Ganji Formula inhibits tumor growth of hepatocellular carcinoma through down-regulating ARPP-19 expression

ZHANG Chunlei; TANG Kaiyue; YANG Lili; ZHANG Yifan; YANG Jinzu; SONG Haiyan

doi:10.16306/j.1008-861x.2021.02.011

您当前的位置：

首页 >

文章列表页 >

Ganji Formula inhibits tumor growth of hepatocellular carcinoma through down-regulating ARPP-19 expression

Experiment Research | 更新时间：2021-12-14

- Ganji Formula inhibits tumor growth of hepatocellular carcinoma through down-regulating ARPP-19 expression
- 上海中医药大学学报 Vol. 35, Issue 2, Pages: 57-67(2021)
- 作者机构：
  
  1.上海中医药大学附属龙华医院脾胃病研究所 (上海 200032)
  2.上海中医药大学附属龙华医院急诊科 (上海 200032)
  3.上海中医药大学附属龙华医院肿瘤科 (上海 200032)
- 作者简介：
  
  YANG Jinzu，E-mail：kingzuy@126.com
  SONG Haiyan，E-mail：songhy@126.com.
- 基金信息：
- DOI：10.16306/j.1008-861x.2021.02.011
  CLC：
扫描看全文
ZHANG Chunlei, TANG Kaiyue, YANG Lili, et al. Ganji Formula inhibits tumor growth of hepatocellular carcinoma through down-regulating ARPP-19 expression. [J]. 上海中医药大学学报 35(2):57-67(2021)
DOI：

ZHANG Chunlei, TANG Kaiyue, YANG Lili, et al. Ganji Formula inhibits tumor growth of hepatocellular carcinoma through down-regulating ARPP-19 expression. [J]. 上海中医药大学学报 35(2):57-67(2021) DOI： 10.16306/j.1008-861x.2021.02.011.

摘要

肝细胞性肝癌 (HCC) 是最常见的恶性肿瘤之一, 迄今仍缺乏有效的治疗方法. 临床观察显示, 中药复方肝积方对肝癌有治疗作用. 本研究旨在评价肝积方对HCC的作用和安全性, 并初步探讨其潜在的分子机制. 选用BALB/c裸鼠建立皮下肝癌异种移植模型, 灌胃给予肝积方干预后, 观察肿瘤生长和肝、肾组织形态学变化, 检测cAMP调节的磷酸化蛋白19 (ARPP-19) 及细胞分裂调控相关分子的表达, 并动态观察荷瘤小鼠存活情况. 结果显示, 肝积方干预后, 荷瘤小鼠体质量和活动能力均有明显改善, 存活时间有延长趋势, 肝、肾组织未见明显损伤, 肿瘤体积和质量呈剂量依赖性降低, 肿瘤增殖指数及癌组织增殖细胞核抗原 (PCNA) 表达均低于对照组. 此外, 肝积方可下调ARPP-19以及周期素依赖性激酶 (Cdks) 底物磷酸化水平, 上调失活的细胞分裂周期蛋白2 (Cdc2) 表达水平. 这些结果表明, 肝积方可有效抑制HCC小鼠肿瘤生长, 改善荷瘤裸鼠生存状态, 其作用机制可能与下调ARPP-19表达、抑制HCC细胞有丝分裂和细胞增殖有关. 研究结果将为该复方的临床应用提供实验依据.

Abstract

Hepatocellular carcinoma（HCC）is one of the most common malignant tumors.Rare effective treatment is available for HCC patients at present.Ganji Formula，one formula of traditional Chinese medicine（TCM），has shown therapeutic effect on HCC in clinical observation.This study aims to evaluate the effect and safety of Ganji Formula on HCC，and explore the potential molecular mechanism.HCC subcutaneous xenograft model was established in BALB/c nude mice，which treated with Ganji Formula by intragastric administration.The tumor growth and the histopathology of liver and kidney were observed.The expressions of cAMP-regulated phosphoprotein 19（ARPP-19）and the related cell mitosis regulatory molecules were measured.The survival of tumor bearing mice with or without Ganji Formula treatment was recorded dynamically.The results showed that，the body weight and activity of Ganji Formulatreated mice were improved obviously，with the tendency of prolonging survival time.No obvious injury was observed in tissues of liver and kidney.The tumor volume and mass was significantly down-regulated in a dose-dependent manner.The tumor proliferation index and the expression of proliferating cell nuclear antigen（PCNA）in tumor tissue were lower than those in the control group.Furthermore，Ganji Formula down-regulated the levels of ARPP-19 and phosphorylated cyclin dependent kinases（Cdks）substrates，up-regulated the level of inactivated cyclin division cycle 2（Cdc2）.These results indicate that Ganji Formula can effectively inhibit tumor growth of HCC and improve the survival status of tumor bearing nude mice.The mechanism is partially related to down-regulating ARPP-19 expression to inhibit mitosis and cell proliferation of HCC.It will provide experimental basis for the clinical application of Ganji Formula.

