Open Access

Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19

  • Authors:
    • Gao Liu
    • Tian Xiang
    • Quan‑Feng Wu
    • Wei‑Xing Wang
  • View Affiliations

  • Published online on: November 4, 2016     https://doi.org/10.3892/ol.2016.5354
  • Pages: 5156-5162
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Curcumin, a major phytochemical in turmeric, inhibits the proliferation of many types of solid cancer cells by enhancing p53 expression. However, the long non‑coding RNA H19 directly inhibits p53 activation and thus promotes gastric cancer progression. The aim of this study was to assess the role of H19 in curcumin-induced proliferative inhibition of gastric cancer. The gastric cancer cell line SGC‑7901 was treated with curcumin at different concentrations and time points. The effect of curcumin on proliferation was assessed using cell counting kit‑8 assays and flow cytometry with Ki67 staining. In addition, H19 expression was quantified by reverse transcription‑quantitative polymerase chain reaction, and apoptosis was evaluated by flow cytometric detection of Annexin V and propidium iodide double staining. The protein expression of p53, B‑cell lymphoma (Bcl)‑2, Bcl‑2‑associated X protein (Bax) and c‑Myc in curcumin‑treated cells was detected by western blotting. The present study demonstrated that curcumin inhibited the proliferation of SGC7901 cells and suppressed H19 expression in a concentration‑dependent manner, while p53 expression was enhanced. Ectopic expression of H19 in SGC7901 cells reversed curcumin‑induced proliferative inhibition and downregulated p53 expression. Furthermore, while curcumin induced cell apoptosis and enhanced the expression ratio of Bax/Bcl‑2, which are downstream molecules of p53, ectopic expression of H19 inhibited curcumin‑induced cell apoptosis. In addition, curcumin decreased the expression of the c‑Myc oncogene, and exogenous c‑Myc protein reversed the curcumin‑induced downregulation of H19 expression. These results suggested that curcumin inhibits the proliferation of gastric cancer cells by downregulating the c‑Myc/H19 pathway. Therefore, curcumin may be considered a novel therapeutic strategy to inhibit gastric cancer cell growth.

Introduction

Curcumin, which is commonly called diferuloylmethane, is derived from Curcuma longa, a plant of the ginger family (1). Extensive research over the last half century has revealed the therapeutic potential of curcumin in tumor progression, including inducing apoptosis, inhibiting angiogenesis and enhancing susceptibility to chemotherapy and radiotherapy (1,2). Furthermore, the anticancer effect of curcumin has been confirmed in a number of clinical trials, in which is has been used as a natural chemoprevention agent in colorectal and pancreatic cancer (35). Accumulating evidence suggests that curcumin has a diverse range of molecular targets, including c-Myc, cyclooxygenase-2, Notch1, nuclear factor-κB and p53 (2,68).

The tumor suppressor p53 plays a pivotal role in the etiology of human cancers; it not only controls the cellular proliferation of tumor cells, but is also capable of inducing cell apoptosis (9). Previous studies reported that curcumin induced p53 expression in prostate cancer, B-cell lymphoma (Bcl) cells and breast cancer, and thereby activated the pro-apoptotic downstream genes p21 and Bcl-2-associated X protein (Bax) and inhibited Bcl-2 (anti-apoptosis) expression to induce apoptotic progress (2,10,11). Furthermore, curcumin induced cell-cycle arrest by downregulating cyclin D1 expression (2,10,11).

In gastric cancer, curcumin attenuated in vivo tumor growth induced by N-methyl-N-nitrosourea by downregulating the expression of cyclin D1 in tumor cells (12). In in vitro studies, curcumin induced cell apoptosis by reducing Bcl-2 expression or enhancing reactive oxygen species production, and induced a G1 cell cycle arrest by downregulating cyclin D1 expression (1215). Activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway was also inhibited by curcumin, and played a role in promoting cell apoptosis (16). Although Bcl-2 and cyclin D1 are downstream molecules of p53 (17), and LY294002 (a PI3K inhibitor) was shown to induce p53 expression and p53-dependent apoptosis in gastric cancer cells by inhibiting the activation of PI3K/AKT signaling (18), there is not yet sufficient evidence to confirm that curcumin regulates p53 expression in gastric cancer cells.

