Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar;24(6):3625-3633.
doi: 10.1111/jcmm.15055. Epub 2020 Feb 12.

Cisplatin resistance in gastric cancer cells is involved with GPR30-mediated epithelial-mesenchymal transition

Xiaofeng Wang  1 , Zhiyuan Xu  2 , Jiancheng Sun  1 , Hang Lv  3 , Yiping Wang  3 , Yixiu Ni  1 , Shangqi Chen  1 , Can Hu  1 , Lijing Wang  4 , Wei Chen  5 , Xiangdong Cheng  2
Affiliations

Cisplatin resistance in gastric cancer cells is involved with GPR30-mediated epithelial-mesenchymal transition

Xiaofeng Wang et al. J Cell Mol Med. 2020 Mar.

Abstract

Cisplatin is the major chemotherapeutic drug in gastric cancer, particularly in treating advanced gastric cancer. Tumour cells often develop resistance to chemotherapeutic drugs, which seriously affects the efficacy of chemotherapy. GPR30 is a novel oestrogen receptor that is involved in the invasion, metastasis and drug resistance of many tumours. Targeting GPR30 has been shown to increase the drug sensitivity of breast cancer cells. However, few studies have investigated the role of GPR30 in gastric cancer. Epithelial-mesenchymal transition (EMT) has been shown to be associated with the development of chemotherapeutic drug resistance. In this study, we demonstrated that GPR30 is involved in cisplatin resistance by promoting EMT in gastric cancer. GPR30 knockdown resulted in increased sensitivity of different gastric cancer (GC) cells to cisplatin and alterations in the epithelial/mesenchymal markers. Furthermore, G15 significantly enhanced the cisplatin sensitivity of GC cells while G1 inhibited this phenomenon. In addition, EMT occurred when AGS and BGC-823 were treated with cisplatin. Down-regulation of GPR30 with G15 inhibited this transformation, while G1 promoted it. Taken together, these results revealed the role of GPR30 in the formation of cisplatin resistance, suggesting that targeting GPR30 signalling may be a potential strategy for improving the efficacy of chemotherapy in gastric cancer.

Keywords: G1; G15; GPR30; cisplatin; epithelial-mesenchymal transition (EMT); gastric cancer; resistance.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Cisplatin sensitivity and EMT are associated with GPR30 in GC cell lines. A, Western blot analysis of GPR30 in GC cells exposed to cisplatin. B, Viability of AGS, BGC‐823 cells transfected with GPR30 siRNA or negative control siRNA and treated with a series of concentrations of cisplatin for 48 h, measured using the CCK‐8 assay. C, Western blot analysis of E‐cadherin and vimentin in GC cells transfected with GPR30 siRNA or negative control siRNA. D,E, GAPDH was used as the control to quantify the expression of related proteins in AGS, BGC‐823 cells. *P < .05, **P < .01 and ***P < .001
Figure 2
Figure 2
G15 improved cisplatin sensitivity in epithelial GC cells. A,B, Viability of the epithelial GC cell lines AGS and BGC‐823 in a series of G15 concentrations for 48 h as determined using the CCK‐8 assay. C,D, Viability of AGS and BGC‐823 cells treated with cisplatin alone or in combination with G15 for 48 h as determined using the CCK‐8 assay. CI < 1 (combination of G15 and cisplatin) in both AGS and BGC823. E,F, EdU staining assays of AGS and BGC‐823 cells treated with cisplatin alone or in combination with G15 for 48 h. *P < .05. G‐H, Western blot analysis of the efficiency of G15 treatment. ***P < .001
Figure 3
Figure 3
G15 reversed EMT in epithelial GC cells. A‐C, Western blot analysis of E‐cadherin and vimentin in the AGS and BGC‐823 cell lines treated with cisplatin alone or in combination with G15 for 48 h compared with the control. *P < .05, **P < .01 and ***P < .001. D, Immunofluorescence analysis of E‐cadherin and vimentin in the AGS and BGC‐823 cells treated with cisplatin alone or in combination with G15 for 48 h compared with the control
Figure 4
Figure 4
Role of G15 in the inhibition of GPR30. A,B, Viability of AGS and BGC‐823 cell lines transfected with GPR30 siRNA and then treated with cisplatin alone or in combination with G15 for 48 h measured using the CCK‐8 assay. C,D, EdU staining assays of AGS and BGC‐823 cells transfected with GPR30 siRNA and then treated with cisplatin alone or in combination with G15 for 48 h. E,F, Western blot analysis of transfection efficiency of GPR30 siRNA. ***P < .001
Figure 5
Figure 5
Effect of G1 activation of GPR30 on GC cells. A,B, Viability of the AGS and BGC‐823 cells treated with various concentrations of G1 for 48 h, as measured using the CCK‐8 assay. *P < .05. C,D, Viability of the AGS and BGC‐823 cells treated with cisplatin alone or in combination with G1 for 48 h, as measured using the CCK‐8 assay. E,F, Viability of the AGS and BGC‐823 cells transfected with GPR30 siRNA after treatment with cisplatin alone or in combination with G1 for 48 h, as measured using the CCK‐8 assay. G, Western blot analysis of E‐cadherin and vimentin in AGS and BGC‐823 cells treated with cisplatin alone or in combination with G1 for 48 h compared with the control. H‐J, EdU staining assays of AGS and BGC‐823 cells treated with cisplatin alone or in combination with G1 for 48 h. **P < .01
Figure 6
Figure 6
KMPLOT database analysed the expression of GPR30 in GC. A, Affy id/Gene symbol: 210640_s_at; Survival: OS (n = 882); B, Affy id/Gene symbol: 211829_s_at; Survival: OS (n = 882)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359‐E386. - PubMed
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7‐30. - PubMed
    1. Shen L, Shan YS, Hu HM, et al. Management of gastric cancer in Asia: resource‐stratified guidelines. Lancet Oncol. 2013;14:e535‐e547. - PubMed
    1. Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8:CD004064. - PMC - PubMed
    1. Sasaki K, Onodera S, Otsuka K, et al. Validity of neoadjuvant chemotherapy with docetaxel, cisplatin, and S‐1 for resectable locally advanced gastric cancer. Med Oncol. 2017;34:139. - PubMed

Publication types

MeSH terms