miR-22 and miR-503 in the tumorassociated DCs was their reduced survival and longevity. Thus, tumor-associated miRNAs can target multiple intracellular signaling molecules to cause the apoptosis of DCs in the tumor environment. Use of miR-22 and miR-503 as inhibitors may therefore represent a new strategy to improve DC-based immunotherapies against tumors.

miRNA-15a/16: As Tumor Suppressors and More

“…It's also reported that at least some kinds of tumor have developed the ability to influence the endogenous level of miR15a/16 in immune cells, thus to ameliorate antitumor immune response. Siping et al [23] found when co-cultured with melanoma cell-line B16, miR-16 level of bone marrow-derived dendritic cells was upregulated, through which way tumor cells promoted apoptosis of DCs. This phenomenon suggests that maybe tumor can restrict antitumor immune response by regulating the miRNA level of immune cells.…”

“…There have been researches aimed at enhancing chemosensitivity of tumor by upregulating miR-15a/16. These two miRNAs are also reported to regulate angiogenesis [16,17] and immune response [18][19][20][21][22][23]. What's puzzling is that miR-15a/16 were also found to be upregulated in some types of cancer, indicating their potential roles as oncomiRs.…”

Tumor-Infiltrating Dendritic Cells in Cancer Pathogenesis

“…In the presence of tumor cells DCs undergo apoptosis at higher rates compared to DCs that were co-cultured with normal fibroblasts. Furthermore, it was observed that these miRNAs specifically targeted PI3K/AKT, MAPK and apoptotic signaling pathways in DCs (53). …”

Identification and characterization of a unique leucine-rich repeat protein (LRRC33) that inhibits Toll-like receptor-mediated NF-κB activation

“…Western Blotting was performed as described previously [12]. Hybridiz ations with primary antibodies were carried out for one hour at room temperat ure in blocking buffer.…”