The long non-coding RNA (lncRNA) H19 is produced from the paternally imprinted H19 gene and is considered an oncogenic lncRNA in various cancers (1922). Furthermore, previous studies have reported that H19 is abnormally upregulated in gastric cancer (2325) and contributes to cellular proliferation by directly inactivating p53 (26). Notably, curcumin downregulated H19 gene transcription and c-Myc expression in human tumor cells (2,27,28). In addition, the c-Myc oncogene was shown to directly induce H19 expression by binding to the H19 promoter, and thereby promoted the proliferation of gastric cancer cells (29,30).

The present study aimed to determine whether curcumin suppresses the proliferation of gastric cancer cells by regulating c-Myc/H19/p53 signaling. It was confirmed that curcumin inhibited the proliferation of gastric cancer cells, suppressed H19 and c-Myc expression, and enhanced p53 expression in a time- and concentration-dependent manner. Overexpression of H19 in gastric cancer cells reversed curcumin-induced cell apoptosis and the inhibitory effect on cell proliferation, as well as decreasing p53 expression in the presence of curcumin. Furthermore, exogenous c-Myc enhanced H19 expression in gastric cancer cells in the presence of curcumin. Together, these results suggested that curcumin exploited a novel mechanism to inhibit gastric cancer cell growth.

Materials and methods

Reagent and cell culture

Curcumin (Sigma-Aldrich; Merck Millipore, Darmstadt, Germany) was dissolved in dimethyl sulfoxide (Sigma-Aldrich; Merck Millipore) and stored at −20°C until use. Active human c-Myc full-length protein was purchased from Abcam (Cambridge, MA, USA) and added to media for a final concentration of 5 µg/ml (31). The human gastric cancer cell line SGC7901 and the immortalized human gastric epithelial mucosa cell line GES-1 were obtained from the American Type Culture Collection (Manassas, VA, USA). All cell lines were maintained in RPMI-1640 medium (Hyclone; GE Healthcare Life Sciences, Logan, UT, USA) supplemented with 10% fetal bovine serum (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) and cultured in a humidified incubator containing 5% CO2 at 37°C. For the c-Myc protocol, recombinant human c-Myc protein (5 µg/ml) was added to the media of SGC7901 cells in the presence of 50 µM curcumin.

RNA extraction and reverse transcription-quantitative polymerase chain reaction (RT-qPCR)

RNA was extracted from the cells using TRIzol® reagent (Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer's protocol. RNase-free DNase I (Thermo Fisher Scientific, Inc.) treatment was performed to remove any contaminating DNA. RT-qPCR was performed using the ReverTra Ace-α first-strand cDNA synthesis kit and the SYBR Green Real-time PCR Master mix kit (both Toyobo Co., Ltd., Osaka, Japan). For mRNA detection, the primers used in this study were as follows: H19 forward, 5′-TACAACCACTGCACTACCTG-3′ and reverse, 5′-TGGAATGCTTGAAGGCTGCT-3′ (32); and GAPDH (as an internal control) forward, 5′-ACCTGACCTGCCGTCTAGAA-3′ and reverse, 5′-TCCACCACCCTGTTGCTGTA-3′ (33). The ABI StepOne Plus (Applied Biosystems; Thermo Fisher Scientific, Inc.) was used to perform qPCR. PCR reactions were performed at 95°C for 5 min, followed by 40 cycles of 95°C for 15 sec and 60°C for 1 min. Each experiment was performed in triplicate. The relative mRNA expression levels were determined using the 2−ΔΔCq method (34).

Transfection

H19 cDNA (GenBank accession no. NR_002196.1) was inserted into the multiple cloning sites of the pcDNA3.1 vector (Invitrogen; Thermo Fisher Scientific, Inc.), as described previously (33). A total of 1×105 cells were plated onto 24-well plates for 24 h and then transfected with 0.5 µg plasmid using Lipofectamine 2000 (Invitrogen; Thermo Fisher Scientific, Inc.) for 48 h. The cells were then subjected to RNA/protein extraction or further functional assays.

