Inhibition Effect of Curcumin on the Invasion and Metastasis in Hepatocellular Carcinoma by Regulating the Expression of MicroRNA-21
HE Yu-jiao, HUANG Mao-lin, YUE Yan, ZHENG Zhe-bin*
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
Abstract：OBJECTIVE To investigate the biological mechanism of curcumin inhibiting the invasion and metastasis in hepatocellular carcinoma. METHODS The cytotoxicity of curcumin was detected by Am-Blue assay. Cell-based luciferase assay was used to detect the change of the microRNA-21 expression level. qRT-PCR was used to detect the expression of mRNA of pri-miR-21, pre-miR-21 and microRNA-21. The protein expression levels of PTEN, PDCD4 and EMT markers were detected by Western blot. Wound healing assay and transwell assay were used to detect cell invasion and migration. RESULTS Curcumin can significantly inhibit the expression of microRNA-21, while inhibiting the mRNA expression of the precursors pri-miR-21, pre-miR-21 and mature microRNA-21. Curcumin can significantly enhance the expression levels of microRNA target proteins PTEN and PDCD4. Curcumin inhibited the epithelial-mesenchymal transition (EMT) process, in which the expression of E-cadherin and β-catenin was increased, and the expression of N-cadherin and vimentin was decreased. Curcumin can inhibit the invasion and metastasis of hepatocellular carcinoma. CONCLUSION Curcumin inhibits the invasion and metastasis in hepatocellular carcinoma by inhibiting the expression of microRNA-21.
何玉娇, 黄茂林, 乐燕, 郑哲彬. 姜黄素通过调控microRNA-21的表达来抑制肝癌细胞的转移和侵袭[J]. 中国药学杂志, 2020, 55(9): 722-727.
HE Yu-jiao, HUANG Mao-lin, YUE Yan, ZHENG Zhe-bin. Inhibition Effect of Curcumin on the Invasion and Metastasis in Hepatocellular Carcinoma by Regulating the Expression of MicroRNA-21. Chinese Pharmaceutical Journal, 2020, 55(9): 722-727.
HA M, KIM V N. Regulation of microRNA biogenesis[J]. Nat Rev Mol Cell Biol, 2014, 15(8):509-524.
[2]
BUSHATI N, COHEN S M. MicroRNA functions[J]. Annu Rev Cell Dev Biol, 2007, 23:175-205.
[3]
AMERES S L, ZAMORE P D. Diversifying microRNA sequence and function[J]. Nat Rev Mol Cell Biol, 2013, 14(8):475-488.
[4]
KROL J, LOEDIGE I, FILIPOWICZ W. The widespread regulation of microRNA biogenesis, function and decay[J]. Nat Rev Genet, 2010, 11(9):597-610.
[5]
SHENOUDA S K, ALAHARI S K. MicroRNA function in cancer:oncogene or a tumor suppressor?[J]. Cancer Metast Rev, 2009, 28(3-4):369-378.
[6]
HEO I, KIM V N. Regulating the regulators:posttranslational modifications of RNA silencing factors[J]. Cell, 2009, 139(1):28-31.
[7]
ESQUELA-KERSCHER A, SLACK F J. Oncomirs-microRNAs with a role in cancer[J]. Nat Rev Cancer, 2006, 6(4):259-269.
[8]
LI D, YAN Y Y, OU H S. MicroRNAs regulate vascular smooth muscle cell apoptosis and cardiovascular disease[J]. Chin Pharm J(中国药学杂志), 2019, 54(8):603-607.
[9]
ASANGANI I A, RASHEED S A K, NIKOLOVA D A, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer[J]. Oncogene, 2008, 27(15):2128-2136.
[10]
SI M L, ZHU S, WU H, et al. miR-21-mediated tumor growth[J]. Oncogene, 2007, 26(19):2799.
[11]
KRICHEVSKY A M, GABRIELY G. miR-21:a small multi-faceted RNA[J]. J Cell Mol Med, 2009, 13(1):39-53.
[12]
ANAND P, KUNNUMAKKARA A B, NEWMAN R A, et al. Bioavailability of curcumin:problems and promises[J]. Mol Pharm, 2007, 4(6):807-818.
[13]
AGGARWAL B B, KUMAR A, BHARTI A C. Anticancer potential of curcumin:preclinical and clinical studies[J]. Anticancer Res, 2003, 23(1/A):363-398.
[14]
HATCHER H, PLANALP R, CHO J, et al. Curcumin:from ancient medicine to current clinical trials[J]. Cell Mol Life Sci, 2008, 65(11):1631-1652.
[15]
DUVOIX A, BLASIUS R, DELHALLE S, et al. Chemopreventive and therapeutic effects of curcumin[J]. Cancer Lett, 2005, 223(2):181-190.
[16]
MUDDULURU G, GEORGE-WILLIAM J N, MUPPALA S, et al. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer[J]. Biosci Rep, 2011, 31(3):185-197.
[17]
MENG F, HENSON R, WEHBE-JANEK H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer[J]. Gastroenterology, 2007, 133(2):647-658.
[18]
ZHU Q, WANG Z, HU Y, et al. miR-21 promotes migration and invasion by the miR-21-PDCD4-AP-1 feedback loop in human hepatocellular carcinoma[J]. Oncol Rep, 2012, 27(5):1660-1668.
[19]
SHI Z, ZHANG J, QIAN X, et al. AC1MMYR2, an inhibitor of dicer-mediated biogenesis of oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression[J]. Cancer Res, 2013, 73(17):5519-5531.
[20]
DEITERS A. Small molecule modifiers of the microRNA and RNA interference pathway[J]. AAPS J, 2010, 12(1):51-60.
[21]
MELO S, VILLANUEVA A, MOUTINHO C, et al. Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing[J]. Proc Natl Acad Sci, 2011, 108(11):4394-4399.
[22]
BERTACCHINI J, HEIDARI N, MEDIANI L, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia[J]. Cell Mol Life Sci, 2015, 72(12):2337-2347.
[23]
FRANKEL L B, CHRISTOFFERSEN N R, JACOBSEN A, et al. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells[J]. J Biol Chem, 2008, 283(2):1026-1033.
2020, Vol. 55 
