miR‐506‐loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple‐negative breast cancer aggressiveness

Abstract

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Some microRNAs (miRNAs) were abnormally expressed in TNBC, and they are closely related to the occurrence and progression of TNBC. Here, we found that miR-506 was significantly downregulated in TNBC and relatively lower miR-506 expression predicted a poorer prognosis. Moreover, we found that miR-506 could inhibit MDA-MB-231 cell viability, colony formation, migration, and invasion, and suppress the ERK/Fos oncogenic signaling pathway through upregulating its direct target protein proenkephalin (PENK). Therefore, miR-506 was proposed as a nucleic acid drug for TNBC therapy. However, miRNA is unstable in vivo, which limiting its application as a therapeutic drug via conventional oral or injected therapies. Here, a gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA. Exogenous miR-506 mimic was loaded on GNs and injected into the in situ TNBC animal model, and the miR-506 could achieve sustained and controlled release. The results confirmed that overexpression of miR-506 and PENK in vivo through loading on GNs inhibited in situ triple-negative breast tumor growth and metastasis significantly in the xenograft model. Moreover, we indicated that the ERK/Fos signaling pathway was intensively inactivated after overexpression of miR-506 and PENK both in vitro and in vivo, which was further validated by the ERK1/2-specific inhibitor SCH772984. In conclusion, this study demonstrates that miR-506-loaded GNs have great potential in anti-TNBC aggressiveness therapy.

Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines

“…In addition, FBLN1 was shown to be elevated in normal FB when compared to CAF [58]. High expression of PENK is associated with improved outcomes in GIST patients and is postulated to act as a tumor suppressor [42], inhibit breast tumor growth [41], and is required, in part, for induction of apoptosis through the NF-κB/p53 pathway [59]. Thus, it is plausible that SLIT3, FBLN1, and PENK cooperate and induce apoptosis through different pathways.…”

“…The literature on the PENK ligand in the context of growth suppression in breast cancer is minimal and very recent [41], but there is evidence that high expression of PENK is associated with favorable outcomes in patients with gastrointestinal stromal tumors [42].…”

MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer

“…In our previous study, GNs were used to deliver miR-506 for the treatment of triple-negative breast cancer. 31 GNs were negatively charged and could bind with positively charged complex miR-4458-Lipofectamine 2000, as verified by the results of zeta potential analysis. miR-4458 could realize controlled release in 21 d with the aid of GNs (Fig.…”

“…The preparation of GNs was similar to the previous study. 31 Briefly, 100 ml acetone solution was added to the same volume of 5% w/v high molecular weight type B gelatin solution, the gelatin was precipitated and dissolved in water at 50 °C, then adjusted to pH 2.5. 2 ml min −1 acetone solution was added to gelatin solution continuously at 1000 rpm to form GNs.…”

miRacle of microRNA-Driven Cancer Nanotherapeutics

“…There are several studies on gelatin-based sustained- and controlled-release delivery systems for miRNA therapeutics. Liu et al [ 106 ] demonstrated for the first time that a gelatin-based nanosphere delivery system incorporating miR-506 mimic led to a marked inhibition of tumor growth and metastasis in TNBC xenograft models in mice.…”