Cell proliferation assay

Cell proliferation assays were performed using a Cell Counting kit-8 (CCK-8; Beyotime Institute of Biotechnology, Shanghai, China), as described previously (35). Briefly, SGC7901 cells (1×104 cells/well) were plated onto 96-well plates, and then treated with curcumin or pre-transfected with pcDNA3.1-H19 or empty vector for 48 h. The number of cells per well was detected by measuring the absorbance (450 nm) of reduced WST-8 at various time points using the SpectraMax® i3x microplate reader (Molecular Devices, LLC, Sunnyvale, CA, USA).

Cell apoptosis

Evaluation of cell apoptosis was performed using the FITC Annexin V Apoptosis Detection kit with PI (BioLegend, Inc., San Diego, CA, USA). Briefly, the cells were washed twice with cold BioLegend's Cell Staining Buffer, and then resuspended in Annexin V Binding Buffer at a concentration of 0.25–1.0×107 cells/ml. This suspension (100 µl) was stained with 5 µl FITC/Annexin V and 10 µl PI, after which the cells were gently vortexed and incubated for 15 min at room temperature (25°C) in the dark. Subsequently. 400 µl Annexin V Binding Buffer was added to each tube, which were analyzed by flow cytometry.

Ki67 staining

The cells were washed twice with PBS by centrifugation at 350 × g for 5 min at 4°C, and then resuspended in 3 ml cold 70% ethanol and incubated at −20°C for 1 h. Subsequently, the cells were resuspended in 100 µl PBS in the presence of phycoerythrin-conjugated anti-human Ki67 antibody (1:20; cat. no., 350504; BioLegend, Inc.), and then incubated at room temperature in the dark for 30 min. Next, 500 µl PBS was added to resuspend the cells for flow cytometric analysis.

Western blotting

Proteins were extracted from the cells using radioimmunoprecipitation assay lysis buffer (Beyotime Institute of Biotechnology) and were quantified using a BCA Protein Assay kit (Beyotime Institute of Biotechnology). Proteins (30 µg) were separated by 10% SDS-PAGE and transferred onto polyvinylidene difluoride membranes (EMD Millipore, Billerica, MA, USA). The membrane was blocked with 5% nonfat milk and incubated with diluted antibodies at 4°C overnight. Primary antibodies against p53 (1:1,000; cat. no. 1C12), Bax (1:1,000; cat. no. D2E11), Bcl-2 (1:1,000; cat. no. 50E3), c-Myc (1:1,000; cat. no. D84C12) and β-actin (1:1,000; cat. no. 13E5) were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA). Subsequently, the membranes were incubated with a horseradish peroxidase-conjugated secondary antibody (1:2,000; cat. no., sc-2055; Santa Cruz Biotechnology, Inc., Dallas, TX, USA) at 37°C for 1 h. The immunoreactive bands were visualized using the Immobilon™ Western Chemiluminescent HRP Substrate (EMD Millipore) and the UVP Bioimaging system (UVP, Inc., Upland, CA, USA).

Statistical analysis

All experiments were performed three times. Data are presented as the mean ± standard deviation and analyzed using GraphPad Prism 5.00 software (GraphPad Software, Inc., La Jolla, CA, USA). Differences among the groups were assessed by one-way analysis of variance followed by Neuman-Keuls post-hoc test. P<0.05 was considered to indicate a statistically significant difference.

Results

Curcumin inhibits gastric cancer cell proliferation and H19 expression

Initially, the effect of curcumin on the proliferation of the gastric cancer cell line SGC7901 was analyzed by CCK-8 assays in the presence of various concentrations of curcumin for 12, 24, 48 and 72 h. As shown in Fig. 1A, curcumin inhibited the growth of SGC7901 cells in a concentration- and a time-dependent manner. In comparison with the untreated cells, cell proliferation was significantly inhibited after 48 h of treatment with 50 µM curcumin (P<0.01). The relative mRNA expression level of H19 was decreased in a dose-dependent manner following treatment with various concentrations of curcumin (Fig. 1B), and, as compared with SGC7901 cells in the absence of curcumin, showed the lowest level at 50 µM (P<0.0001). As for p53 expression in SGC7901 cells, curcumin markedly increased the expression level of p53 after 12 h (Fig. 1C and attained a peak at 48 h following treatment with 25 µM curcumin (Fig. 1D).

