Therapeutic silence of pleiotrophin by targeted delivery of siRNA and its effect on the inhibition of tumor growth and metastasis

Abstract

Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene. However, efficient delivery of small interfering RNA (siRNA) in vivo remains a significant hurdle for its successful therapeutic application. In this study, we first identified, on a cell-based experiment, applying a 1:1 mixture of two PTN specific siRNA engenders a higher silencing efficiency on both mRNA and protein level than using any of them discretely at the same dose. As a consequence, slower melanoma cells growth was also observed for using two specific siRNA combinatorially. To establish a robust way for siRNA delivery in vivo and further investigate how silence of PTN affects tumor growth, we tested three different methods to deliver siRNA in vivo: first non-targeted in-vivo delivery of siRNA via jetPEI; second lung targeted delivery of siRNA via microbubble coated jetPEI; third tumor cell targeted delivery of siRNA via transferrin-polyethylenimine (Tf-PEI). As a result, we found that all three in-vivo siRNAs delivery methods led to an evident inhibition of melanoma growth in non-immune deficiency C57BL/6 mice without a measureable change of ALT and AST activities. Both targeted delivery methods showed more significant curative effect than jetPEI. The lung targeted delivery by microbubble coated jetPEI revealed a comparable therapeutic effect with Tf-PEI, indicating its potential application for target delivery of siRNA in vivo.

miR-627-3p inhibits osteosarcoma cell proliferation and metastasis by targeting PTN

“…High PTN expression reportedly contributes to cell metastasis, at least in part through effects on the activities of metal matrix proteases (MMPs) [10]. We used Transwell assays (with or without Matrigel) to study the effect of miR-627-3p on osteosarcoma metastasis (Figure 4A–4D).…”

“…Less is known about the role of miR-627 in osteosarcoma and the mechanism through which it acts. PTN is highly expressed in various types of cancer, including melanoma, breast cancer, glioma, prostate cancer, leukemia, choriocarcinoma and lung cancer, where it appears to play a critical role in mediating angiogenesis, tumor cell proliferation and metastasis [10]. Studies have shown that PTN may be a reliable prognostic indicator in osteosarcoma patients, and inhibitors of PTN could potentially improve chemotherapeutic efficacy in patients with unresponsive and recurrent osteosarcoma [9].…”

LncRNA CRNDE promotes cell proliferation, invasion and migration by competitively binding miR-384 in papillary thyroid cancer

“…PTN, also known as heparin-binding growth-associated molecule, is a 136-amino acid secreting growth/differentiation cytokine that is developmentally regulated [ 30 ]. PTN was found to be up-regulated in various types of human cancers, and overexpression of PTN was suggested to promote cell proliferation and angiogenesis, contributing to cancer progression [ 31 – 33 ]. Recent study also demonstrated the concentration in the fine-needle aspiration thyroid tissues was increased PTC [ 34 ].…”

Whole-Genome Methylation Study of Congenital Lung Malformations in Children

“…MEIS1 might limit the proliferation of non-small-cell lung adenocarcinoma ( 34 ) and was described methylated in squamous cell carcinomas ( 35 ). PTN is highly expressed in embryonic and postnatal development, while it is quite down-regulated in adult life; however, it is strongly expressed in lung tumor and other types of cancer ( 36 ). Hypermethylation was found in our samples for the DMR close to MEIS1 and PTN.…”