关键词

肝积方肝细胞性肝癌cAMP调节的磷酸化蛋白19细胞增殖裸鼠肝积方肝细胞性肝癌cAMP调节的磷酸化蛋白19细胞增殖裸鼠

Keywords

Ganji Formulahepatocellular carcinomaARPP-19cell proliferationnude mouse

references

VILLANUEVA A. Hepatocellular Carcinoma[J]. N Engl J Med，2019，380(15)：1450-1462.

CHEN W，ZHENG R，BAADE P D，et al. Cancer statistics in China，2015[J]. CA Cancer J Clin，2016，66(2)：115-132.

KIM E，VIATOUR P. Hepatocellular carcinoma：old friends and new tricks[J]. Exp Mol Med，2020，52(12)：1898-1907.

SAGNELLI E，MACERA M，RUSSO A，et al. Epidemiological and etiological variations in hepatocellular carcinoma[J]. Infection，2020，48(1)：7-17.

ZENG H，ZHENG R，GUO Y，et al. Cancer survival in China，2003-2005：A population-based study[J]. Int J Cancer，2015，136(8)：1921-1930.

DUTTA R，MAHATO R I. Recent advances in hepatocellular carcinoma therapy[J]. Pharmacol Ther，2017，173：106-117.

ANDREOU A，VAUTHE J N，CHERQU D，et al. Improved Long-Term Survival after Major Resection for Hepatocellular Carcinoma：A Multicenter Analysis Based on a New Definition of Major Hepatectomy[J]. J Gastrointest Surg，2013，17(1)：66-77.

XIE B，WANG D H，SPECHLER S J. Sorafenib for Treatment of Hepatocellular Carcinoma：A Systematic Review[J]. Dig Dis Sci，2012，57(5)：1122-1129.

SONBOL M B，RIAZ I B，NAQVI S A A，et al. Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma：A Systematic Review and Network Meta-analysis[J]. JAMA Oncol，2020，6(12)：e204930.

PONZIANI F R，BHOORI S，GERMINI A，et al. Inducing tolerability of adverse events increases sorafenib exposure and optimizes patient’s outcome in advanced hepatocellular carcinoma[J]. Liver Int，2016，36(7)：1033-1042.

IEZZI R，POMPILI M，RINNINELLA E，et al. TACE with degradable starch microspheres（DSM-TACE） as second-line treatment in HCC patients dismissing or ineligible for sorafenib[J]. Eur Radiol，2018，29(3)：1285-1292.

HU B. Traditional Chinese medicine for prevention and treatment of hepatocarcinoma：From bench to bedside[J]. World J Hepatol，2015，7(9)：1209-1232.

ZHENG T，QUE Z，JIAO L，et al. Herbal formula YYJD inhibits tumor growth by inducing cell cycle arrest and senescence in lung cancer[J]. Sci Rep，2017，7(1)：4984.

PANG L，HAN S，JIAO Y，et al. Bu Fei Decoction attenuates the tumor associated macrophage stimulated proliferation，migration，invasion and immunosuppression of non-small cell lung cancer，partially via IL-10 and PD-L1 regulation[J]. Int J Oncol，2017，51(1)：25-38.

QI F，LI A，INAGAKI Y，et al. Chinese herbal medicines as adjuvant treatment during chemo or radio-therapy for cancer[J]. Biosci Trends，2010，4(6)：297-307.

YU N，XIONG Y，WANG C. Bu-Zhong-Yi-Qi Decoction，the Water Extract of Chinese Traditional Herbal Medicine，Enhances Cisplatin Cytotoxicity in A549/DDP Cells through Induction of Apoptosis and Autophagy[J]. Biomed Res Int，2017，2017：3692797.

ZHAO J，LIU L，ZHANG Y，et al. The herbal mixture Xiao-chai-hu-tang（XCHT）induces apoptosis of human hepatocellular carcinoma Huh7 cells in vitro and in vivo[J]. Afr J Tradit Complement Altern Med，2017，14(3)：231-241.

XIONG W，REN Z G，QIU S J，et al. Residual hepatocellular carcinoma after oxaliplatin treatment has increased metastatic potential in a nude mouse model and is attenuated by Songyou Yin[J]. BMC Cancer，2010，10：219.

ZHENG S，JIA Q，SHEN H，et al. Treatment with the herbal formula Songyou Yin inhibits epithelial-mesenchymal transition in hepatocellular carcinoma through downregulation of TGF-β1 expression and inhibition of the SMAD2/3 signaling pathway[J]. OncoL Lett，2017，13(4)：2309-2315.

CHU E. Wedding Rigorous Scientific Methodology and Ancient Herbal Wisdom to Benefit Cancer Patients：The Development of PHY906[J]. Oncology（Williston Park），2018，32(2)：e20-e27.

LAM W，JIANG Z，GUAN F，et al. PHY906（KD018），an adjuvant based on a 1800-year-old Chinese medicine，enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment[J]. Sci Rep，2015，5：9384.

