Abstract
Hepatic metastasis is one of the critical progressions of colon cancer. Blocking this process is key to prolonging survival time in cancer patients. Studies on activatable cell-penetrating peptides (dtACPPs) have demonstrated their potential as gene carriers. It showed high tumor cell-targeting specificity and transfection efficiency and low cytotoxicity in the in vitro settings of drug delivery. However, using this system to silence target genes to inhibit metastasis in colorectal cancer cells has not been widely reported and requires further investigation. In this study, we observed that expression of Rac1, a key molecule for cytoskeletal reorganization, was higher in hepatic metastatic tumor tissue compared with prime colon cancer tissue and that patients with high Rac1-expressing colon cancer showed shorter survival time. Base on these findings, we created dtACPP-PEG-DGL (dtACPPD)/shRac1 nanoparticles and demonstrated that they downregulated Rac1 expression in colon cancer cells. Moreover, we observed inhibitory effects on migration, invasion and adhesion in HCT116 colorectal cancer cells in vitro, and our results showed that Rac1 regulated colon cancer cell matrix adhesion through the regulation of cytofilament dynamics. Moreover, mechanically, repression of Rac1 inhibiting cells migration and invasion by enhancing cell to cell adhesion and reducing cell to extracellular matrix adhesion. Furthermore, when atCDPPD/shRac1 nanoparticles were administered intravenously to a HCT116 xenograft model, significant tumor metastasis to the liver was inhibited. Our results suggest that atCDPP/shRac1 nanoparticles may enable the blockade of hepatic metastasis in colon cancer.
Highlights
Colorectal cancer ranks the third most common cancer in the world
Mounting evidence showed that Rac1 expression and activity are both increased in many cancer types, including colon cancer and it enhanced the metastasis in cells [18]
We found that Rac1 was related to the metastasis and survival time of colon cancer
Summary
Colorectal cancer ranks the third most common cancer in the world. Metastasis is the major course of cancer mortality. Huang et al developed an activatable cell-penetrating peptide (dtACPP) that is dual-activated by the specific tumor microenvironment, including reduced pH (pH 5.8-7.2) and overexpressed MMP2 [13] In this system, via R-malemidyl-ω-N-hydroxysuccinimidyl polyethyleneglycol (MAL-PEG-NHS), dtACPP was conjugated to the surface of poly-L-lysine (DGL), which has been used to deliver gene into tumor cells, due to its ability to encapsulate DNA to form nanoparticles, which provides a tool to target specific genes in tumor cells [13], and shows the EPR (enhanced permeability and retention) effect. Via R-malemidyl-ω-N-hydroxysuccinimidyl polyethyleneglycol (MAL-PEG-NHS), dtACPP was conjugated to the surface of poly-L-lysine (DGL), which has been used to deliver gene into tumor cells, due to its ability to encapsulate DNA to form nanoparticles, which provides a tool to target specific genes in tumor cells [13], and shows the EPR (enhanced permeability and retention) effect This system showed a promising efficacy in the induction of anti-angiogenesis and apoptosis, it did not show an anti-invasion effect in colon cancer cells. We employed dtACPPD/shRac nanoparticles, evaluated their therapeutic efficacy in vitro and in vivo, and investigated the underlying mechanisms both in vitro and in vivo
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