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CLC number: R945

On-line Access: 2020-03-05

Received: 2019-08-02

Revision Accepted: 2019-10-24

Crosschecked: 2020-02-22

Cited: 0

Clicked: 2002

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Fu-Qiang Hu

https://orcid.org/0000-0002-9847-134X

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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.3 P.218-233

http://doi.org/10.1631/jzus.B1900468


Inhibition of chemotherapy-related breast tumor EMT by application of redox-sensitive siRNA delivery system CSO-ss-SA/siRNA along with doxorubicin treatment


Author(s):  Xuan Liu, Xue-Qing Zhou, Xu-Wei Shang, Li Wang, Yi Li, Hong Yuan, Fu-Qiang Hu

Affiliation(s):  College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China

Corresponding email(s):   hufq@zju.edu.cn

Key Words:  Doxorubicin, Tumor metastasis, Ras-related C3 botulinum toxin substrate 1 (RAC1), Epithelial-mesenchymal transition (EMT), Chitosan micelles, Small interfering RNA (siRNA)


Xuan Liu, Xue-Qing Zhou, Xu-Wei Shang, Li Wang, Yi Li, Hong Yuan, Fu-Qiang Hu. Inhibition of chemotherapy-related breast tumor EMT by application of redox-sensitive siRNA delivery system CSO-ss-SA/siRNA along with doxorubicin treatment[J]. Journal of Zhejiang University Science B, 2020, 21(3): 218-233.

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author="Xuan Liu, Xue-Qing Zhou, Xu-Wei Shang, Li Wang, Yi Li, Hong Yuan, Fu-Qiang Hu",
journal="Journal of Zhejiang University Science B",
volume="21",
number="3",
pages="218-233",
year="2020",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1900468"
}

%0 Journal Article
%T Inhibition of chemotherapy-related breast tumor EMT by application of redox-sensitive siRNA delivery system CSO-ss-SA/siRNA along with doxorubicin treatment
%A Xuan Liu
%A Xue-Qing Zhou
%A Xu-Wei Shang
%A Li Wang
%A Yi Li
%A Hong Yuan
%A Fu-Qiang Hu
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 3
%P 218-233
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1900468

TY - JOUR
T1 - Inhibition of chemotherapy-related breast tumor EMT by application of redox-sensitive siRNA delivery system CSO-ss-SA/siRNA along with doxorubicin treatment
A1 - Xuan Liu
A1 - Xue-Qing Zhou
A1 - Xu-Wei Shang
A1 - Li Wang
A1 - Yi Li
A1 - Hong Yuan
A1 - Fu-Qiang Hu
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 3
SP - 218
EP - 233
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1900468


Abstract: 
Metastasis is one of the main reasons causing death in cancer patients. It was reported that chemotherapy might induce metastasis. In order to uncover the mechanism of chemotherapy-induced metastasis and find solutions to inhibit treatment-induced metastasis, the relationship between epithelial-mesenchymal transition (EMT) and doxorubicin (DOX) treatment was investigated and a redox-sensitive small interfering RNA (siRNA) delivery system was designed. DOX-related reactive oxygen species (ROS) were found to be responsible for the invasiveness of tumor cells in vitro, causing enhanced EMT and cytoskeleton reconstruction regulated by ras-related C3 botulinum toxin substrate 1 (RAC1). In order to decrease RAC1, a redox-sensitive glycolipid drug delivery system (chitosan-ss-stearylamine conjugate (CSO-ss-SA)) was designed to carry siRNA, forming a gene delivery system (CSO-ss-SA/siRNA) downregulating RAC1. CSO-ss-SA/siRNA exhibited an enhanced redox sensitivity compared to nonresponsive complexes in 10 mmol/L glutathione (GSH) and showed a significant safety. CSO-ss-SA/siRNA could effectively transmit siRNA into tumor cells, reducing the expression of RAC1 protein by 38.2% and decreasing the number of tumor-induced invasion cells by 42.5%. When combined with DOX, CSO-ss-SA/siRNA remarkably inhibited the chemotherapy-induced EMT in vivo and enhanced therapeutic efficiency. The present study indicates that RAC1 protein is a key regulator of chemotherapy-induced EMT and CSO-ss-SA/siRNA silencing RAC1 could efficiently decrease the tumor metastasis risk after chemotherapy.