KUMMAR S，COPUR M S，ROSE M，et al. A PhaseⅠ Study of the Chinese Herbal Medicine PHY906 as a Modulator of Irinotecan-based Chemotherapy in Patients with Advanced Colorectal Cancer[J]. Clin Colorectal Cancer，2011，10(2)：85-96.

QIU J X，YANG J K. Clinical observation and experimental study of Jianpi Liqi，Qingre Jiedu and Rujian Huatan prescription in treating advanced liver cancer[J]. Chin J Integrated Tradit Chin West Med，1987，7(5)：275-277.

ZHAO A，YANG J，XIAO Z. The Effect of SRRS Prenventing P53 Gene from Mutation[J]. Cancer Res Prev Treat，1999，26(3)：181-183.

HORIUCHI A，WILLIAMS K R，KURIHARA T，et al. Purification and cDNA cloning of ARPP-16，a cAMP-regulated phosphoprotein enriched in basal ganglia，and of a related phosphoprotein，ARPP-19[J]. J Biol Chem. 1990，265(16)：9476-9484.

EICHHORN P，CREYGHTON M P，BERNARDS R. Protein phosphatase 2A regulatory subunits and cancer[J]. Biochim Biophys Acta，2009，1795(1)：1-15.

GIRAULT J A，SHALABY I A，ROSEN N L，et al. Regulation by cAMP and vasoactive intestinal peptide of phosphorylation of specific proteins in striatal cells in culture[J]. Proc Natl Acad Sci U S A，1988，85(20)：7790-7794.

VELJKOVIC M，DOPSAJ V，DOPSAJ M，et al. Physical Activity and Natural Anti-VIP Antibodies：Potential Role in Breast and Prostate Cancer Therapy[J]. PLoS One，2011，6(11)：e28304.

SACHLOS E，RISUEÑO R M，LARONDE S，et al. Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells[J]. Cell，2012，149(6)：1284-1297.

SONG H，PAN J，LIU Y，et al. Increased ARPP-19 expression is associated with hepatocellular carcinoma[J]. Int J Mol Sci，2014，16(1)：178-192.

WANG L，TANG Z Y，QIN L X，et al. High-Dose and Long-Term Therapy With Interferon-Alfa Inhibits Tumor Growth and Recurrence in Nude Mice Bearing Human Hepatocellular Carcinoma Xenografts With High Metastatic Potential[J]. Hepatology，2000，32(1)：43-48.

SCHWARTZ G K，SHAH M A. Targeting the Cell Cycle：A New Approach to Cancer Therapy[J]. J Clin Oncol，2005，23(36)：9408-9421.

WANG P，SHE G，YANG Y，et al. Synthesis and Biological Evaluation of New Ligustrazine Derivatives as Anti-Tumor Agents[J]. Molecules，2012，7(5)：4972-4978.

YANG X B，WU W Y，LONG S Q，et al. Fuzheng Kang’ai decoction combined with gefitinib in advanced non-small cell lung cancer patients with epidermal growth factor receptor mutations：study protocol for a randomized controlled trial[J]. Trials，2015，16：146.

LI W，CHEN C，SAUD S M，et al. Fei-Liu-Ping ointment inhibits lung cancer growth and invasion by suppressing tumor inflammatory microenvironment[J]. BMC Complement Altern Med，2014，14：153.

QIU J X，YANG J K，TANG L D，et al. The effect of traditional Chinese medicine Jianpi Liqi，Qingre Jiedu and Rujian Huatan prescription on liver cancer induced by diethylnitrosamine in rats[J]. Chin J Integrated Tradit Chin West Med，1988，8(12)：734-735.

GIRAULT J A，HORIUCHI A，GUSTAFSON E L，et al. Differential expression of ARPP-16 and ARPP-19，two highly related cAMP-regulated phosphoproteins，one of which is specifically associated with dopamine-innervated brain regions[J]. J Neurosci，1990，10(4)：1124-1133.

GHARBI-AYACHI A，LABBÉ J C，BURGESS A，et al. The Substrate of Greatwall Kinase，Arpp19，Controls Mitosis by Inhibiting Protein Phosphatase 2A[J]. Science，2010，330(6011)：1673-1677.

OKUMURA E，MORITA A，WAKAI M，et al. Cyclin B-Cdk1 inhibits protein phosphatase PP2A-B55 via a Greatwall kinase-independent mechanism[J]. J Cell Biol，2014，204(6)：881-889.

LORCA T，CASTRO A. The Greatwall kinase：a new pathway in the control of the cell cycle[J]. Oncogene，2013，32(5)：537-543.

DUPRÉ A，BUFFIN E，ROUSTAN C，et al. The phosphorylation of ARPP19 by Greatwall renders the auto-amplification of MPF independently of PKA in Xenopus oocytes[J]. J Cell Sci，2013，126(Pt 17)：3916-3926.

查看原文

Views

下载量

CSCD

CNKI被引量

Alert me when the article has been cited

提交

Tools

Publicity Resources

No data

Related Author

No data

Related Institution

No data

⁰