Ectopic expression of H19 reverses curcumin-mediated inhibition of proliferation

To further elucidate the role of H19 in curcumin-induced proliferative inhibition of gastric cancer cells, H19 was overexpressed in SGC7901 cells, which were subsequently treated with 50 µM curcumin, as this concentration of curcumin induced the highest level of proliferative inhibition (Fig. 1A). As compared with the empty vector control, ectopic expression of H19 significantly enhanced cell proliferation in the presence of curcumin, as determined using the CCK-8 assay (P<0.05; Fig. 2A) or Ki67 staining (Fig. 2B), which is a nuclear antigen only present in proliferating cells (36). In pcDNA3.1-H19-transfected cells, curcumin downregulated H19 expression (Fig. 2C), but did not enhance p53 expression (Fig. 2D). As H19 directly binds to p53 and deactivates p53 expression (26), curcumin may depend on the inhibition of H19 expression to enhance the tumor-suppressive activity of p53. These results suggest that curcumin enhances p53 expression by downregulating H19 expression.

Ectopic expression of H19 reverses curcumin-induced cell apoptosis

Subsequently, the role of H19 in curcumin-induced apoptosis of SGC7901 cells was analyzed. As shown in Fig. 3A and B, there was no significant difference in cell apoptosis between the cells transfected with empty vector and pcDNA3.1-H19 (PI-positive, 4.7 vs. 4.4%), which suggested that plasmid transfection did not induce a difference in cell apoptosis. Curcumin significantly induced the apoptosis of cells transfected with empty vector (~34.3% were PI-positive), whereas, in H19-transfected cells, the percentage of apoptotic cells was ~15.5%, which was significantly lower compared with cells transfected with empty vector (P<0.0001). An increase in the ratio of Bax/Bcl-2 is known to initiate apoptosis (17); it was noted that curcumin markedly increased Bax expression and decreased Bcl-2 expression in empty vector-transfected cells, while this effect was almost diminished in H19-overexpressed cells (Fig. 3C). These results suggest that curcumin induces cell apoptosis by downregulating H19 expression.

c-Myc enhances H19 expression in curcumin-treated gastric cancer cells

As an oncogene, the expression of c-Myc has been shown to be upregulated in patients with gastric cancer and to induce H19 expression in gastric cancer cells (29,30). Furthermore, curcumin inhibited c-Myc expression in Bcl and skin cancer (2,28). Therefore, the present study further evaluated the role of c-Myc in regulating H19 expression in the presence of curcumin. As shown in Fig. 4A, curcumin markedly decreased c-Myc expression in gastric cancer cells in a concentration-dependent manner. Similar to H19, exogenous c-Myc induced cell proliferation in the presence of 50 µM curcumin (Fig. 4B). In addition, exogenous c-Myc enhanced H19 expression and decreased p53 expression in curcumin-treated SGC7901 cells (Fig. 4C). These results confirm that curcumin inhibits H19 expression by regulating c-Myc expression in gastric cancer.

Discussion

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-associated mortality worldwide, with an estimated 952,000 new cases diagnosed and 723,000 deaths registered in 2012 (37). Previous studies have demonstrated that H19 plays an oncogenic role in gastric cancer and predicts a poor prognosis in patients with gastric cancer (25,26,29,33,38). However, an agent that is able to downregulate H19 expression in tumor cells has rarely been reported (39). The present study demonstrated that curcumin, a naturally occurring phytochemical, was able to inhibit H19 expression in gastric cancer cells and thereby induce apoptosis and inhibit cellular proliferation.

Curcumin is able to suppress the proliferation and survival of cancer cells by directly or indirectly binding to various targets, including transcription factors, growth factors and several proteins that are involved in cell signal transduction pathways (40). c-Myc is an important oncogene that has been shown to be downregulated by curcumin (2). Similarly, the present study observed that curcumin decreased c-Myc expression in a concentration-dependent manner in gastric cancer. c-Myc regulates numerous gene targets that subsequently execute its many biological activities, including cell proliferation, transformation, angiogenesis and apoptosis (41). Furthermore, elevated expression of c-Myc correlates with a poor prognosis in various cancers, including head and neck squamous cell carcinoma, breast cancer and hepatocellular carcinomas (4245). The present study also demonstrated that exogenous c-Myc was able to reverse curcumin-induced proliferative inhibition in gastric cancer cells.