RAC1蛋白靶向氧化还原敏感型siRNA递释系统抑制化疗诱导乳腺肿瘤转移的研究

目的:探明RAC1蛋白调控阿霉素(DOX)诱导肿瘤转移机制,设计靶向RAC1的小干扰RNA(siRNA)递释系统,抑制DOX治疗诱导的肿瘤皮质间质样(EMT)转化.
创新点:探明了DOX通过RAC1蛋白诱导肿瘤细胞发生转移性变化的机制,构建了靶向沉默RAC1蛋白的siRNA递释系统,有效降低了DOX化疗后肿瘤组织转移的风险.
方法:选用MCF-7细胞为模型细胞,体外考察DOX相关活性氧(ROS)对RAC1蛋白的调控作用.针对肿瘤细胞内高谷胱甘肽(GSH)浓度的氧化还原条件,选用二硫键为敏感桥链,壳聚糖为亲水性骨架,硬脂胺为疏水基团,构建氧化还原敏感型基因药物载体CSO-ss-SA.选择靶向沉默RAC1的siRNA为模型药物,构建基因药物递释系统CSO-ss-SA/siRNA.考察CSO-ss-SA/siRNA的理化性质、体外敏感释放及细胞摄取.通过免疫荧光染色法、蛋白免疫印迹法和细胞侵袭性实验考察基因药物递释系统的细胞药效.选用Balb/c裸鼠构建MCF-7乳腺肿瘤原位荷瘤动物模型,考察CSO-ss-SA/siRNA对DOX治疗诱导肿瘤组织EMT转化的抑制作用.
结论:RAC1是DOX诱导细胞侵袭性的关键蛋白.靶向沉默RAC1的siRNA基因递释系统可在体内外有效抑制DOX治疗诱导的肿瘤组织EMT转化,降低化疗诱导转移的风险.

关键词:阿霉素(DOX);肿瘤转移;RAC1;皮质间质样转化(EMT);壳聚糖胶束;小干扰RNA(siRNA)

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]Cadenas S, 2018. ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med, 117:76-89.

[2]Chan TS, Hsu CC, Pai VC, et al., 2016. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med, 213(13):2967-2988.

[3]De P, Aske JC, Dey N, 2019. RAC1 takes the lead in solid tumors. Cells, 8(5):382.

[4]Ebos JML, 2015. Prodding the beast: assessing the impact of treatment-induced metastasis. Cancer Res, 75(17):3427-3435.

[5]Fu XD, 2017. Both sides of the same coin: Rac1 splicing regulation by EGF signaling. Cell Res, 27(4):455-456.

[6]Grobe H, Wüstenhagen A, Baarlink C, et al., 2018. A Rac1-FMNL2 signaling module affects cell-cell contact formation independent of Cdc42 and membrane protrusions. PLoS ONE, 13(3):e0194716.

[7]Hao LG, Rong W, Bai LJ, et al., 2019. Upregulated circular RNA circ_0007534 indicates an unfavorable prognosis in pancreatic ductal adenocarcinoma and regulates cell proliferation, apoptosis, and invasion by sponging miR-625 and miR-892b. J Cell Biochem, 120(3):3780-3789.

[8]Hu YW, Du YZ, Liu N, et al., 2015. Selective redox-responsive drug release in tumor cells mediated by chitosan based glycolipid-like nanocarrier. J Control Release, 206:91-100.

[9]Huang D, Cao L, Xiao L, et al., 2019. Hypoxia induces actin cytoskeleton remodeling by regulating the binding of CAPZA1 to F-actin via PIP2 to drive EMT in hepatocellular carcinoma. Cancer Lett, 448:117-127.

