Oncotarget

Research Papers:

Blocking hepatic metastases of colon cancer cells using an shRNA against Rac1 delivered by activatable cell-penetrating peptide

Ying Bao, Huihui Guo, Yongliang Lu, Wenming Feng, Xinrong Sun, Chengwu Tang, Xiang Wang and Mo Shen _

PDF  |  HTML  |  How to cite

Oncotarget. 2016; 7:77183-77195. https://doi.org/10.18632/oncotarget.12854

Metrics: PDF 2283 views  |   HTML 2824 views  |   ?  


Abstract

Ying Bao1,*, Huihui Guo1,*, Yongliang Lu2, Wenming Feng1, Xinrong Sun1, Chengwu Tang1, Xiang Wang1, Mo Shen3

1Department of Surgery, First Affiliated Hospital, Huzhou University, The First People’s Hospital of Huzhou, Huzhou, 313000, China

2Department of Medicine, Huzhou University, Huzhou, 313000, China

3Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University,Wenzhou, 325000, China

*These authors contributed equally to this work

Correspondence to:

Xiang Wang, email: [email protected]

Mo Shen, email: [email protected]

Keywords: cell penetrating peptide, Rac1, metastasis, adhesion, tumor targeting nanoparticle

Received: September 06, 2016     Accepted: October 14, 2016     Published: October 24, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 12854