Previous studies have indicated that c-Myc promotes cancer progression by upregulating tumor-promotive lncRNAs, including prostate cancer gene expression marker 1 and HOX transcript antisense RNA (46,47). In addition, c-Myc has been reported to directly bind to the promoter of H19 in order to induce its expression and potentiate tumor progression in primary breast and lung carcinomas (30). In gastric cancer, c-Myc has been shown to induce H19 expression, and its expression was positively correlated with H19 expression in gastric cancer patients (29). The present study demonstrated that exogenous c-Myc enhanced H19 expression in the presence of curcumin, which provided evidence to explain how curcumin inhibited H19 expression, and provides a direct molecular link between curcumin and H19. However, whether c-Myc is indispensable for curcumin to regulate H19-mediated p53 deactivation still needs to be clarified in future.

The role of H19 in the progression of gastric cancer may be due to its association with p53 (26). p53, which is an important tumor suppressor, plays a pivotal role in inhibiting the proliferation and inducing the apoptosis of cancer cells (11). In the present study, curcumin significantly enhanced p53 expression, and simultaneously induced cell apoptosis and inhibited proliferation of gastric cancer cells. Conversely, ectopic expression of H19 abrogated curcumin-induced p53 expression, and the following effects on proliferation and apoptosis of cancer cells.

In conclusion, the major findings of this study can be summarized as follows: i) Curcumin inhibits H19 expression in gastric cancer cells; ii) H19 plays a pivotal role in curcumin-induced proliferative inhibition and apoptosis of gastric cancer cells; and iii) c-Myc can be downregulated by curcumin and is an important mediator between curcumin and H19. To the best of our knowledge, the present study demonstrated, for the first time, a novel mechanism by which curcumin exploits a lncRNA to inhibit gastric cancer growth. Therefore, curcumin may be considered a value therapeutic strategy for the treatment of gastric cancer.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant no. 81370562).

References

1 

Bar-Sela G, Epelbaum R and Schaffer M: Curcumin as an anti-cancer agent: Review of the gap between basic and clinical applications. Curr Med Chem. 17:190–197. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Han SS, Chung ST, Robertson DA, Ranjan D and Bondada S: Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin Immunol. 93:152–161. 1999. View Article : Google Scholar : PubMed/NCBI

3 

Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V and Kurzrock R: Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 14:4491–4499. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, Marczylo TH, Morgan B, Hemingway D, Plummer SM, et al: Phase I clinical trial of oral curcumin: Biomarkers of systemic activity and compliance. Clin Cancer Res. 10:6847–6854. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Carroll RE, Benya RV, Turgeon DK, Vareed S, Neuman M, Rodriguez L, Kakarala M, Carpenter PM, McLaren C, Meyskens FL Jr and Brenner DE: Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). 4:354–364. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Goel A, Boland CR and Chauhan DP: Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett. 172:111–118. 2001. View Article : Google Scholar : PubMed/NCBI

7 

Wang Z, Zhang Y, Banerjee S, Li Y and Sarkar FH: Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer. 106:2503–2513. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Marin YE, Wall BA, Wang S, Namkoong J, Martino JJ, Suh J, Lee HJ, Rabson AB, Yang CS, Chen S and Ryu JH: Curcumin downregulates the constitutive activity of NF-kappaB and induces apoptosis in novel mouse melanoma cells. Melanoma Res. 17:274–283. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Nagamine M, Okumura T, Tanno S, Sawamukai M, Motomura W, Takahashi N and Kohgo Y: PPAR gamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer cells. Cancer Sci. 94:338–343. 2003. View Article : Google Scholar : PubMed/NCBI

