Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer.
Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer.
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毛蕊花苷通过调节人结直肠癌中的 HIPK2-p53 信号传导促进细胞凋亡
DOI：
10.1186/1471-2407-14-747
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发表时间：
2014-10-05
期刊：
影响因子：
3.8
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Zhou L;Feng Y;Jin Y;Liu X;Sui H;Chai N;Chen X;Liu N;Ji Q;Wang Y;Li Q
我们通过体内和体外实验研究了HIPK2-p53信号通路在结直肠癌（CRC）肿瘤发生和对毛蕊花苷（VB）耐药中的作用。通过免疫组化（IHC）分析原发性人结直肠癌样本和患者正常肠道组织中HIPK2的表达，发现其表达与患者的临床病理特征相关。将人结直肠癌HCT-116细胞植入BALB/c裸鼠；移植肿瘤小鼠随机给予对照、20、40或80 mg/mL VB或1 mg/mL氟尿嘧啶（5-FU）。通过免疫组化检测HIPK2、p53、Bax和Bcl-2在这些肿瘤中的表达。采用CCK-8法和流式细胞术检测VB对结直肠癌细胞增殖和凋亡的影响；western blot检测HIPK2、p53、p-p53、Bax、Bcl-2。对100例人结直肠癌肿瘤样本和20例正常肠组织的免疫组化分析显示，HIPK2表达与结直肠癌Dukes分期和浸润深度呈负相关（P < 0.05）。在体内，20mg /mL、40mg /mL和80mg /mL VB对CRC异种移植肿瘤重量的抑制率分别为42.79%、53.90%和60.99%，并伴有治疗肿瘤中HIPK2、p53和Bax表达升高，Bcl-2表达降低。在体外，VB显著抑制CRC细胞系HCT-116、HT-29、LoVo和SW620的增殖，并呈时间和剂量依赖性。25、50、100 μM VB对HCT-116细胞的凋亡率分别为10.83±1.28、11.25±1.54、20.19±2.87%，对HT-29细胞的凋亡率分别为18.92±6.12、21.57±4.05、25.14±6.73%。综上所述，VB处理显著提高了CRC细胞中促凋亡蛋白HIPK2、p53、p-p53、Bax的表达，降低了抗凋亡Bcl-2的表达。HIPK2蛋白调节CRC中p53的磷酸化状态以及Bax和Bcl-2的水平。我们还发现VB有效激活HIPK2-p53信号通路，导致CRC细胞凋亡增加。
We investigated the role of the HIPK2–p53 signaling pathway in tumorigenesis and resistance to the drug Verbascoside (VB) in colorectal cancer (CRC), using in vivo and in vitro experiments. Primary human CRC samples and normal intestinal tissues from patients were analyzed for HIPK2 expression by immunohistochemistry (IHC) and its expression was correlated against patients’ clinicopathological characteristics. Human CRC HCT-116 cells were implanted in BALB/c nude mice; mice with xenografted tumors were randomly administrated vehicle (control), 20, 40, or 80 mg/mL VB, or 1 mg/mL fluorouracil (5-FU). HIPK2, p53, Bax, and Bcl-2 expression in these tumors were determined by IHC. In vitro effects of VB on CRC cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry; HIPK2, p53, p-p53, Bax, and Bcl-2 were measured by western blot. IHC analysis for 100 human CRC tumor samples and 20 normal intestinal tissues, showed HIPK2 expression to inversely correlate with Dukes stage and depth of invasion in CRC (P < 0.05). In vivo, the inhibition rates of 20, 40, and 80 mg/mL VB on CRC xenograft tumor weight were 42.79%, 53.90%, and 60.99%, respectively, and were accompanied by increased expression of HIPK2, p53, and Bax, and decreased Bcl-2 expression in treated tumors. In vitro, VB significantly inhibited proliferation of CRC cell lines HCT-116, HT-29, LoVo, and SW620, in a time- and dose-dependent manner. The apoptosis rates of 25, 50, and 100 μM VB on HCT-116 cells were 10.83 ± 1.28, 11.25 ± 1.54, and 20.19 ± 2.87%, and on HT-29 cells were 18.92 ± 6.12, 21.57 ± 4.05, and 25.14 ± 6.73%, respectively. In summary, VB treatment significantly enhanced the protein expression of pro-apoptotic HIPK2, p53, p-p53, Bax, and decreased anti-apoptotic Bcl-2 expression in CRC cells. HIPK2 protein modulates the phosphorylation status of p53, and levels of Bax and Bcl-2 in CRC. We also found that VB effectively activated the HIPK2–p53 signaling pathway, resulting in increased CRC cell apoptosis.
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影响因子：
8
作者：
Mao, J-H;Wu, D.;Kim, I-J;Kang, H. C.;Wei, G.;Climent, J.;Kumar, A.;Pelorosso, F. G.;DelRosario, R.;Huang, E. J.;Balmain, A.
通讯作者：
Balmain, A.
影响因子：
3.8
作者：
Funari, Cristiano Soleo;Passalacqua, Thais Gaban;Siqueira Silva, Dulce Helena
通讯作者：
Siqueira Silva, Dulce Helena
影响因子：
3.6
作者：
Esposito, Emanuela;Dal Toso, Roberto;Cuzzocrea, Salvatore
通讯作者：
Cuzzocrea, Salvatore
影响因子：
3.7
作者：
Nardinocchi L;Puca R;Sacchi A;Rechavi G;Givol D;D'Orazi G
通讯作者：
D'Orazi G
DOI：
10.1016/j.bbamcr.2008.10.013
发表时间：
2009-02-01
影响因子：
5.1
作者：
Nardinocchi, Lavinia;Puca, Rosa;D'Orazi, Gabriella
通讯作者：
D'Orazi, Gabriella