[10]Hung CM, Hsu YC, Chen TY, et al., 2017. Cyclophosphamide promotes breast cancer cell migration through CXCR4 and matrix metalloproteinases. Cell Biol Int, 41(3):345-352.

[11]Karagiannis GS, Condeelis JS, Oktay MH, 2018. Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin Exp Metastasis, 35(4):269-284.

[12]Keklikoglou I, Cianciaruso C, Güç E, et al., 2019. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat Cell Biol, 21(2):190-202.

[13]Korol A, Taiyab A, West-Mays JA, 2016. RhoA/ROCK signaling regulates TGFβ-induced epithelial-mesenchymal transition of lens epithelial cells through MRTF-A. Mol Med, 22(1):713-723.

[14]Liu J, Meng T, Yuan M, et al., 2016. MicroRNA-200c delivered by solid lipid nanoparticles enhances the effect of paclitaxel on breast cancer stem cell. Int J Nanomed, 11:6713-6725.

[15]Liu X, Cheng BL, Meng TT, et al., 2016. Synthesis and biological application of BKT-140 peptide modified polymer micelles for treating tumor metastasis with an enhanced cell internalization. Polym Chem, 7(7):1375-1386.

[16]Liu XX, Liu WD, Wang L, et al., 2018. Roles of flotillins in tumors. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 19(3):171-182.

[17]Liu ZL, Shen N, Tang ZH, et al., 2019. An eximious and affordable GSH stimulus-responsive poly(α-lipoic acid) nanocarrier bonding combretastatin A4 for tumor therapy. Biomater Sci, 7(7):2803-2811.

[18]Meng TT, Wu J, Yi HX, et al., 2016. A spermine conjugated stearic acid-g-chitosan oligosaccharide polymer with different types of amino groups for efficient p53 gene therapy. Coll Surf B-Biointerf, 145:695-705.

[19]Mirzaei S, Hadadi Z, Attar F, et al., 2018. ROS-mediated heme degradation and cytotoxicity induced by iron nanoparticles: hemoglobin and lymphocyte cells as targets. J Biomol Struct Dyn, 36(16):4235-4245.

[20]Polyakov N, Leshina T, Fedenok L, et al., 2018. Redox-active quinone chelators: properties, mechanisms of action, cell delivery, and cell toxicity. Antiox Redox Signal, 28(15):1394-1403.

[21]Quail DF, Joyce JA, 2013. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 19(11):1423-1437.

[22]Sun T, Wang GF, Zhang Y, 2017. Primary splenic carcinosarcoma with local invasion of chest wall: a rare case. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 18(8):717-722.

[23]Tan YN, Zhu Y, Zhao Y, et al., 2018. Mitochondrial alkaline pH-responsive drug release mediated by celastrol loaded glycolipid-like micelles for cancer therapy. Biomaterials, 154:169-181.

[24]Vaquero J, Fouassier L, 2016. Rac1 and EMT: a dangerous liaison? Transl Cancer Res, 5(Suppl 7):S1483-S1485.

[25]Weidenfeld K, Barkan D, 2018. EMT and stemness in tumor dormancy and outgrowth: are they intertwined processes? Front Oncol, 8:381.

[26]Wen LJ, Tan YN, Dai SH, et al., 2017. VEGF-mediated tight junctions pathological fenestration enhances doxorubicin-loaded glycolipid-like nanoparticles traversing BBB for glioblastoma-targeting therapy. Drug Deliv, 24(1):1843-1855.

[27]Yan JJ, Du YZ, Chen FY, et al., 2013. Effect of proteins with different isoelectric points on the gene transfection efficiency mediated by stearic acid grafted chitosan oligosaccharide micelles. Mol Pharm, 10(7):2568-2577.

[28]Zhao M, Ding XF, Shen JY, et al., 2017. Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 18(1):15-26.

[29]Zhu Y, Yan L, Zhu WJ, et al., 2019. MMP2/3 promote the growth and migration of laryngeal squamous cell carcinoma via PI3K/AKT-NF-κB-mediated epithelial-mesenchymal transformation. J Cell Physiol, 234(9):15847-15855.

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