A novel colon cancer gene therapy using rAAV-mediated expression of human shRNA-FHL2

被引：20

作者：

Wu, Yao ^{[1
]}

Guo, Zheng ^{[2
]}

Zhang, Di ^{[1
]}

Zhang, Wenjing ^{[1
]}

Yan, Qingqing ^{[1
]}

Shi, Xinpeng ^{[1
]}

Zhang, Mengnan ^{[3
]}

Zhao, Yingying ^{[1
]}

Zhang, Yali ^{[1
]}

Jiang, Bo ^{[1
]}

Cheng, Tianming ^{[1
]}

Bai, Yang ^{[1
]}

Wang, Jide ^{[1
]}

机构：

[1] Southern Med Univ, Nanfang Hosp, Dept Digest Med, Guangdong Prov Key Lab Gastroenterol, Guangzhou 510515, Guangdong, Peoples R China

[2] Gannan Med Univ, Affiliated Hosp 1, Dept Oncol, Ganzhou 341000, Peoples R China

[3] Guangzhou Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou 510210, Guangdong, Peoples R China

来源：

INTERNATIONAL JOURNAL OF ONCOLOGY | 2013年 / 43卷 / 05期

基金：

中国国家自然科学基金;

关键词：

four and a half LIM-only protein 2; adeno-associated virus; gene therapy; cell cycle; apoptosis; colon cancer; LIM-ONLY PROTEIN; INDUCED APOPTOSIS; FHL2; DOMAIN; SUPPRESSION; ACTIVATION; INTERACTS; 4-AND-A-HALF-LIM; DIFFERENTIATION; CLONING;

D O I：

10.3892/ijo.2013.2090

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

FHL2 (Four and a half LIM-only protein 2) has been identified as an oncogene in colon cancer and suppression of FHL2 induces cell differentiation and tumorigenesis in colon cancer cell lines. The aim of this study was to develop a novel and effective approach to knockdown FHL2, which can serve as a promising target of colon cancer therapy. Recombinant adeno-associated virus (rAAV) was generated bearing with FHL2-shRNA and transfected into LoVo cells. Cell cycle and growth were assessed. The interaction between FHL2 and G0/G1 cell cycle and growth was evaluated by flow cytometry, western blot analysis and WST-1 assay. We showed that suppression of FHL2 by rAAV-shRNA induced G0/G1 cell cycle arrest and inhibited cell growth. Apoptosis-related proteins and their activity was investigated at the same time. rAAV-FHL2-shRNA activated intrinsic and extrinsic apoptotic pathways and increased cell susceptibility to apoptotic stimuli by 5-FU. Moreover, a xenograft model was established to explore rAAV-FHL2-shRNA with 5-FU mediated tumorigenesis in vivo. A strong anti-tumorigenic effect of rAAV-FHL2-shRNA was shown in nude mice and this antitumor effect was enhanced when combined with 5-FU treatment. These findings implicate FHL2 as a cell cycle and growth modulator and thus inhibit apoptosis in colon cancer cells. rAAV-shRNA-FHL2 may serve as a novel and potent therapeutic or 5-FU co-therapeutic agent for colon cancer.

引用

页码：1618 / 1626

页数：9

共 35 条

[1] FHL2 suppresses growth and differentiation of the colon cancer cell line HT-29 [J].

Amann, Thomas ;

Egle, Yvonne ;

Bosserhoff, Anja-Katrin ;

Hellerbrand, Claus .

ONCOLOGY REPORTS, 2010, 23 (06) :1669-1674

[2] The LIM domain: regulation by association [J].

Bach, I .

MECHANISMS OF DEVELOPMENT, 2000, 91 (1-2) :5-17

[3] Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart [J].

Chan, KK ;

Tsui, SKW ;

Lee, SMY ;

Luk, SCW ;

Liew, CC ;

Fung, KP ;

Waye, MMY ;

Lee, CY .

GENE, 1998, 210 (02) :345-350

[4]

Chao TC, 1997, J SURG ONCOL, V65, P123, DOI 10.1002/(SICI)1096-9098(199706)65:2<123::AID-JSO9>3.0.CO

[5]

2-9

[6] Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways [J].

Chatfield, K ;

Eastman, A .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 323 (04) :1313-1320

[7] Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-β-like signaling pathway [J].

Ding, Lihua ;

Wang, Zhaoyun ;

Yan, Jinghua ;

Yang, Xiao ;

Liu, Aijun ;

Qiu, Weiyi ;

Zhu, Jianhua ;

Han, Juqiang ;

Zhang, Hao ;

Lin, Jing ;

Cheng, Long ;

Qin, Xi ;

Niu, Chang ;

Yuan, Bin ;

Wang, Xiaohui ;

Zhu, Cui ;

Zhou, Yan ;

Li, Jiezhi ;

Song, Haifeng ;

Huang, Cuifen ;

Ye, Qinong .

JOURNAL OF CLINICAL INVESTIGATION, 2009, 119 (02) :349-361

[8] The LIM-only coactivator FHL2 modulates WT1 transcriptional activity during gonadal differentiation [J].

Du, XJ ;

Hublitz, P ;

Günther, T ;

Wilhelm, D ;

Englert, C ;

Schüle, R .

BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 2002, 1577 (01) :93-101

[9] Androgen deprivation induces senescence characteristics in prostate cancer cells in vitro and in vivo [J].

Ewald, Jonathan A. ;

Desotelle, Joshua A. ;

Church, Dawn R. ;

Yang, Bing ;

Huang, Wei ;

Laurila, Timo A. ;

Jarrard, David F. .

PROSTATE, 2013, 73 (04) :337-345

[10] A family of LIM-only transcriptional coactivators: Tissue-specific expression and selective activation of CREB and CREM [J].

Fimia, GM ;

De Cesare, D ;

Sassone-Corsi, P .

MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (22) :8613-8622

← 1 2 3 4 →