Abstract
A wide range of studies has demonstrated the potent anticancer activity of Chinese herbs. Here, we evaluated the anticancer activity and molecular mechanisms of Actinidia chinensis root extract (acRoots) on hepatocellular carcinoma (HCC). HepG2 HCC cells were treated with various concentrations of acRoots for 72 h and examined by mRNA expression profiling, revealing alterations in cellular immunity, inflammation, proliferation, cell cycle, and metabolic signaling responses. Further analysis of the altered genes in cellular immunity and inflammation gene clusters identified prostaglandin E receptor 3 (EP3) as a key regulator of gene expression in response to acRoots. Further analysis revealed inhibition of cell growth, migration, and invasion in HCC in response to acRoots, along with increased apoptosis due to downregulation of EP3 expression. Treatment with acRoots and EP3 antagonist L-798106 led to decreases in VEGF, EGFR, MMP2, and MMP9 expression in HCC cells, along with significant effects on growth, migration, invasion, and apoptosis; the effects were reversed/blocked by the EP3 agonist sulprostone. Taken together, these data clearly demonstrated that acRoots inhibit HCC cell invasion and metastasis via inhibition of EP3 expression, resulting in decreased activation of VEGF, EGFR, MMP2, and MMP9.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Amano H, Hayashi I, Endo H, et al. Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003;197:221–32.
Berasain C, Castillo J, Perugorria MJ, et al. Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci. 2009;1155:206–21.
Brown GT, Murray GI. Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol. 2015;237:273–81.
Cheng QL, Li HL, Huang ZQ, et al. 2beta, 3beta, 23-Trihydroxy-urs-12-ene-28-olic acid (TUA) isolated from Actinidia chinensis Radix inhibits NCI-H460 cell proliferation by decreasing NF-kappaB expression. Chem Biol Interact. 2015;240:1–11.
Claesson-Welsh L. VEGF receptor signal transduction - A brief update. Vascul Pharmacol. 2016. doi:10.1016/j.vph.2016.05.011
Diakos CI, Charles KA, McMillan DC, et al. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15:e493–503.
Du M, Shi F, Zhang H, et al. Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of beta-catenin expression via EP3-4 receptor. Oncol Rep. 2015;34:715–26.
Guillem-Llobat P, Dovizio M, Bruno A, et al. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget. 2016. doi:10.18632/oncotarget.8655.
Hiyama A, Yokoyama K, Nukaga T, et al. Response to tumor necrosis factor-alpha mediated inflammation involving activation of prostaglandin E2 and Wnt signaling in nucleus pulposus cells. J Orthop Res. 2015;33:1756–68.
Jiang C, Wang Q, Xu Z, et al. Cyclooxygenase-2 knockdown using retinoic acid chalcone (RAC), a promising therapeutic strategy for colon cancer. Am J Cancer Res. 2015;5:2012–21.
Kang JH, Song KH, Jeong KC, et al. Involvement of Cox-2 in the metastatic potential of chemotherapy-resistant breast cancer cells. BMC Cancer. 2011;11:334.
Kashiwagi E, Shiota M, Yokomizo A, et al. Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells. Endocr Relat Cancer. 2013;20:431–41.
Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039–49.
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.
Kim S, Lewis C, Nadel JA. Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells. Exp Cell Res. 2011;317:2650–60.
Komposch K, Sibilia M. EGFR signaling in liver diseases. Int J Mol Sci. 2016;17(1):30. doi:10.3390/ijms17010030.
Ku CY, Wang YR, Lin HY, et al. Corosolic acid inhibits hepatocellular carcinoma cell migration by targeting the VEGFR2/Src/FAK pathway. PLoS One. 2015;10:e126725.
Ma J, Chen M, Xia SK, et al. Prostaglandin E2 promotes liver cancer cell growth by the upregulation of FUSE-binding protein 1 expression. Int J Oncol. 2013;42:1093–104.
Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006;33:369–85.
Miyata Y, Ohba K, Matsuo T, et al. Tumor-associated stromal cells expressing E-prostanoid 2 or 3 receptors in prostate cancer: correlation with tumor aggressiveness and outcome by angiogenesis and lymphangiogenesis. Urology. 2013;81:136–42.
Ogawa Y, Suzuki T, Oikawa A, et al. Bone marrow-derived EP3-expressing stromal cells enhance tumor-associated angiogenesis and tumor growth. Biochem Biophys Res Commun. 2009;382:720–5.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.
Song WY, Xu GH, Zhang GJ. [Effect of Actinidia chinensis Planch polysaccharide on the growth and apoptosis, and p-p38 expression in human gastric cancer SGC-7901 cells]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014;34:329–33.
Sugimoto Y, Narumiya S. Prostaglandin E receptors. J Biol Chem. 2007;282:11613–7.
Tang ZY, Ye SL, Liu YK, et al. A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:187–96.
Xu WH, Zhang JB, Dang Z, et al. Long non-coding RNA URHC regulates cell proliferation and apoptosis via ZAK through the ERK/MAPK signaling pathway in hepatocellular carcinoma. Int J Biol Sci. 2014;10:664–76.
Yamaki T, Endoh K, Miyahara M, et al. Prostaglandin E2 activates Src signaling in lung adenocarcinoma cell via EP3. Cancer Lett. 2004;214:115–20.
Yokoyama Y, Xin B, Shigeto T, et al. Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers. J Cancer Res Clin Oncol. 2011;137:1219–28.
Zhu WJ, Yu DH, Zhao M, et al. Antiangiogenic triterpenes isolated from Chinese herbal medicine Actinidia chinensis Planch. Anti Cancer Agents Med Chem. 2013;13:195–8.
Acknowledgments
All authors have read the journal’s authorship agreement and policy on disclosure of potential conflicts of interest. The authors have no financial disclosures to make and no conflicts of interest to disclose. This study was sponsored by grants from the National Natural Science Foundation of China (Nos. 81272732 and 81572395), the Shanghai Leading Academic Discipline Project (Project Number B115), and the Shanghai Outstanding Academic Leaders (Project Number 14XD1401100).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Tingting Fang, Jiayun Hou, Mingyan He, and Lingyan Wang contributed to the article equally as the first authors.
Rights and permissions
About this article
Cite this article
Fang, T., Hou, J., He, M. et al. Actinidia chinensis Planch root extract (acRoots) inhibits hepatocellular carcinoma progression by inhibiting EP3 expression. Cell Biol Toxicol 32, 499–511 (2016). https://doi.org/10.1007/s10565-016-9351-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10565-016-9351-z