10 

Choudhuri T, Pal S, Agwarwal ML, Das T and Sa G: Curcumin induces apoptosis in human breast cancer cells through p53-dependent Bax induction. FEBS Lett. 512:334–340. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Choudhuri T, Pal S, Das T and Sa G: Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner. J Biol Chem. 280:20059–20068. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Sintara K, Thong-Ngam D, Patumraj S and Klaikeaw N: Curcumin attenuates gastric cancer induced by N-methyl-N-nitrosourea and saturated sodium chloride in rats. J Biomed Biotechnol. 2012:9153802012. View Article : Google Scholar : PubMed/NCBI

13 

Cai XZ, Wang J, Li XD, Wang GL, Liu FN, Cheng MS and Li F: Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression. Cancer Biol Ther. 8:1360–1368. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Cai XZ, Huang WY, Qiao Y, Du SY, Chen Y, Chen D, Yu S, Che RC, Liu N and Jiang Y: Inhibitory effects of curcumin on gastric cancer cells: A proteomic study of molecular targets. Phytomedicine. 20:495–505. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Liang T, Zhang X, Xue W, Zhao S, Zhang X and Pei J: Curcumin induced human gastric cancer BGC-823 cells apoptosis by ROS-mediated ASK1-MKK4-JNK stress signaling pathway. Int J Mol Sci. 15:15754–15765. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Song G, Ming Y, Mao Y, Bao S and Ouyang G: Osteopontin prevents curcumin-induced apoptosis and promotes survival through Akt activation via alpha v beta 3 integrins in human gastric cancer cells. Exp Biol Med (Maywood). 233:1537–1545. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Tanigawa S, Fujii M and Hou DX: Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. Biosci Biotechnol Biochem. 72:797–804. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Xing CG, Zhu BS, Liu HH, et al: LY294002 induces p53-dependent apoptosis of SGC7901 gastric cancer cells. Acta pharmacologica Sinica. 29:489–498. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Adriaenssens E, Dumont L, Lottin S, Bolle D, Leprêtre A, Delobelle A, Bouali F, Dugimont T, Coll J and Curgy JJ: H19 overexpression in breast adenocarcinoma stromal cells is associated with tumor values and steroid receptor status but independent of p53 and Ki-67 expression. Am J Pathol. 153:1597–1607. 1998. View Article : Google Scholar : PubMed/NCBI

20 

Ariel I, Miao HQ, Ji XR, Schneider T, Roll D, de Groot N, Hochberg A and Ayesh S: Imprinted H19 oncofetal RNA is a candidate tumour marker for hepatocellular carcinoma. Mol Pathol. 51:21–25. 1998. View Article : Google Scholar : PubMed/NCBI

21 

Luo M, Li Z, Wang W, Zeng Y, Liu Z and Qiu J: Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett. 333:213–221. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Shi Y, Wang Y, Luan W, Wang P, Tao T, Zhang J, Qian J, Liu N and You Y: Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS One. 9:e862952014. View Article : Google Scholar : PubMed/NCBI

23 

Wang J, Song YX and Wang ZN: Non-coding RNAs in gastric cancer. Gene. 560:1–8. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Li PF, Chen SC, Xia T, Jiang XM, Shao YF, Xiao BX and Guo JM: Non-coding RNAs and gastric cancer. World J Gastroenterol. 20:5411–5419. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Song H, Sun W, Ye G, Ding X, Liu Z, Zhang S, Xia T, Xiao B, Xi Y and Guo J: Long non-coding RNA expression profile in human gastric cancer and its clinical significances. J Transl Med. 11:2252013. View Article : Google Scholar : PubMed/NCBI

26 

Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J and Fang G: Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J. 279:3159–3165. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Kujundzić R Novak, Grbesa I, Ivkić M, Katdare M and Gall-Troselj K: Curcumin downregulates H19 gene transcription in tumor cells. J Cell Biochem. 104:1781–1792. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Kakar SS and Roy D: Curcumin inhibits TPA induced expression of c-fos, c-jun and c-myc proto-oncogenes messenger RNAs in mouse skin. Cancer Lett. 87:85–89. 1994. View Article : Google Scholar : PubMed/NCBI

29 

Zhang EB, Han L, Yin DD, Kong R, De W and Chen J: c-Myc-induced, long, noncoding H19 affects cell proliferation and predicts a poor prognosis in patients with gastric cancer. Med Oncol. 31:9142014. View Article : Google Scholar : PubMed/NCBI

30 

Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, Tsao MS and Penn LZ: The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 66:5330–5337. 2006. View Article : Google Scholar : PubMed/NCBI

31 

Geiler C, Andrade I and Greenwald D: Exogenous c-Myc Blocks Differentiation and Improves Expansion of Human Erythroblasts In vitro. International journal of stem cells. 7:153–157. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Tsang WP, Ng EK, Ng SS, Jin H, Yu J, Sung JJ and Kwok TT: Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis. 31:350–358. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Zhuang M, Gao W, Xu J, Wang P and Shu Y: The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1. Biochem Biophys Res Commun. 448:315–322. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

35 

Xie B, Zhou J, Shu G, Liu DC, Zhou J, Chen J and Yuan L: Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: Tumor suppressive role of klotho in gastric cancer. Cancer Cell Int. 13:182013. View Article : Google Scholar : PubMed/NCBI

36 

Li N, Deng W, Ma J, et al: Prognostic evaluation of Nanog, Oct4, Sox2, PCNA, Ki67 and E-cadherin expression in gastric cancer. Med Oncol. 32:4332015. View Article : Google Scholar : PubMed/NCBI

37 

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Li H, Yu B, Li J, Su L, Yan M, Zhu Z and Liu B: Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget. 5:2318–2329. 2014. View Article : Google Scholar : PubMed/NCBI

39 

Sorin V, Ohana P, Mizrahi A, et al: Regional therapy with DTA-H19 vector suppresses growth of colon adenocarcinoma metastases in the rat liver. International journal of oncology. 39:1407–1412. 2011.PubMed/NCBI

40 

Zang S, Liu T, Shi J and Qiao L: Curcumin: A promising agent targeting cancer stem cells. Anticancer Agents Med Chem. 14:787–792. 2014. View Article : Google Scholar : PubMed/NCBI

41 

Dang CV: c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 19:1–11. 1999. View Article : Google Scholar : PubMed/NCBI

42 

Field JK, Spandidos DA, Stell PM, Vaughan ED, Evan GI and Moore JP: Elevated expression of the c-myc oncoprotein correlates with poor prognosis in head and neck squamous cell carcinoma. Oncogene. 4:1463–1468. 1989.PubMed/NCBI

43 

Deming SL, Nass SJ, Dickson RB and Trock BJ: C-myc amplification in breast cancer: A meta-analysis of its occurrence and prognostic relevance. Br J Cancer. 83:1688–1695. 2000. View Article : Google Scholar : PubMed/NCBI

44 

Nair R, Roden DL, Teo WS, McFarland A, Junankar S, Ye S, Nguyen A, Yang J, Nikolic I, Hui M, et al: c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer. Oncogene. 33:3992–4002. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Jang KY, Noh SJ, Lehwald N, Tao GZ, Bellovin DI, Park HS, Moon WS, Felsher DW and Sylvester KG: SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas. PLoS One. 7:e451192012. View Article : Google Scholar : PubMed/NCBI

46 

Ma MZ, Li CX, Zhang Y, Weng MZ, Zhang MD, Qin YY, Gong W and Quan ZW: Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol Cancer. 13:1562014. View Article : Google Scholar : PubMed/NCBI

47 

Hung CL, Wang LY, Yu YL, Chen HW, Srivastava S, Petrovics G and Kung HJ: A long noncoding RNA connects c-Myc to tumor metabolism. Proc Natl Acad Sci USA. 111:18697–18702. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

December-2016
Volume 12 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Liu G, Xiang T, Wu QF and Wang WX: Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19. Oncol Lett 12: 5156-5162, 2016
APA
Liu, G., Xiang, T., Wu, Q., & Wang, W. (2016). Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19. Oncology Letters, 12, 5156-5162. https://doi.org/10.3892/ol.2016.5354
MLA
Liu, G., Xiang, T., Wu, Q., Wang, W."Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19". Oncology Letters 12.6 (2016): 5156-5162.
Chicago
Liu, G., Xiang, T., Wu, Q., Wang, W."Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19". Oncology Letters 12, no. 6 (2016): 5156-5162. https://doi.org/10.3892/ol.2016.5354